Next Article in Journal
Folic Acid-Grafted Chitosan-Alginate Nanocapsules as Effective Targeted Nanocarriers for Delivery of Turmeric Oil for Breast Cancer Therapy
Next Article in Special Issue
Anti-Glioma Activity Achieved by Dual Blood–Brain Barrier/Glioma Targeting Naive Chimeric Peptides-Based Co-Assembled Nanophototheranostics
Previous Article in Journal
In-Depth Analysis of Physiologically Based Pharmacokinetic (PBPK) Modeling Utilization in Different Application Fields Using Text Mining Tools
Previous Article in Special Issue
Photo-Phytotherapeutic Gel Composed of Copaifera reticulata, Chlorophylls, and k-Carrageenan: A New Perspective for Topical Healing
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Pharmaceutics
Volume 15
Issue 1
10.3390/pharmaceutics15010109
pharmaceutics-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Multifunctional Photoactive Nanomaterials for Photodynamic Therapy against Tumor: Recent Advancements and Perspectives

by
Rupesh Jain
1,
Shambo Mohanty
1,
Ila Sarode
1,
Swati Biswas
2,
Gautam Singhvi
1,* and
Sunil Kumar Dubey
1,*,†
1
Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Pilani Campus, Pilani 333031, Rajasthan, India
2
Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Hyderabad 500078, Telangana, India
*
Authors to whom correspondence should be addressed.
†
Current Affiliation: R&D Healthcare Division, Emami Ltd., 13, BT Road, Belgharia, Kolkata 700056, West Bengal, India.
Pharmaceutics 2023, 15(1), 109; https://doi.org/10.3390/pharmaceutics15010109
Submission received: 17 November 2022 / Revised: 16 December 2022 / Accepted: 20 December 2022 / Published: 28 December 2022
(This article belongs to the Special Issue Design and Characterization of Functional, Light-Responsive Materials for Drug Delivery and Tissue Engineering)
Browse Figures
Review Reports Versions Notes

Abstract

:
Numerous treatments are available for cancer, including chemotherapy, immunotherapy, radiation therapy, hormone therapy, biomarker testing, surgery, photodynamic therapy, etc. Photodynamic therapy (PDT) is an effective, non-invasive, novel, and clinically approved strategy to treat cancer. In PDT, three main agents are utilized, i.e., photosensitizer (PS) drug, oxygen, and light. At first, the photosensitizer is injected into blood circulation or applied topically, where it quickly becomes absorbed or accumulated at the tumor site passively or actively. Afterward, the tumor is irradiated with light which leads to the activation of the photosensitizing molecule. PS produces the reactive oxygen species (ROS), resulting in the death of the tumor cell. However, the effectiveness of PDT for tumor destruction is mainly dependent on the cellular uptake and water solubility of photosensitizer molecules. Therefore, the delivery of photosensitizer molecules to the tumor cell is essential in PDT against cancer. The non-specific distribution of photosensitizer results in unwanted side effects and unsuccessful therapeutic outcomes. Therefore, to improve PDT clinical outcomes, the current research is mostly focused on developing actively targeted photosensitizer molecules, which provide a high cellular uptake and high absorption capacity to the tumor site by overcoming the problem associated with conventional PDT. Therefore, this review aims to provide current knowledge on various types of actively and passively targeted organic and inorganic nanocarriers for different cancers.

1. Introduction

Cancer is the second biggest cause of mortality and, therefore, is a serious public health concern worldwide [1]. The early therapeutics and traditional therapies mostly aim to reduce the incidence rates of cancers, but the basic problem with curing cancer patients with conventional therapies is that these treatments have a low selectivity for cancer cells and hence must be given at high lethal chemical doses to be efficacious [2]. When patients receive conventional types of treatment, e.g., chemotherapy or radiation, the high amount of toxic drugs is likely to harm normal body cells as well, causing serious side effects. Furthermore, tumor heterogeneity, drug resistance, and systemic toxicity cause significant barriers to most conventional cancer treatments [3,4].
Several management techniques are available to treat cancer, such as chemotherapy, radiation immunotherapy, surgery, stem cell or bone marrow transplant, and hormone therapy [5]. Photodynamic therapy (PDT) is a comparatively recent treatment strategy that has been examined in greater depth. PDT is a clinically approved, non-invasive novel therapy used to treat various cancers [6,7,8,9]. PDT treatment involves a group of essential molecules called photosensitizers (PS). When PS molecules are irradiated at a specific wavelength of light, a tremendous amount of energy is transferred to oxygen molecules or other substrates in the surrounding area of the tumor to form highly reactive oxygen species (ROS), such as singlet oxygen (1O2), resulting in cell death by the mechanism of cellular autophagy, cellular apoptotic and cellular necrosis [10,11,12,13]. At first, the photosensitizer is injected into blood circulation or applied topically, where it quickly becomes absorbed or enters the cells. The delivery of nanoparticles containing PS is based on the difference between the physiology of tumor cells and normal cells. Due to the enhanced permeability of tumor blood vessels and disrupted lymphatic drainage, nanoparticles reside in tumor cells [14,15,16]. Then, the tumor is irradiated with a specific wavelength of light which leads to activating the PS molecule and generating the ROS, resulting in the death of tumor cells and therapeutic effects in PDT [12,17,18]. The application of PDT on a solid tumor is schematically represented in Figure 1.
There are three potential ways a tumor can be destroyed by PDT. In the first mechanism, the tumor can be destroyed during light irradiation to the tumor, and ROS species will become engendered and kill the cancer cells by the mechanism of apoptosis, autophagy, and necrosis. In the second mechanism, PDT destroys tumor cells by attacking the vasculature and tumor environment. In the third mechanism, tumors can be destroyed by the generation or activation of an immune response. A few factors involved in the activation of the immune response are inflammatory mediators or T- helper cells (Figure 2) [19,20,21,22]. Additionally, significant pathways of proteolytic cleavage of cellular substrates by effector caspases include one pathway where the mitochondria release protein into the cytoplasm to activate caspase 9. Caspase 9 activations inside the mitochondria may have been triggered by stressful mitochondrial environmental conditions. Apoptogenic proteins such as cytochrome c are released in the cytosol of the mitochondria from the intermembranous space under stress. Cytochrome c further makes a complex with apoptotic protease activating factor 1 (Apaf-1), procaspase 9, and dATP/ATP (apoptosome) by acting as a co-factor. This complex activates caspase 9, which comes out of the mitochondria into the cytoplasm and triggers cleavage of executioner caspases such as caspase 3, 6, and 7. These caspases inactivate the proteins that work to prevent cellular apoptosis. Such inactivation inevitably leads to mitochondria-mediated apoptosis of tumor cells in PDT. There are other caspases, e.g., caspase 8, however, with PDT, only caspase 9 activity has been observed predominantly [23,24].
There are several pathways to reach such a fate. More precisely, PDT triggers a wide range of changes in cellular metabolism that ultimately leads to cell death and tumor destruction. Either the cells follow a caspase or cytochrome-c mediated mitochondrial pathway or follow a pathway involving ceramides or death receptors.
PDT has been shown to increase the cellular Ca2+ levels via ion channel influx, activation of ion exchange mechanism, etc. High Ca2+ levels in the cytoplasm activate phospholipase A2. This pathway is of great significance in cellular apoptosis [23]. Furthermore, the mitogen-activated protein kinase (MAPK) pathway modulates the extracellular signal-regulated kinase pathway (ERK-1/2). Upon PDT, a steep decrease in ERK expression was observed, which was directly related to the sharp increase in cell death. Transcriptor factors may also have some effects in dictating the cell death pathway by PDT. The activation of promoter regions in genes by chemical as well as physical stresses induced by PDT has been shown to be controlling apoptosis induction in cells. Several PDT studies have indicated the involvement of PDT in the expression of cytokines inside the cells. The overexpression or underexpression of these proteins dictates tumor regression as well as tumor eradication via changing the membrane-protein expression and the proliferation of effector molecules. Another possible PDT-induced cell death pathway includes heat shock proteins (Hsps) and glucose-regulated proteins (Grps). A few studies have postulated that the light activation of photosensitizers triggers a specific gene expression that is directly associated with Hsps and Grps. This further decides if the cell will die or develop resistance against PDT. Another gene expression that may have a significant role in cellular apoptosis is the hypoxia-inducible factor (HIF-1). As PDT induces hypoxia rapidly in the tumor microenvironment by cutting off the blood supply and using excess oxygen in the cells to activate the photosensitizer molecules, an association of HIF-1 in PDT is probable However, further investigation is required to establish this pathway as a legitimate PDT-triggered cell death pathway in cancer therapy [23,25,26].
In comparison to conventional therapy, PDT has a lower occurrence of side effects, and it also increases the target specificity. Although PDT has many advantages over standard cancer therapies, it still has yet to be wildly utilized in clinical health care. PS molecules possess several intrinsic properties such as poor targeting, low solubility, and high hydrophobicity because of which they easily form aggregates in physiological conditions [27,28,29]. Even though several PS molecules have been modified to increase water solubility, their selectivity of the target site is still inadequate, leading to their unsuccessful clinical uses. Table 1 represents the clinical trials and approval status of various photosensitizers [30,31,32,33,34,35,36,37,38,39,40,41,42,43,44].
In this context, the fabrication of an effective strategy is required for delivering PS molecules at the specific site or targeted area of the tumor, while overcoming the critical obstacle associated with conventional therapies. The combination of actively targeted nanomaterials with PDT therapy has shown extensive interest in treating cancer with high selectivity and specificity. The above actively-targeted functionalized nanomaterials enhance the rate of treatment outcomes, patient compliance and reduce the problems associated with conventional therapy or traditional therapeutics [45,46,47,48,49].
Recently, nanomaterials have shown significant promise in order to maximize PS solubility and targeting, which enhances the therapeutic outcomes of PDT. PS molecules can easily achieve passive targeting with the help of enhanced permeation and retention (EPR) effect when fabricated as nanoparticles. Further, surface modification of nanoparticles by binding with active targeting moieties such as functionalized groups, antibodies, peptides, and aptamers can extensively improve the cell target specificity of PS molecules [50,51,52,53,54].
Numerous nano-platforms based on a wide range of organic and inorganic nanomaterials have been developed over the year for effective uptake and targeted PS delivery [27,55]. Among the organic nanomaterials liposomes, polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, etc., have been evaluated for delivering PS molecules to the site of action and have been found effective, and safe delivery has been achieved [56,57]. The use of organic nanocarriers has successfully achieved flexibility in the formulation, such as increasing bioavailability, permeability, tumor accumulation, etc. Inorganic nanoparticles also have significant advantages over organic nanoparticles because of their high stability, ease of surface modification to make them suitable for specific targeting (specific ligand), tunable size, and optical properties. They are also more useful in diagnosis or imagining purposes [58,59].
Different types of organic and inorganic nanoparticles have shown significant effects. They both provide massive application in drug therapeutics by overcoming the problem associated with the PS molecules, such as instability at physiological conditions, improper specificity, high hydrophobicity, etc. In addition, both organic and inorganic nanoparticles are explored in combination with PS via chemical modification or chemical bonding, electrostatic interaction, and conjugation process for cancer treatment.

2. Targeting Photosensitizers via Active/Passive Targeting

Cellular uptake of PS molecules from subcellular localization can be categorized as either passive or active targeting. Passive targeting mainly occurs via the EPR effect of tumor-associated leaky vasculature and lymphatic drainage of tumor tissues. Moreover, target cell specificity of PS molecules has been proved to be efficient when those are attached to the surface-active moieties including aptamer, antibodies, peptides, small ligands, folic acid, etc. It was also observed to increase the therapeutic effect and cytotoxicity against the cancer cells. Active targeting has significant advantages over passive targeting because of its more selective target specificity, and tendency to accumulate more PS molecules in the intracellular tumor environment [46,60,61,62].
Passive targeting is based on the difference between the physiology of tumor cells and normal cells. Due to the enhanced permeability of tumor blood vessels and disrupted lymphatic drainage, nanoparticles reside in tumor cells. Passive targeting is not found to be effective in all cases, e.g., early-stage tumors do not show an EPR effect. Efficacy and specificity are compromised in passive targeting as the permeability of blood vessels is not the same all over the tumor cells. Active targeting has the potential to overcome the disadvantages of passive targeting. Targeting ligands are attached to the photosensitizer or the nanocarriers containing the photosensitizer, which binds to the receptors or antigens that are overexpressed on the tumor cells. Two types of active targeting are tumor targeting and vascular targeting. Tumor targeting refers to the ligands binding to specific receptors, while vascular targeting refers to the ligands binding to the receptors present on the endothelial cell surface. The uptake of nanoparticles by tumor cells is enhanced due to tumor targeting. In contrast, in vascular targeting, the concentration of nanoparticles is enhanced in vascular tissue, even in non-leaky vessels. Vascular targeting helps to kill the tumor by targeting blood vessels responsible for the supply of oxygen and nutrients. The tumor cell markers include folic acid receptors, integrin receptors, transferrin receptors, low-density lipoprotein receptors, glucose transporters, and growth factor receptors [63,64]. Antibody-based targeting has been considered one of the best strategies for drug delivery due to its antigen specificity. Photoimmunotherapy refers to the tumor-targeting strategy in which the antibody fragment or antibody is coupled to the photosensitizer for targeting the tumor antigen. Hydrophilic photosensitizers are preferred for photoimmunotherapy [63,65]. Aptamer-based targeting has been explored for targeting cancer cells in photodynamic therapy. Aptamers are three-dimensional structures of short nucleotides that can bind to membrane receptors and extracellular and intracellular targets. They are found to bind with high specificity and affinity to protein as well as non-protein targets. They exhibit unique features, including lack of immunogenicity, structural stability, ease of isolation, and small size. The single-stranded deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) molecules can regulate the function of genes by binding to the target sites and beginning replication and translation [63,65,66]. Peptides are amino acids linked by the amide bond. The amino acids present in the peptide are less than fifty, and hence the peptide has a low molecular weight. This property leads to an indefinite tertiary structure and good receptor binding affinity. However, they are subjected to peptidases and rapid clearance. Several approaches have been introduced to overcome this problem, including developing modified peptides that are less susceptible to peptidases, thereby enhancing their bioavailability. A modification of the amino acids can be performed, which enhances their in vivo stability. They have several advantages, such as they form non-toxic degradation products since they are made of natural amino acids. These peptides can alter their confirmation to secondary structure in response to changes in pH or temperature. Folic acid is one of the many vitamins which has promised its use in targeted photodynamic therapy. Its stability, non-toxicity, non-immunogenicity, and low cost have further enhanced its use in PDT. It can be coupled with photosensitizers quite easily. It has an affinity for folate receptors which are overexpressed in several cancers, including lung, brain, kidney, breast, and ovary [63,65,67].

3. Inorganic and Organic Nanoparticulate for Active or Passive Photosensitizer Drug Delivery

3.1. Inorganic Nanoparticulate for Active or Passive Photosensitizer Drug Delivery

In the last decade, the nanotechnology sector has grown and has been explored at a rapid rate, resulting in the development of potential nanocarriers for applications in various areas such as medicine, electronics, biomaterial engineering, etc. Nanomedicine is the use of nanotechnology in biomedical research, and it involves the use of nanoparticulate that have been carefully designed for novel diagnostic and drug delivery purposes to enhance therapeutic efficacy [68,69,70].
In a nanoparticulate drug delivery system, PS are encapsulated with polymer or lipids or a ligand-based system with covalent bonding or noncovalent interaction. A few significant advantages of attaching the nanoparticles with the PS molecules are the high drug loading capacity, and a high surface-to-volume ratio may be observed. The nanoparticulate system is attractive in PDT therapy for the following points: first, PS molecule concentration becomes enhanced at the desired targeted site because of targeting potential and reduces the unwanted toxic effect on healthy cells. Second, the solubility of hydrophobic PS molecules can be significantly improved by the nanoparticulate system. Third, the nanoparticulate system can deliver the drug at the desired targeted site in a sustained and controlled manner. Therefore, the functionalization of the nanoparticle platform is used to enhance the effectiveness of PDT and to deliver the PS molecules at the desired targeted site by utilizing the active or passive mechanism. PDT with actively targeted nanoparticles consists of numerous types of organic and inorganic nanoparticles, including liposomes, lipid-based nanoparticulate, polymeric micelles, carbon dots, gold nanoparticles, magnetic nanoparticles, quantum dots, etc. [71,72,73,74,75]. Some recent major outcomes of nanoparticulate in the delivery of PS to the desired site of the tumor by utilizing the overexpressed receptors site and their ligands are mentioned in Table 2 [76,77,78,79,80,81,82,83,84,85,86,87,88].
Inorganic nanoparticles are preferred over organic nanoparticles as they show several advantages, including tunable size, high stability, ease of surface modification, and optical properties. They exhibit lower degradation as compared to the organic nanoparticles [89]. They include quantum dots, gold nanoparticles, mesoporous silica nanoparticles, graphene, fullerene, and magnetic nanoparticles. The PS in these non-biodegradable nanostructures produces singlet oxygen without them being released. However, in organic nanoparticles, the singlet oxygen species must have the ability to diffuse across these nanostructures to produce the desired photodynamic effect. [63]. The intrinsic functions of inorganic nanoparticles and the special characteristics of each of these nanoparticles have attracted the attention of the scientific community in biomedical applications. Gold nanoparticles show a photothermal effect due to surface plasmon resonance; iron oxide nanoparticles can be utilized as T2 magnetic resonance imaging contrast agents, and mesoporous silica nanoparticles have high loading capacity, large surface area, and facile size control [49,90,91].

3.1.1. Silica Nanoparticles

Mesoporous silica nanoparticles are utilized in photodynamic therapy because of their pore volume, large surface area, and biocompatible nature. Photosensitizers can be covalently linked to the silica nanoparticles, or they can be encapsulated. These nanoparticles facilitate the attachment of ligand and stimuli-responsive substances that can be integrated to release the drug at the diseased site [92]. Ozge et al. developed Cetuximab-targeted mesoporous silica nanoparticles capped with imidazole for the delivery of zinc phthalocyanine to treat human pancreatic cancer. The cell viability of targeted mesoporous silica nanoparticles was found to be 6.2%, 12.5%, and 17.5% for PANC-1, AsPC-1, and MIA PaCa-2 cells, respectively while that of zinc(II) 2,3,9,10,16,17,23,24-octa(tert-butylphenoxy))phthalocyaninato(2-)-N29,N30,N31,N32 (ZnPcOBP) was found to be 35%, 55%, and 39%. The increase in efficacy was attributed to cetuximab’s targeting effect, which recognizes the cells and internalizes the cells through receptor mediation [93]. Planas et al. synthesized amino and mannose-targeted mesoporous silica nanoparticles loaded with methylene blue (MMSNP-MB) and evaluated their antibacterial activity. MMSNP-MB decreased 8-log10 the bacterial survival fraction on exposure to 16 J/cm2 while amino- or mannose-modified mesoporous silica nanoparticles (AMSNP-MB) showed a reduction of 5-log10 on exposure to 32 J/cm2. It was concluded that the photodynamic effect shown by MMSNP-MB and AMSNP-MB was similar. However, for E.coli, dark toxicity was improved, and mannose proved to be a better target for P. aeruginosa than amino groups [94]. Ma et al. developed folic acid functionalized hollow mesoporous silica nanoparticles for photodynamic therapy containing aminolevulinic acid to treat skin cancer. Results indicated accumulation of protoporphyrin IX (PpIX) in skin cancer cells through folate receptor-mediated endocytosis. These nanoparticles were activated at 635 nm and released Aminolevulinic acid (ALA), which killed skin cancer cells because of the conversion of ALA to PpIX [95].

3.1.2. Gold Nanoparticles

Gold nanoparticles are employed in medicine because of their photophysical, optical, and photochemical properties. In addition, gold nanoparticles are biocompatible and show low toxicity. They are employed in photodynamic therapy as they offer several benefits, including an increase in singlet oxygen production, their potential to become conjugated to biological ligands, and the dispersion of hydrophobic photosensitizers in aqueous media. Several types of gold nanoparticles can be employed in photodynamic therapy, including spherical-shaped nanoparticles, nanoclusters, nanorods, and nanostars. Gold nanorods offer the advantage of combining photodynamic therapy with photothermal therapy. Photosensitizers are coupled to gold nanoparticles with a different approach which is based on self-assembly. Electrostatic interactions and covalent binding are some of the techniques for preparing these metallic nanoparticles [96]. Goddard et al. developed peptide-directed gold nanoparticles containing phthalocyanine for photodynamic therapy. The IC50 of zinc phthalocyanine C11Pc poly(ethylene glycol) (PEG) gold nanoparticles (peptide-C11Pc-PEG-AuNps) was found to be 105.8 nM on irradiation while >250 nM without irradiation. No phototoxic response was recorded when the cells were incubated with non-targeted C11Pc-PEG-AuNps. It was concluded that the phototoxicity of peptide-C11Pc-PEG-AuNps was due to the dual effect of photocatalytic activity of C11Pc and the targeting effect [97]. Shiao et al. developed gold nanoparticles modified with aptamer for co-drug delivery in photodynamic therapy. It was found that the therapeutic efficacy of 5,10,15,20-tetrakis(1-methylpyridinium-4-yl) porphyrin (TMPyP4)-loaded dox-NPs was raised to 4.6 and 2.5-fold as compared to chemotherapy and photodynamic therapy alone. This depicted that a combination of the treatment majorly improved the antitumor efficacy. Nanoparticular delivery ensures effective intracellular transport and overcomes tumor drug resistance. Thereby, it increases antitumor effectiveness [98].

3.1.3. Carbon Nanomaterials

Carbon nanomaterials are of different types based on their dimensions, such as fullerenes are zero-dimensional, carbon nanotubes are one-dimensional, and graphene nano molecules are two-dimensional. They exhibit unique physicochemical properties and structures that do not cause chemotherapeutic toxicity and are effective in novel therapies. Carbon nanotubes and graphene are generally used in delivery systems due to their large surface area and loading capacity of PS and drugs [99]. They show high mechanical strength, good optical properties, biocompatibility, and low toxicity, which has promoted their use in the biomedical field. They are used in photodynamic therapy due to their unique properties, such as C60 acting as a photosensitizer. Carbon nanotubes can convert the near infra-red light into heat. They display high drug loading because of pi-pi stacking. However, there is a need to reduce their dose-dependent toxicity and increase aqueous solubility [100].

3.1.4. Carbon Nanotubes

The distinct chemical and physical properties of carbon nanotubes have attracted their attention in biomedical applications. PS can be conjugated to carbon nanotubes to enhance the solubility, targeting, and bioavailability of PS [101]. They have the ability to transform light into heat which can be used to design thermal therapy. They can load hydrophobic drugs and absorb light strongly in the near IR region, enhancing the penetration of light to deeper tissues. As compared to iron oxide nanoparticles, they show a high heating rate and there is no need to remove metallic material [102]. Zhang et al. developed single-walled carbon nanotubes coated with aptamer conjugated magnetofluorescent iron oxide carbon quantum dots for chemo/photodynamic/photothermal triple modal therapeutic agents for the treatment of lung cancer. The aptamer targeting enhanced cellular uptake. The aptamer conjugated PEG 2000 N modified Fe3O4@carbon quantum dot coated single-walled carbon nanotubes (SWCNTs-PEG-Fe3O4@CQDs/doxorubicin (DOX) exhibited more cytotoxicity against HeLa cells as compared to that of non-targeted. It was concluded that the developed SWCNTs showed multiple effects such as NIR photothermal heater, drug carrier, combination therapy of cancer, and multimodal imaging probe [103]. Shi et al. developed hyaluronic acid-modified carbon nanotubes (HA-CNT) containing hematoporphyrin monomethyl ether (HMME) for photodynamic therapy. The rate of inhibition of HMME-HA-CNTs at a concentration of 12.5 µg/mL was found to be 76.8% with 532/808 nm laser and 41.1% for HA-CNT with 808 nm laser. It was found that the photodynamic and photothermal effect of HMME-HA-CNTs was more than that of photodynamic/photothermal therapy given alone [104].

3.1.5. Fullerene

Fullerenes are employed in photodynamic therapy because of their photostability and undergo relatively less photobleaching than tetrapyrroles. It is easy to modify fullerenes and achieve the desired lipophilicity. Light-harvesting antennae are conjugated to fullerenes to enhance the generation of reactive oxygen species. Fullerenes can undergo self-assembly and form fullerosome. This fullerosome possesses targeting properties and can function as multivalent drug delivery vehicle. The core of fullerene is composed of C60 to which amphiphilic or fused ring structures or hydrophilic side chains can be attached. However, fullerenes absorb in the ultraviolet or blue, or green regions of the spectrum, which limits the penetration of light to deeper tissues. Some approaches have been developed to overcome these limitations, such as the conjugation of red light-absorbing antennae to the core. Optical clearing agents can also be utilized to overcome this limitation [105]. The core of fullerene, composed of C60, undergoes a transition from the S0 state to short-lived the S1 state. The excited state decays at 5 × 108 sec-1 and undergoes intersystem crossing to the T1 triplet state, which has a long lifetime. The triplet state of fullerene is quenched due to the presence of molecular oxygen, which is present as a triplet in the ground state. The quenched triplet state of oxygen generates singlet oxygen by energy transfer. This process generates a singlet oxygen quantum yield near the theoretical maximum of 1 [105,106]. Liu et al. developed R13 aptamer conjugated trimalonic acid modified C70 fullerene to increase the effectiveness of photodynamic therapy for the treatment of lung cancer. The cell viability shown by TF70-R13 was 0.1 while that of TF70 and control was 0.4 and 1, respectively [107]. Zhang et al. formulated supramolecular hydrogel of dipeptide fullerene for antibacterial photodynamic therapy. Hydrogel avoids the aggregation of fullerene because of the non-covalent interactions between fullerene and peptides. It was observed that 42% of bacteria were killed by C-60 pyrrolidine tris acid while no bacteria were found on treatment with peptide fullerene and light irradiation. It was concluded that the non-covalent interactions have a synergistic effect on hydrogel properties. The peptide nanofibers enhance the singlet oxygen generation capacity. The fullerene nanoparticles are responsible for enhancing the mechanical properties of the hydrogel, thereby ensuring a targeted effect [108]. Shi et al. prepared doxorubicin (DOX) fullerene nanoaggregates nanoparticles and attached the hydrophilic moiety, distearoyl-sn-glycero-3-phosphoethanolamine-PEG-CNGRCK2HK3HK11 (DSPE-PEG-NGR) (C60-DOX-NGR-NP) which showed high antitumor efficacy and low toxicity to the normal cells as shown in fig 4T1 cell targeting ability of C60-DOX-NGR-NP, C60-DOX-PEG NP, and DOX was evaluated and results indicated higher red fluorescence in case of C60-DOX-NGR-NP as compared to C60-DOX-PEG-NP, suggesting its higher tumor targeting ability. In vitro studies revealed the highest decrease in cell viability in the case of C60-DOX-NGR-NP to 58.7% on the application of laser light. The in vivo studies indicated the highest concentration of doxorubicin in tumors from C60-DOX-NGR-NPs and inhibited tumor growth after applying the laser light twice [109].

3.1.6. Graphene

Scientists have used graphene and graphene oxide to explore their role in the treatment of cancers and photodynamic therapy. Graphene nanoparticles are classified as graphene oxide, single-layered graphene, reduced graphene oxide, and few-layered graphene. Graphene oxide (GO) has a large specific surface area that ensures the effective loading of photosensitizers and drugs with the help of surface functional groups. Graphene nanoparticles in PDT have been proved to be more stable, bioavailable, and photodynamically efficient. Its unique optical, mechanical, and electronic properties have enhanced its use in biomedical science [110,111]. Graphene oxide increases the photodynamic activity of inorganic nanoparticles such as Titanium dioxide (TiO2) and Zinc oxide (ZnO). These inorganic nanoparticles produce reactive oxygen species like hydroxyl radicals, superoxide radicals, and hydrogen peroxide by irradiating them with UV light. UV light has a major limitation in that it cannot penetrate deeper tissues. The ROS which is generated by this type of light has a short life span, which lowers the antitumor efficacy. Hu et al. reported that graphene oxide on the surface of TiO2 could activate visible light responsive activity. Graphene exhibits high electrical conductivity, which transfers the light-triggered electron by TiO2 to graphene oxide. This process suppresses electron-hole recombination. The holes in the valence band of TiO2 move to the surface and interacts with water to form hydroxyl radicals. The electron transferred by TiO2 to GO reacts with oxygen to form singlet oxygen. In this way, GO can increase the photodynamic efficiency of inorganic nanomaterials [111]. Wei et al. developed the integrin αvβ3 functionalized nanosystem of graphene oxide (NGO). The surface of the NGO was covered with polyethylene glycol, which was conjugated to pyropheophorbide. Pyropheophorbide-a (PPa) provided a phototoxic effect. The PPa only PDT treatment showed a cell death of 50%, while αvβ3 NGO resulted in 70% of cell death. The results were attributed to the targeting activity of the antibody and enhanced drug loading/transporting ability. Huang et al. formulated folic acid conjugated graphene oxide containing the photosensitizer chlorin e6. Loading of chlorin e6 in GO was carried out by pi-pi stacking and hydrophobic interactions. Cytotoxicity results indicated that FolicAcid-GO was non-toxic to cancer cells. A 1:1 ratio of mFA-GO/m-Ce6 showed a cell viability of less than 50%. It was concluded that the developed novel nanosystem could be formulated with low cytotoxicity and improved solubility. The developed system increased the amount of photosensitizer in the cancer cells [112].

3.1.7. Iron Oxide Nanoparticles

Iron oxide nanoparticles have been utilized in biomedicine due to their targeting properties, biocompatibility, superparamagnetic nature, easy surface modification, and small size. Iron oxide nanoparticles were developed for delivering a combination of photodynamic therapy and magnetic resonance imaging [113]. Zeng et al. developed folic acid-targeted superparamagnetic iron oxide nanoparticles containing photosensitizers (FA-NPs-PS) for visualized photodynamic therapy and magnetic resonance imaging. Fluorescence of photosensitizer was noted in MCF-7, HeLa cells, and MCF-7 tumors proving that folic acid showed a good targeting effect. The results indicated that the cell viability in MCF-7 and HeLa cells treated with FA-NPs-PS was 18.4% and 30.7%, while that of the cells treated with NPs-PS was 25.7% and 34.4%, respectively. MCF-7 tumors showed an inhibition of about 94.9%. It was concluded that the prepared nanoparticles were effective magnetic resonance imaging (MRI)/PDT nanoprobes for visualized therapy of breast cancers and in vivo diagnosis [114]. Patel et al. developed novel folic acid-modified iron oxide-zinc oxide nanoparticles as a photosensitizer in photodynamic therapy. Zinc oxide is an n-type semiconductor that exhibits high photosensitivity, low cost, and is environmentally friendly. Zinc oxide undergoes photoexcitation when subjected to UV light which has higher energy than its bandgap energy. This photoexcitation results in the formation of positive holes and negative electrons in the valence band and conduction band, respectively. The electron-hole pair possesses reduction and oxidation properties that recombine or are captured by water or oxygen, leading to ROS formation. The hybrid iron oxide-zinc oxide nanoparticles enhanced photophysical properties due to the decrease in charge recombination in zinc oxide by the presence of iron oxide, which acts as electron trapping sites. The photokilling effect was enhanced by conjugating folic acid, which reduced cell viability to 34% on irradiation with FZ-SFA50. It was concluded that the synthesized nanoparticles showed effectiveness in photodynamic therapy [115].

3.1.8. Quantum Dots

They are used in multifunctional nanocarriers for photodynamic therapy because of their facile surface modification, high emission quantum yield, and tunable optical properties. The size of the quantum dots from 1 to 6 nm offers them antique optical properties that can be changed from ultraviolet to infrared by adjusting the composition and size. The quantum confinement effect regulates the emission properties, and they can be tuned to emit in the infrared region. This is in opposition to that the visible emission of most photosensitizers. This effect allows deep penetration of light and can be used to cure deep tumors. This deep penetration of light is attributed to the minimal scattering and absorption of light in the near-infrared region. Quantum dots (QD) exhibit large transition dipole moments, making them strong absorbers and facilitating their use in photodynamic therapy [116]. Li et al. formulated peptide-targeted quantum dots to be used in photodynamic therapy to treat pancreatic cancer. The relative tumor volume after treatment with RGD-QD was found to be 3.24, while that of PDT treatment without injection of RGD-QD was found to be 7.25. It was concluded that RGD-QD in photodynamic therapy was found to be successful in the treatment of pancreatic cancer [117]. Cao et al. developed aptamer conjugated graphene quantum dots (GQD) for photodynamic and photothermal synergistic therapy and as the diagnostic agent of cancer-related micro-RNA. The GQD-PEGP treated cells showed cell viability of 14%, while the control groups recorded a cell viability of 90%. It was concluded that a novel theranostic agent of aptamer-conjugated PEGylated GQD loaded with porphyrin derivatives was successfully developed [118].

3.2. Organic Nanoparticulate for Photosensitizer Drug Delivery

3.2.1. Liposomes

Liposomes are used to enhance the concentration of photosensitizers at the tumor site in photodynamic therapy due to their high loading capacity. They can also encapsulate photosensitizers of different physicochemical properties. Actively targeted liposomes show enhanced plasma half-life, thereby enhancing efficacy [119]. Active targeting of liposomes ensures increased photosensitizer accumulation at the tumor site and increases the photodynamic effect. It eliminates the undesired side effects of the photosensitizer. The binding site barrier is the limitation of targeted liposomes. The targeted liposomes bind to the target that they first encounter, thus retarding their penetration. However, PDT is used for the treatment of superficial tumors because of the limited penetration of light. Hence, not much attention needs to be paid to this phenomenon [56]. Peptide-targeted liposomes exhibit less immunogenicity and small molecular weight as compared to antibodies. They can be synthesized, stabilized, and modified easily. However, they have less binding affinity as compared to antibodies [120]. Huang et al. developed GE11 Peptide conjugated liposomes containing indocyanine green and curcumin for epidermal growth receptors targeting cancer cells. It was reported that the cell viability was reduced by curcumin/indocyanine green and curcumin/indocyanine green-liposomes was 52% and 35.2%, respectively while GE11-curcumin/indocyanine green-liposomes reduced cell viability to 12%. It indicated a greater cytotoxic and phototoxic effect on cancer cells [121]. Antibody-targeted liposomes identify the antigens which are overexpressed on the tumor cells and exert a targeting effect. They are the most widely used targeting agents. [120]. Broekgarden et al. developed an approach for site-specific conjugation of EGa1 sdAbs antibodies on liposomes encapsulating zinc phthalocyanine targeting the epidermal growth factor receptor. It was found that the antibody-conjugated liposomes exhibited selective uptake characteristics and enhanced the photodynamic efficacy in comparison to the non-targeted liposomes [122]. In a study, Anilkumar et al. prepared dual-targeted dual-mode nano-vehicles. Targeting properties were induced by magnetic, as well as, ligand-based approaches while dual-mode was achieved via photothermal and photodynamic therapies. 1,2-distearoylsn-glycero-3-phosphocholine, dimethyldioctadecyl ammonium bromide (DDAB), and cholesterol were used to prepare magnetic photosensitive liposomes (MPLs) that encapsulated the PS molecules (indocyanine green), and Fe3O4 (coated magnetic nanoparticles or CMNPs). Then, the MPLs were coated using Hyaluronic acid-polyethylene glycol (HA-PEG) to ultimately form HA-PEG-MPLs. The coating was performed by utilizing the negative charge of HA and the innate positive charge of DDAB. Self-assembly of HA-PEG over MPLs was observed. The resulting NPs showed promising PTT and PDT effects when irradiated by successive NIR laser regimens. A nude mice model was used to show the effects where this novel strategy resulted in ~7.8-fold reduction in tumor volume compared to the control at the end of the treatment [123]. Wohrle et al. prepared Zn(II)-2,3-naphthalocyanines including four zinc naphthalocyanines (ZnNc), the unsubstituted ZnNc 1, tetraacetylamido substituted ZnNc 2, tetraamino-substituted ZnNc 3, and tetramethoxy substituted ZnNc 4 and loaded them in liposomes for photodynamic therapy. The pharmacokinetic properties of ZnNc 1 dipalmitoylphosphatidylcholine liposomes and the photodynamic effect of ZnNc 2-4 were studied by their intraperitoneal administration in hamsters infected with rhabdomyosarcoma. The phototherapeutic effect was determined by mean tumor diameter, photonecrosis, and the percentage of animals recovered. ZnNc 2 showed the highest percentage (50%) of animals recovered. ZnNc 4 recovered 40% of animals while ZnNc 3 did not show any effect upon photodynamic therapy and studies on ZnNc 1 indicated a very low effect. Zn(II)-2.3-naphthalocyanines were found to be effective at low doses and show selective targeting and slow clearance from the tumor [124].
Reddi et al. studied the pharmacokinetic properties and phototherapeutic effect of Zn (II)-phthalocyanine (ZnPc) loaded in dipalmitoylphosphatidylcholine and low-density lipoprotein liposomes by injecting them intravenously in mice infected with MS-2 fibrosarcoma. The photodynamic effect at various doses of irradiation was measured by determining the efficiency of tumor necrosis which indicated that 0.07–0.35 mg/kg dose of Zn-Pc is enough for producing an effective tumor response. On increasing the irradiation from 50 to 200 mW/cm2, a six-fold increase in necrosis was observed. Zn-Pc was found to be an effective photodynamic agent because of its slow clearance, local effect, and high tumor necrosis efficiency at low doses [125].

3.2.2. Solid Lipid Nanoparticles

Solid lipid nanoparticles are used in photodynamic therapy due to their biocompatibility, less toxicity, and protection of photosensitizers from the external environment [126]. Stevens et al. formulated and evaluated folate receptor-targeted solid lipid nanoparticles of hematoporphyrin. It was found that targeted solid lipid nanoparticles gave IC50 of 1.57 micromolar whereas non-targeted solid lipid nanoparticles gave IC50 of 5.17 micromolar [74].

3.2.3. Polymeric Micelles

Polymeric micelles have attracted attention in photodynamic therapy. They enhance aqueous solubility and retain photo–sensitizer in the blood for a longer period, allowing its accumulation at the desired site –enhanced permeability and retention. However, these photosensitizers loaded polymeric micelles can cause skin photosensitivity, damaging the blood vessel cells or the endothelial cells [127]. Lamch et al. fabricated folic acid conjugated polymeric micelles containing phthalocyanine for anticancer photodynamic therapy. The cell viability of free zinc phthalocyanine and FA conjugated zinc phthalocyanine polymeric micelles was found to be 65% and 59%, respectively in HaCaT cells. It was concluded that the synthesized functionalized polymeric micelles showed effectiveness in photodynamic therapy to treat metastatic melanoma and ovarian cancer [128]. Liu et al. developed EGa1 modified polymeric micelles for photodynamic therapy containing the photosensitizer meta-Tetra(hydroxyphenyl)chlorin. It was noted that the relative viability of photosensitizer-loaded polymeric micelles was found to be 25%, while that of EGa1-modified polymeric micelles showed relative viability of 10%. It was concluded that the developed nanoparticles enter the tumor cells upon binding of nanobody to EGFR receptors and result in enhancement of efficacy and selectivity of photodynamic therapy [129]. Lu et al. synthesized RGD-modified disulfide bond-conjugated prodrug polymer comprising of polyethylene glycol and camptothecin. The polymer self-assembled to form polymeric micelles. These micelles showed the potential to cross the blood-brain barrier and target the glioma cells. The normalized cell viability of CPD@IR780 was found to be 25% while that of only CPT was found to be 60%. It was concluded that photodynamic therapy and chemotherapy increased the efficacy of treatment [130].

4. Future Perspectives

PDT is entirely a non-invasive approach for treating cancer and this is its prime advantage over other conventional approaches such as surgery, curettage, cryosurgery etc., which are all invasive in nature. Additionally, PDT shows little to no side effects when compared to radiotherapy. Another advantage is that tumor cells have almost zero resistance to PDT, given that development of resistance is the major drawback associated with chemotherapy. We acknowledge that PDT as a treatment approach has a few disadvantages associated with it, such as development of phototoxicity post the treatment sessions. However, this occurs due to non-specific accumulation of photosensitizers and this challenge is being addressed by utilizing active nanoparticles which aim towards circumventing this problem. This helps in achieving reduced phototoxicity. PDT has been widely investigated in head and neck cancer, breast cancer, skin cancer, lung cancer, brain cancer, etc. Clinically, it has been in use for more than a decade now. Several clinical trials are ongoing in the present scenario where the effectiveness of PDT with different PS is being investigated in the treatment of cancers. In one clinical trial, the maximum tolerable dose of HPPH-PDT is being investigated in pleural malignancy [131]. In another similar clinical trial, the efficiency and safety of PDT with hexaminolevulinate (HAL) are being investigated in cervical neoplasia [132]. Despite all the clinical trials and positive results, a few disadvantages of classical PDT are yet to be overcome. The low water solubility of photosensitizer molecules and their poor tumor selectivity are the fundamental problems associated with classical PDT. The approach of incorporating nanocarriers into PDT is an effective strategy that has successfully solved these shortcomings of classical PDT. Surface modification of nanocarriers with PS molecules using aptamers, peptides, ligands, etc., is one of the most logical strategies to overcome the problems associated with conventional PDT therapy [61]. Additionally, several types of organic and inorganic nanomaterials combined with PS molecules result in the enhancement of water solubility of hydrophobic PS molecules as well as create a specific target approach for the delivery of the PS molecules via active and passive mechanisms [133]. However, fabrication targeted PS drug delivery parameters need to be thoroughly examined, including uses of the targeted moiety, biocompatibility of surface functionalization, loading capacity, and use of the specific wavelength of light for activation of PS. Moreover, significantly growing uses of nanomaterials for PDT face several obstacles in the way of clinical application such as long-term toxicity, systemic toxicity, phototoxicity, and dose-dependent toxicity. The development of high wavelength photoactive molecules needs to be fabricated in parallel with the development of actively targeted nanocarriers. Using a diverse set of multifunctional lipids, natural polymers, aptamers, peptides, etc., is an effective approach to avoid long-term and dose-dependent toxicity. Additionally, the use of site-responsive such as pH and temperature, etc., responsive drug delivery systems can overcome the problem associated with systemic and dose-dependent toxicity [134,135]. Several studies have also shown the effectiveness of using PDT and photothermal therapy (PTT) together. In this review, we have compiled various actively targeted organic and inorganic nanocarriers with targeted moiety to provide the site-specific delivery of PS molecules.

5. Conclusions

PDT is a promising treatment strategy in cancer treatment because of its non-invasive, patient-compliant, and highly effective nature. This review tries to present all the information available about actively and passively targeted NPs that are used in PDT specifically in cancer, in a concise manner. Serval cancer therapeutics strategy have been mentioned in an organized manner to give the reader a sense of fulfillment in the subject of using targeted nanocarriers in photodynamic therapy. To increase the site specificity, various means are being investigated continuously. The incidence of active as well as passive targeting via polymeric nanoparticles, inorganic nanoparticles, lipidic nanoparticles, and other novel nanocarriers are presented in the literature. However, a few common disadvantages are still prevalent with the nano strategy that need to be overcome in the future. These include unpredictable drug release profiles, inconsistent tumor permeation, long-term toxicity, etc. Other than this, the main hindrance to PDT is government body approvals. Numerous studies with PDT are still in clinical trial phases. Although backed by the scientific community, various factors have slowed the growth of the usage of PDT. The active interest of pharmaceutical companies and government bodies is needed to make this treatment strategy easy to follow for cancer patients. In conclusion, it can be said that incorporating targeted nanocarriers in PDT for cancer treatment shows enormous potential and possibility toward a more reliable, patient-compliant treatment strategy that should be explored further.

Author Contributions

R.J.: Conceptualization, methodology, figures, tables, writing—original draft; S.M.: writing—original draft; I.S.: writing—original draft; S.B.: review and editing; G.S.: Conceptualization, project administration, resources, supervision, and review and editing; S.K.D.: Conceptualization, project administration, resources, supervision, and review and editing. All authors have read and agreed to the published version of the manuscript.

Funding

The review paper was not supported by any funding agency.

Conflicts of Interest

There is no conflict of interest between the authors.

References

  1. World Health Organisation. Cancer—Key Facts. 2018. Available online: http://www.who.int/news-room/fact-sheets/detail/cancer (accessed on 24 July 2022).
  2. Sánchez-Moreno, P.; Ortega-Vinuesa, J.L.; Peula-García, J.M.; Marchal, J.A.; Boulaiz, H. Smart Drug-Delivery Systems for Cancer Nanotherapy. Curr. Drug Targets 2018, 19, 339–359. [Google Scholar] [CrossRef] [PubMed]
  3. Ediriwickrema, A.; Saltzman, W.M. Nanotherapy for Cancer: Targeting and Multifunctionality in the Future of Cancer Therapies. ACS Biomater. Sci. Eng. 2015, 1, 64–78. [Google Scholar] [CrossRef] [PubMed]
  4. Jain, R.; Dubey, S.K.; Singhvi, G. The Hedgehog pathway and its inhibitors: Emerging therapeutic approaches for basal cell carcinoma. Drug Discov. Today 2021, 27, 1176–1183. [Google Scholar] [CrossRef] [PubMed]
  5. Cancer Treatment—Mayo Clinic. Available online: https://www.mayoclinic.org/tests-procedures/cancer-treatment/about/pac-20393344 (accessed on 24 July 2021).
  6. Agostinis, P.; Berg, K.; Cengel, K.A.; Foster, T.H.; Girotti, A.W.; Gollnick, S.O.; Hahn, S.M.; Hamblin, M.R.; Juzeniene, A.; Kessel, D.; et al. Photodynamic therapy of cancer: An update. CA Cancer J. Clin. 2011, 61, 250–281. [Google Scholar] [CrossRef] [PubMed]
  7. Anand, S.; Ortel, B.J.; Pereira, S.P.; Hasan, T.; Maytin, E.V. Biomodulatory approaches to photodynamic therapy for solid tumors. Cancer Lett. 2012, 326, 8–16. [Google Scholar] [CrossRef] [Green Version]
  8. Dougherty, T.J.; Gomer, C.J.; Henderson, B.W.; Jori, G.; Kessel, D.; Korbelik, M.; Moan, J.; Peng, Q. Photodynamic Therapy. J. Natl. Cancer Inst. 1998, 90, 889–905. [Google Scholar] [CrossRef] [Green Version]
  9. Banerjee, S.M.; El-Sheikh, S.; Malhotra, A.; Mosse, C.A.; Parker, S.; Williams, N.R.; MacRobert, A.J.; Hamoudi, R.; Bown, S.G.; Keshtgar, M.R. Photodynamic Therapy in Primary Breast Cancer. J. Clin. Med. 2020, 9, 483. [Google Scholar] [CrossRef] [Green Version]
  10. Dolmans, D.E.; Fukumura, D.; Jain, R.K. Photodynamic therapy for cancer. Nat. Rev. Cancer 2003, 3, 380–387. [Google Scholar] [CrossRef]
  11. Hopper, C. Photodynamic therapy: A clinical reality in the treatment of cancer. Lancet Oncol. 2000, 1, 212–219. [Google Scholar] [CrossRef] [PubMed]
  12. Jain, R.; Sarode, I.; Singhvi, G.; Dubey, S.K. Nanocarrier Based Topical Drug Delivery—A Promising Strategy for Treatment of Skin Cancer. Curr. Pharm. Des. 2020, 26, 4615–4623. [Google Scholar] [CrossRef]
  13. Hu, Z.; Oleinick, N.; Hamblin, M.R. Photodynamic Therapy as an Emerging Treatment Modality for Cancer and Non-Cancer Diseases. J. Anal. Bioanal. Tech. 2014, S1, 1. [Google Scholar] [CrossRef] [Green Version]
  14. Niculescu, A.-G.; Grumezescu, A. Photodynamic Therapy—An Up-to-Date Review. Appl. Sci. 2021, 11, 3626. [Google Scholar] [CrossRef]
  15. Foresto, E.; Gilardi, P.; Ibarra, L.E.; Cogno, I.S. Light-activated green drugs: How we can use them in photodynamic therapy and mass-produce them with biotechnological tools. Phytomed. Plus 2021, 1, 100044. [Google Scholar] [CrossRef]
  16. Kwiatkowski, S.; Knap, B.; Przystupski, D.; Saczko, J.; Kędzierska, E.; Knap-Czop, K.; Kotlińska, J.; Michel, O.; Kotowski, K.; Kulbacka, J. Photodynamic therapy—Mechanisms, photosensitizers and combinations. Biomed. Pharmacother. 2018, 106, 1098–1107. [Google Scholar] [CrossRef] [PubMed]
  17. Detty, M.R.; Gibson, S.L.; Wagner, S.J. Current Clinical and Preclinical Photosensitizers for Use in Photodynamic Therapy. J. Med. Chem. 2004, 47, 3897–3915. [Google Scholar] [CrossRef]
  18. Dubey, S.K.; Pradyuth, S.K.; Saha, R.N.; Singhvi, G.; Alexander, A.; Agrawal, M.; Shapiro, B.A.; Puri, A. Application of photodynamic therapy drugs for management of glioma. J. Porphyr. Phthalocyanines 2019, 23, 1216–1228. [Google Scholar] [CrossRef] [Green Version]
  19. Castano, A.P.; Mroz, P.; Hamblin, M.R. Photodynamic therapy and anti-tumour immunity. Nat. Rev. Cancer 2006, 6, 535–545. [Google Scholar] [CrossRef] [Green Version]
  20. Castano, A.P.; Demidova, T.N.; Hamblin, M.R. Mechanisms in photodynamic therapy: Part one—Photosensitizers, photochemistry and cellular localization. Photodiagn. Photodyn. Ther. 2004, 1, 279–293. [Google Scholar] [CrossRef] [Green Version]
  21. Castano, A.P.; Demidova, T.N.; Hamblin, M.R. Mechanisms in photodynamic therapy: Part three—Photosensitizer pharmacokinetics, biodistribution, tumor localization and modes of tumor destruction. Photodiagn. Photodyn. Ther. 2005, 2, 91–106. [Google Scholar] [CrossRef] [Green Version]
  22. Castano, A.P.; Demidova, T.N.; Hamblin, M.R. Mechanisms in photodynamic therapy: Part two—Cellular signaling, cell metabolism and modes of cell death. Photodiagn. Photodyn. Ther. 2005, 2, 1–23. [Google Scholar] [CrossRef]
  23. Robertson, C.A.; Evans, D.H.; Abrahamse, H. Photodynamic therapy (PDT): A short review on cellular mechanisms and cancer research applications for PDT. J. Photochem. Photobiol. B 2009, 96, 1–8. [Google Scholar] [CrossRef] [PubMed]
  24. Takahashi, H.; Itoh, Y.; Miyauchi, Y.; Nakajima, S.; Sakata, I.; Ishida-Yamamoto, A.; Iizuka, H. Activation of two caspase cascades, caspase 8/3/6 and caspase 9/3/6, during photodynamic therapy using a novel photosensitizer, ATX-S10(Na), in normal human keratinocytes. Arch. Dermatol. Res. 2003, 295, 242–248. [Google Scholar] [CrossRef] [PubMed]
  25. Nowis, D.; Makowski, M.; Stokłosa, T.; Legat, M.; Issat, T.; Gołąb, J. Direct tumor damage mechanisms of photodynamic therapy. Acta Biochim. Pol. 2005, 25, 339–352. [Google Scholar] [CrossRef] [Green Version]
  26. Hypoxia Inducible Factor (HIF-1a and HIF-2a) Expression in Early Esophageal Cancer and Response to Photodynamic Therapy and Radiotherapy|Cancer Research|American Association for Cancer Research. Available online: https://aacrjournals.org/cancerres/article/61/5/1830/508681/Hypoxia-Inducible-Factor-HIF-1a-and-HIF-2a (accessed on 14 December 2021).
  27. Bechet, D.; Couleaud, P.; Frochot, C.; Viriot, M.-L.; Guillemin, F.; Barberi-Heyob, M. Nanoparticles as vehicles for delivery of photodynamic therapy agents. Trends Biotechnol. 2008, 26, 612–621. [Google Scholar] [CrossRef]
  28. Keene, J.P.; Kessel, D.; Land, E.J.; Redmond, R.W.; Truscott, T.G. Direct detection of singlet oxygen sensitized by haematoporphyrin and related compounds. Photochem. Photobiol. 1986, 43, 117–120. [Google Scholar] [CrossRef]
  29. Jain, R.; Pradhan, R.; Hejmady, S.; Singhvi, G.; Dubey, S.K. Fluorescence-based method for sensitive and rapid estimation of chlorin e6 in stealth liposomes for photodynamic therapy against cancer. Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 2020, 244, 118823. [Google Scholar] [CrossRef]
  30. Tsukagoshi, S. Porfimer sodium (Photofrin-II). Gan to Kagaku ryoho. Cancer Chemother. 1995, 22, 1271–1278. [Google Scholar]
  31. Photodynamic Therapy with Porfimer Sodium in Treating Patients With Precancerous Lesions, Cancer, or Other Disease of the Aerodigestive Tract—Full Text View—ClinicalTrials.Gov. Available online: https://clinicaltrials.gov/ct2/show/NCT00453336 (accessed on 22 August 2022).
  32. Hpph|C39H48N4O4—PubChem. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/Hpph#section=Names-and-Identifiers (accessed on 23 August 2022).
  33. Wu, D.; Liu, Z.; Fu, Y.; Zhang, Y.; Tang, N.; Wang, Q.; Tao, L. Efficacy of 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a in photodynamic therapy of human esophageal squamous cancer cells. Oncol. Lett. 2013, 6, 1111–1119. [Google Scholar] [CrossRef] [Green Version]
  34. AL(III) Phthalocyanine Chloride Tetrasulfonic Acid|C32H16AlClN8O12S4—PubChem. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/AL_III_-Phthalocyanine-chloride-tetrasulfonic-acid (accessed on 23 August 2022).
  35. Aluminum Phthalocyanine|C32H16AlN8+—PubChem. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/Aluminum-phthalocyanine (accessed on 23 August 2022).
  36. Osuchowski, M.; Bartusik-Aebisher, D.; Osuchowski, F.; Aebisher, D. Photodynamic therapy for prostate cancer—A narrative review. Photodiagn. Photodyn. Ther. 2020, 33, 102158. [Google Scholar] [CrossRef]
  37. Akimoto, J. Photodynamic Therapy for Malignant Brain Tumors. Neurol. Med.-Chir. 2016, 56, 151–157. [Google Scholar] [CrossRef] [Green Version]
  38. Aminolevulinic Acid Hydrochloride, Known as ALA HCl (Gleolan, NX Development Corp.) as an Optical Imaging Agent Indicated in Patients with Gliomas|FDA. Available online: https://www.fda.gov/drugs/resources-information-approved-drugs/aminolevulinic-acid-hydrochloride-known-ala-hcl-gleolan-nx-development-corp-optical-imaging-agent (accessed on 22 August 2022).
  39. An, J.S.; Kim, J.E.; Lee, D.H.; Kim, B.Y.; Cho, S.; Kwon, I.H.; Choi, W.W.; Kang, S.M.; Won, C.H.; Chang, S.E.; et al. 0.5% Liposome-encapsulated 5-aminolevulinic acid (ALA) photodynamic therapy for acne treatment. J. Cosmet. Laser Ther. 2011, 13, 28–32. [Google Scholar] [CrossRef] [PubMed]
  40. Schwake, M.; Schipmann, S.; Müther, M.; Köchling, M.; Brentrup, A.; Stummer, W. 5-ALA fluorescence–guided surgery in pediatric brain tumors—A systematic review. Acta Neurochir. 2019, 161, 1099–1108. [Google Scholar] [CrossRef] [PubMed]
  41. Hermann, G.G.; Mogensen, K.; Carlsson, S.; Marcussen, N.; Duun, S. Fluorescence-guided transurethral resection of bladder tumours reduces bladder tumour recurrence due to less residual tumour tissue in T a/T1 patients: A randomized two-centre study. BJU Int. 2011, 108, E297–E303. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. A Randomized, Comparative Study of Hexvix Fluorescence Cystoscopy and Standard Cystoscopy in Patients with Non-Invasive Bladder Cancer—Full Text View—ClinicalTrials.Gov. Available online: https://clinicaltrials.gov/ct2/show/NCT00412971 (accessed on 22 August 2022).
  43. Sharman, W.M.; Allen, C.M.; van Lier, J.E. Photodynamic therapeutics: Basic principles and clinical applications. Drug Discov. Today 1999, 4, 507–517. [Google Scholar] [CrossRef] [PubMed]
  44. Temoporfin|C44H32N4O4—PubChem. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/60751 (accessed on 23 August 2022).
  45. Konan, Y.N.; Gurny, R.; Allémann, E. State of the art in the delivery of photosensitizers for photodynamic therapy. J. Photochem. Photobiol. B Biol. 2002, 66, 89–106. [Google Scholar] [CrossRef]
  46. Lim, C.-K.; Heo, J.; Shin, S.; Jeong, K.; Seo, Y.H.; Jang, W.-D.; Park, C.R.; Park, S.Y.; Kim, S.; Kwon, I.C. Nanophotosensitizers toward advanced photodynamic therapy of Cancer. Cancer Lett. 2013, 334, 176–187. [Google Scholar] [CrossRef] [PubMed]
  47. Chen, J.; Fan, T.; Xie, Z.; Zeng, Q.; Xue, P.; Zheng, T.; Chen, Y.; Luo, X.; Zhang, H. Advances in nanomaterials for photodynamic therapy applications: Status and challenges. Biomaterials 2020, 237, 119827. [Google Scholar] [CrossRef]
  48. Chatterjee, D.K.; Fong, L.S.; Zhang, Y. Nanoparticles in photodynamic therapy: An emerging paradigm. Adv. Drug Deliv. Rev. 2008, 60, 1627–1637. [Google Scholar] [CrossRef]
  49. Abrahamse, H.; Kruger, C.A.; Kadanyo, S.; Mishra, A. Nanoparticles for Advanced Photodynamic Therapy of Cancer. Photomed. Laser Surg. 2017, 35, 581–588. [Google Scholar] [CrossRef]
  50. Maeda, H.; Wu, J.; Sawa, T.; Matsumura, Y.; Hori, K. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: A review. J. Control. Release 2000, 65, 271–284. [Google Scholar] [CrossRef]
  51. Paszko, E.; Ehrhardt, C.; Senge, M.O.; Kelleher, D.P.; Reynolds, J.V. Nanodrug applications in photodynamic therapy. Photodiagn. Photodyn. Ther. 2011, 8, 14–29. [Google Scholar] [CrossRef] [PubMed]
  52. Allison, R.; Mota, H.; Bagnato, V.; Sibata, C. Bio-nanotechnology and photodynamic therapy—State of the art review. Photodiagn. Photodyn. Ther. 2008, 5, 19–28. [Google Scholar] [CrossRef] [PubMed]
  53. Kadkhoda, J.; Tarighatnia, A.; Barar, J.; Aghanejad, A.; Davaran, S. Recent advances and trends in nanoparticles based photothermal and photodynamic therapy. Photodiagn. Photodyn. Ther. 2022, 37, 102697. [Google Scholar] [CrossRef] [PubMed]
  54. Lee, D.; Kwon, S.; Jang, S.-Y.; Park, E.; Lee, Y.; Koo, H. Overcoming the obstacles of current photodynamic therapy in tumors using nanoparticles. Bioact. Mater. 2021, 8, 20–34. [Google Scholar] [CrossRef]
  55. Kim, H.; Mun, S.; Choi, Y. Photosensitizer-conjugated polymeric nanoparticles for redox-responsive fluorescence imaging and photodynamic therapy. J. Mater. Chem. B 2012, 1, 429–431. [Google Scholar] [CrossRef]
  56. DeRycke, A.S.L. Liposomes for photodynamic therapy. Adv. Drug Deliv. Rev. 2004, 56, 17–30. [Google Scholar] [CrossRef]
  57. Van Nostrum, C.F. Polymeric micelles to deliver photosensitizers for photodynamic therapy. Adv. Drug Deliv. Rev. 2003, 56, 9–16. [Google Scholar] [CrossRef]
  58. Alivisatos, P. The use of nanocrystals in biological detection. Nat. Biotechnol. 2003, 22, 47–52. [Google Scholar] [CrossRef]
  59. Katz, E.; Willner, I. Integrated Nanoparticle-Biomolecule Hybrid Systems: Synthesis, Properties, and Applications. Angew. Chem. Int. Ed. 2004, 43, 6042–6108. [Google Scholar] [CrossRef]
  60. Naidoo, C.; Kruger, C.A.; Abrahamse, H. Photodynamic Therapy for Metastatic Melanoma Treatment: A Review. Technol. Cancer Res. Treat. 2018, 17, 1533033818791795. [Google Scholar] [CrossRef] [Green Version]
  61. Debele, T.A.; Peng, S.; Tsai, H.-C. Drug Carrier for Photodynamic Cancer Therapy. Int. J. Mol. Sci. 2015, 16, 22094–22136. [Google Scholar] [CrossRef] [PubMed]
  62. Hodgkinson, N.; Kruger, C.A.; Abrahamse, H. Targeted photodynamic therapy as potential treatment modality for the eradication of colon cancer and colon cancer stem cells. Tumor Biol. 2017, 39, 1–17. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Lin, L.; Xiong, L.; Wen, Y.; Lei, S.; Deng, X.; Liu, Z.; Chen, W.; Miao, X. Active Targeting of Nano-Photosensitizer Delivery Systems for Photodynamic Therapy of Cancer Stem Cells. J. Biomed. Nanotechnol. 2015, 11, 531–554. [Google Scholar] [CrossRef] [PubMed]
  64. Danhier, F.; Feron, O.; Préat, V. To exploit the tumor microenvironment: Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. J. Control. Release 2010, 148, 135–146. [Google Scholar] [CrossRef] [PubMed]
  65. Bugaj, A.M. Targeted photodynamic therapy—A promising strategy of tumor treatment. Photochem. Photobiol. Sci. 2011, 10, 1097–1109. [Google Scholar] [CrossRef]
  66. Zhang, C.; Chen, W.; Zhang, T.; Jiang, X.; Hu, Y. Hybrid nanoparticle composites applied to photodynamic therapy: Strategies and applications. J. Mater. Chem. B 2020, 8, 4726–4737. [Google Scholar] [CrossRef]
  67. Dos Santos, A.F.; Arini, G.S.; de Almeida, D.R.Q.; Labriola, L. Nanophotosensitizers for cancer therapy: A promising technology? J. Phys. Mater. 2021, 4, 032006. [Google Scholar] [CrossRef]
  68. Peer, D.; Karp, J.M.; Hong, S.; Farokhzad, O.C.; Margalit, R.; Langer, R. Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotechnol. 2007, 2, 751–760. [Google Scholar] [CrossRef]
  69. Ferrari, M. Cancer nanotechnology: Opportunities and challenges. Nat. Rev. Cancer 2005, 5, 161–171. [Google Scholar] [CrossRef]
  70. Singhvi, G.; Rapalli, V.K.; Nagpal, S.; Dubey, S.K.; Saha, R.N. Nanocarriers as Potential Targeted Drug Delivery for Cancer Therapy. In Nanoscience in Medicine; Springer: Cham, Switzerland, 2020; Volume 1, pp. 51–88. [Google Scholar] [CrossRef]
  71. Liao, Z.; Wong, S.W.; Yeo, H.L.; Zhao, Y. Smart nanocarriers for cancer treatment: Clinical impact and safety. NanoImpact 2020, 20, 100253. [Google Scholar] [CrossRef]
  72. Couvreur, P.; Vauthier, C. Nanotechnology: Intelligent Design to Treat Complex Disease. Pharm. Res. 2006, 23, 1417–1450. [Google Scholar] [CrossRef] [PubMed]
  73. Akhtar, M.J.; Ahamed, M.; Alhadlaq, H.A.; Alrokayan, S.A.; Kumar, S. Targeted anticancer therapy: Overexpressed receptors and nanotechnology. Clin. Chim. Acta 2014, 436, 78–92. [Google Scholar] [CrossRef] [PubMed]
  74. Wu, J.; Liu, Q.; Lee, R.J. A folate receptor-targeted liposomal formulation for paclitaxel. Int. J. Pharm. 2006, 316, 148–153. [Google Scholar] [CrossRef] [PubMed]
  75. Hejmady, S.; Pradhan, R.; Alexander, A.; Agrawal, M.; Singhvi, G.; Gorain, B.; Tiwari, S.; Kesharwani, P.; Dubey, S.K. Recent advances in targeted nanomedicine as promising antitumor therapeutics. Drug Discov. Today 2020, 25, 2227–2244. [Google Scholar] [CrossRef] [PubMed]
  76. Chang, M.-H.; Pai, C.-L.; Chen, Y.-C.; Yu, H.-P.; Hsu, C.-Y.; Lai, P.-S. Enhanced Antitumor Effects of Epidermal Growth Factor Receptor Targetable Cetuximab-Conjugated Polymeric Micelles for Photodynamic Therapy. Nanomaterials 2018, 8, 121. [Google Scholar] [CrossRef] [Green Version]
  77. Lin, X.; Yan, S.-Z.; Qi, S.-S.; Xu, Q.; Han, S.-S.; Guo, L.-Y.; Zhao, N.; Chen, S.-L.; Yu, S.-Q. Transferrin-Modified Nanoparticles for Photodynamic Therapy Enhance the Antitumor Efficacy of Hypocrellin A. Front. Pharmacol. 2017, 8, 815. [Google Scholar] [CrossRef]
  78. Syu, W.-J.; Yu, H.-P.; Hsu, C.-Y.; Rajan, Y.C.; Hsu, Y.-H.; Chang, Y.-C.; Hsieh, W.-Y.; Wang, C.-H.; Lai, P.-S. Improved Photodynamic Cancer Treatment by Folate-Conjugated Polymeric Micelles in a KB Xenografted Animal Model. Small 2012, 8, 2060–2069. [Google Scholar] [CrossRef]
  79. Kato, T.; Jin, C.S.; Ujiie, H.; Lee, D.; Fujino, K.; Wada, H.; Hu, H.-P.; Weersink, R.A.; Chen, J.; Kaji, M.; et al. Nanoparticle targeted folate receptor 1-enhanced photodynamic therapy for lung cancer. Lung Cancer 2017, 113, 59–68. [Google Scholar] [CrossRef] [Green Version]
  80. Zhang, D.; Zheng, A.; Li, J.; Wu, M.; Wu, L.; Wei, Z.; Liao, N.; Zhang, X.; Cai, Z.; Yang, H.; et al. Smart Cu(II)-aptamer complexes based gold nanoplatform for tumor micro-environment triggered programmable intracellular prodrug release, photodynamic treatment and aggregation induced photothermal therapy of hepatocellular carcinoma. Theranostics 2017, 7, 164–179. [Google Scholar] [CrossRef]
  81. Lucky, S.S.; Idris, N.M.; Huang, K.; Kim, J.; Li, Z.; Thong, P.S.P.; Xu, R.; Soo, K.C.; Zhang, Y. In vivo Biocompatibility, Biodistribution and Therapeutic Efficiency of Titania Coated Upconversion Nanoparticles for Photodynamic Therapy of Solid Oral Cancers. Theranostics 2016, 6, 1844–1865. [Google Scholar] [CrossRef]
  82. Wang, M.; You, C.; Gao, Z.; Wu, H.; Sun, B.; Zhu, X.; Chen, R. A dual-targeting strategy for enhanced drug delivery and synergistic therapy based on thermosensitive nanoparticles. J. Biomater. Sci. Polym. Ed. 2018, 29, 1360–1374. [Google Scholar] [CrossRef]
  83. Tan, X.; Pang, X.; Lei, M.; Ma, M.; Guo, F.; Wang, J.; Yu, M.; Tan, F.; Li, N. An efficient dual-loaded multifunctional nanocarrier for combined photothermal and photodynamic therapy based on copper sulfide and chlorin e6. Int. J. Pharm. 2016, 503, 220–228. [Google Scholar] [CrossRef]
  84. Sun, B.; Wang, L.; Li, Q.; He, P.; Liu, H.; Wang, H.; Yang, Y.; Li, J. Bis(pyrene)-Doped Cationic Dipeptide Nanoparticles for Two-Photon-Activated Photodynamic Therapy. Biomacromolecules 2017, 18, 3506–3513. [Google Scholar] [CrossRef] [PubMed]
  85. Tsai, W.-H.; Yu, K.-H.; Huang, Y.-C.; Lee, C.-I. EGFR-targeted photodynamic therapy by curcumin-encapsulated chitosan/TPP nanoparticles. Int. J. Nanomed. 2018, ume 13, 903–916. [Google Scholar] [CrossRef] [Green Version]
  86. Rad, J.K.; Mahdavian, A.R.; Khoei, S.; Shirvalilou, S. Enhanced Photogeneration of Reactive Oxygen Species and Targeted Photothermal Therapy of C6 Glioma Brain Cancer Cells by Folate-Conjugated Gold–Photoactive Polymer Nanoparticles. ACS Appl. Mater. Interfaces 2018, 10, 19483–19493. [Google Scholar] [CrossRef]
  87. Hah, H.J.; Kim, G.; Orringer, D.A.; Sagher, O.; Philbert, M.A.; Kopelman, R.; Lee, Y.-E.K. Methylene Blue-Conjugated Hydrogel Nanoparticles and Tumor-Cell Targeted Photodynamic Therapy. Macromol. Biosci. 2011, 11, 90–99. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Bharathiraja, S.; Moorthy, M.S.; Manivasagan, P.; Seo, H.; Lee, K.D.; Oh, J. Chlorin e6 conjugated silica nanoparticles for targeted and effective photodynamic therapy. Photodiagn. Photodyn. Ther. 2017, 19, 212–220. [Google Scholar] [CrossRef] [PubMed]
  89. Montaseri, H.; Kruger, C.; Abrahamse, H. Inorganic Nanoparticles Applied for Active Targeted Photodynamic Therapy of Breast Cancer. Pharmaceutics 2021, 13, 296. [Google Scholar] [CrossRef] [PubMed]
  90. Yi, G.; Hong, S.H.; Son, J.; Yoo, J.; Park, C.; Choi, Y.; Koo, H. Recent advances in nanoparticle carriers for photodynamic therapy. Quant. Imaging Med. Surg. 2018, 8, 433–443. [Google Scholar] [CrossRef]
  91. Lucky, S.S.; Soo, K.C.; Zhang, Y. Nanoparticles in Photodynamic Therapy. Chem. Rev. 2015, 115, 1990–2042. [Google Scholar] [CrossRef]
  92. Bayir, S.; Barras, A.; Boukherroub, R.; Szunerits, S.; Raehm, L.; Richeter, S.; Durand, J.-O. Mesoporous silica nanoparticles in recent photodynamic therapy applications. Photochem. Photobiol. Sci. 2018, 17, 1651–1674. [Google Scholar] [CrossRef]
  93. Er, Ö.; Colak, S.; Ocakoglu, K.; Ince, M.; Bresolí-Obach, R.; Mora, M.; Sagristá, M.; Yurt, F.; Nonell, S. Selective Photokilling of Human Pancreatic Cancer Cells Using Cetuximab-Targeted Mesoporous Silica Nanoparticles for Delivery of Zinc Phthalocyanine. Molecules 2018, 23, 2749. [Google Scholar] [CrossRef] [Green Version]
  94. Planas, O.; Bresolí-Obach, R.; Nos, J.; Gallavardin, T.; Ruiz-González, R.; Agut, M.; Nonell, S. Synthesis, Photophysical Characterization, and Photoinduced Antibacterial Activity of Methylene Blue-loaded Amino- and Mannose-Targeted Mesoporous Silica Nanoparticles. Molecules 2015, 20, 6284–6298. [Google Scholar] [CrossRef] [Green Version]
  95. Ma, X.; Qu, Q.; Zhao, Y. Targeted Delivery of 5-Aminolevulinic Acid by Multifunctional Hollow Mesoporous Silica Nanoparticles for Photodynamic Skin Cancer Therapy. ACS Appl. Mater. Interfaces 2015, 7, 10671–10676. [Google Scholar] [CrossRef]
  96. Calavia, P.G.; Bruce, G.; Pérez-García, L.; Russell, D.A. Photosensitiser-gold nanoparticle conjugates for photodynamic therapy of cancer. Photochem. Photobiol. Sci. 2018, 17, 1534–1552. [Google Scholar] [CrossRef] [Green Version]
  97. Goddard, Z.R.; Beekman, A.M.; Cominetti, M.M.D.; O’Connell, M.A.; Chambrier, I.; Cook, M.J.; Marín, M.J.; Russell, D.A.; Searcey, M. Peptide directed phthalocyanine–gold nanoparticles for selective photodynamic therapy of EGFR overexpressing cancers. RSC Med. Chem. 2020, 12, 288–292. [Google Scholar] [CrossRef]
  98. Shiao, Y.-S.; Chiu, H.-H.; Wu, P.-H.; Huang, Y.-F. Aptamer-Functionalized Gold Nanoparticles as Photoresponsive Nanoplatform for Co-Drug Delivery. ACS Appl. Mater. Interfaces 2014, 6, 21832–21841. [Google Scholar] [CrossRef]
  99. Sundaram, P.; Abrahamse, H. Phototherapy Combined with Carbon Nanomaterials (1D and 2D) and their Applications in Cancer Therapy. Materials 2020, 13, 4830. [Google Scholar] [CrossRef]
  100. Lu, D.; Tao, R.; Wang, Z. Carbon-based materials for photodynamic therapy: A mini-review. Front. Chem. Sci. Eng. 2018, 13, 310–323. [Google Scholar] [CrossRef]
  101. Wang, L.; Shi, J.; Liu, R.; Liu, Y.; Zhang, J.; Yu, X.; Gao, J.; Zhang, C.; Zhang, Z. Photodynamic effect of functionalized single-walled carbon nanotubes: A potential sensitizer for photodynamic therapy. Nanoscale 2014, 6, 4642–4651. [Google Scholar] [CrossRef]
  102. Ruan, H.; Li, H.; Li, Q. Nanocarbon Materials for Photodynamic Therapy and Photothermal Therapy. Pharm. Nanotechnol. 2014, 2, 58–64. [Google Scholar] [CrossRef]
  103. Zhang, M.; Wang, W.; Cui, Y.; Chu, X.; Sun, B.; Zhou, N.; Shen, J. Magnetofluorescent Fe3O4/carbon quantum dots coated single-walled carbon nanotubes as dual-modal targeted imaging and chemo/photodynamic/photothermal triple-modal therapeutic agents. Chem. Eng. J. 2018, 338, 526–538. [Google Scholar] [CrossRef]
  104. Shi, J.; Ma, R.; Wang, L.; Zhang, J.; Liu, R.; Liu, Y.; Yu, X.; Gao, J.; Li, L.; Hou, L.; et al. The application of hyaluronic acid-derivatized carbon nanotubes in hematoporphyrin monomethyl ether-based photodynamic therapy for in vivo and in vitro cancer treatment. Int. J. Nanomed. 2013, 8, 2361–2373. [Google Scholar] [CrossRef] [Green Version]
  105. Huang, Y.; Sharma, S.K.; Ying-Ying, H.; Agrawal, T.; Chiang, L.Y.; Hamblin, M.R. Functionalized Fullerenes in Photodynamic Therapy. J. Biomed. Nanotechnol. 2014, 10, 1918–1936. [Google Scholar] [CrossRef]
  106. Mroz, P.; Tegos, G.P.; Gali, H.; Wharton, T.; Sarna, T.; Hamblin, M.R. Photodynamic therapy with fullerenes. Photochem. Photobiol. Sci. 2007, 6, 1139–1149. [Google Scholar] [CrossRef] [Green Version]
  107. Liu, Q.; Xu, L.; Zhang, X.; Li, N.; Zheng, J.; Guan, M.; Fang, X.; Wang, C.; Shu, C. Enhanced Photodynamic Efficiency of an Aptamer-Guided Fullerene Photosensitizer toward Tumor Cells. Chem. Asian J. 2013, 8, 2370–2376. [Google Scholar] [CrossRef]
  108. Zhang, Y.; Zhang, H.; Zou, Q.; Xing, R.; Jiao, T.; Yan, X. An injectable dipeptide–fullerene supramolecular hydrogel for photodynamic antibacterial therapy. J. Mater. Chem. B 2018, 6, 7335–7342. [Google Scholar] [CrossRef]
  109. Shi, J.; Wang, B.; Wang, L.; Lu, T.; Fu, Y.; Zhang, H.; Zhang, Z. Fullerene (C 60)-based tumor-targeting nanoparticles with “off-on” state for enhanced treatment of cancer. J. Control. Release 2016, 235, 245–258. [Google Scholar] [CrossRef]
  110. Jaleel, J.A.; Sruthi, S.; Pramod, K. Reinforcing nanomedicine using graphene family nanomaterials. J. Control. Release 2017, 255, 218–230. [Google Scholar] [CrossRef]
  111. Shi, D.; Li, Y.; Dong, H.; Li, Y. Graphene-based nanovehicles for photodynamic medical therapy. Int. J. Nanomed. 2015, 4, 2451–2459. [Google Scholar] [CrossRef]
  112. Huang, P.; Xu, C.; Lin, J.; Wang, C.; Wang, X.; Zhang, C.; Zhou, X.; Guo, S.; Cui, D. Folic Acid-conjugated Graphene Oxide loaded with Photosensitizers for Targeting Photodynamic Therapy. Theranostics 2011, 1, 240–250. [Google Scholar] [CrossRef] [PubMed]
  113. Mukherjee, S.; Liang, L.; Veiseh, O. Recent Advancements of Magnetic Nanomaterials in Cancer Therapy. Pharmaceutics 2020, 12, 147. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Zeng, L.; Luo, L.; Pan, Y.; Luo, S.; Lu, G.; Wu, A. In vivo targeted magnetic resonance imaging and visualized photodynamic therapy in deep-tissue cancers using folic acid-functionalized superparamagnetic-upconversion nanocomposites. Nanoscale 2015, 7, 8946–8954. [Google Scholar] [CrossRef]
  115. Patel, K.; Raj, B.S.; Chen, Y.; Lou, X. Novel folic acid conjugated Fe3O4 -ZnO hybrid nanoparticles for targeted photodynamic therapy. Colloids Surf. B Biointerfaces 2017, 150, 317–325. [Google Scholar] [CrossRef] [PubMed]
  116. Samia, A.C.S.; Chen, X.; Burda, C. Semiconductor Quantum Dots for Photodynamic Therapy. J. Am. Chem. Soc. 2003, 125, 15736–15737. [Google Scholar] [CrossRef]
  117. Li, M.-M.; Cao, J.; Yang, J.-C.; Shen, Y.-J.; Cai, X.-L.; Chen, Y.-W.; Qu, C.-Y.; Zhang, Y.; Shen, F.; Xu, L.-M. Effects of arginine–glycine–aspartic acid peptide-conjugated quantum dots-induced photodynamic therapy on pancreatic carcinoma in vivo. Int. J. Nanomed. 2017, ume 12, 2769–2779. [Google Scholar] [CrossRef] [Green Version]
  118. Cao, Y.; Dong, H.; Yang, Z.; Zhong, X.; Chen, Y.; Dai, W.; Zhang, X. Aptamer-Conjugated Graphene Quantum Dots/Porphyrin Derivative Theranostic Agent for Intracellular Cancer-Related MicroRNA Detection and Fluorescence-Guided Photothermal/Photodynamic Synergetic Therapy. ACS Appl. Mater. Interfaces 2016, 9, 159–166. [Google Scholar] [CrossRef]
  119. Montaseri, H.; Kruger, C.A.; Abrahamse, H. Review: Organic nanoparticle based active targeting for photodynamic therapy treatment of breast cancer cells. Oncotarget 2020, 11, 2120–2136. [Google Scholar] [CrossRef]
  120. Jin, C.S.; Zheng, G. Liposomal nanostructures for photosensitizer delivery. Lasers Surg. Med. 2011, 43, 734–748. [Google Scholar] [CrossRef]
  121. Huang, X.; Chen, L.; Zhang, Y.; Zhou, S.; Cai, H.-H.; Li, T.; Jin, H.; Cai, J.; Zhou, H.; Pi, J. GE11 Peptide Conjugated Liposomes for EGFR-Targeted and Chemophotothermal Combined Anticancer Therapy. Bioinorg. Chem. Appl. 2021, 2021, 1–15. [Google Scholar] [CrossRef]
  122. Broekgaarden, M.; van Vught, R.; Oliveira, S.; Roovers, R.C.; Henegouwen, P.M.P.V.B.E.; Pieters, R.J.; Van Gulik, T.M.; Breukink, E.; Heger, M. Site-specific conjugation of single domain antibodies to liposomes enhances photosensitizer uptake and photodynamic therapy efficacy. Nanoscale 2016, 8, 6490–6494. [Google Scholar] [CrossRef]
  123. Anilkumar, T.; Lu, Y.-J.; Chen, H.-A.; Hsu, H.-L.; Jose, G.; Chen, J.-P. Dual targeted magnetic photosensitive liposomes for photothermal/photodynamic tumor therapy. J. Magn. Magn. Mater. 2018, 473, 241–252. [Google Scholar] [CrossRef]
  124. Wöhrle, D.; Shopova, M.; Müller, S.; Milev, A.; Mantareva, V.; Krastev, K. Liposome-delivered Zn(II)-2,3-naphthalocyanines as potential sensitizers for PDT: Synthesis, photochemical, pharmacokinetic and phototherapeutic studies. J. Photochem. Photobiol. B Biol. 1993, 21, 155–165. [Google Scholar] [CrossRef]
  125. Reddi, E.; Zhou, C.; Biolo, R.; Menegaldo, E.; Jori, G. Liposome- or LDL-administered Zn (II)-phthalocyanine as a photodynamic agent for tumours. I. Pharmacokinetic properties and phototherapeutic efficiency. Br. J. Cancer 1990, 61, 407–411. [Google Scholar] [CrossRef] [Green Version]
  126. Navarro, F.P.; Creusat, G.; Frochot, C.; Moussaron, A.; Verhille, M.; Vanderesse, R.; Thomann, J.-S.; Boisseau, P.; Texier, I.; Couffin, A.-C.; et al. Preparation and characterization of mTHPC-loaded solid lipid nanoparticles for photodynamic therapy. J. Photochem. Photobiol. B Biol. 2014, 130, 161–169. [Google Scholar] [CrossRef]
  127. Gibot, L.; Demazeau, M.; Pimienta, V.; Mingotaud, A.-F.; Vicendo, P.; Collin, F.; Martins-Froment, N.; Dejean, S.; Nottelet, B.; Roux, C.; et al. Role of Polymer Micelles in the Delivery of Photodynamic Therapy Agent to Liposomes and Cells. Cancers 2020, 12, 384. [Google Scholar] [CrossRef] [Green Version]
  128. Lamch, L.; Kulbacka, J.; Dubińska-Magiera, M.; Saczko, J.; Wilk, K.A. Folate-directed zinc (II) phthalocyanine loaded polymeric micelles engineered to generate reactive oxygen species for efficacious photodynamic therapy of cancer. Photodiagn. Photodyn. Ther. 2019, 25, 480–491. [Google Scholar] [CrossRef]
  129. Liu, Y.; Scrivano, L.; Peterson, J.D.; Fens, M.H.A.M.; Hernández, I.B.; Mesquita, B.; Toraño, J.S.; Hennink, W.E.; Van Nostrum, C.F.; Oliveira, S. EGFR-Targeted Nanobody Functionalized Polymeric Micelles Loaded with mTHPC for Selective Photodynamic Therapy. Mol. Pharm. 2020, 17, 1276–1292. [Google Scholar] [CrossRef] [Green Version]
  130. Lu, L.; Zhao, X.; Fu, T.; Li, K.; He, Y.; Luo, Z.; Dai, L.; Zeng, R.; Cai, K. An iRGD-conjugated prodrug micelle with blood-brain-barrier penetrability for anti-glioma therapy. Biomaterials 2019, 230, 119666. [Google Scholar] [CrossRef]
  131. Study Record|Beta ClinicalTrials.Gov. Available online: https://beta.clinicaltrials.gov/study/NCT01673074?distance=50&term=PDT&cond=cancer&rank=2 (accessed on 22 October 2022).
  132. Study Record|Beta ClinicalTrials.Gov. Available online: https://beta.clinicaltrials.gov/study/NCT01256424?distance=50&term=PDT&cond=cancer&rank=3%5D (accessed on 22 October 2022).
  133. Kydd, J.; Jadia, R.; Velpurisiva, P.; Gad, A.; Paliwal, S.; Rai, P. Targeting Strategies for the Combination Treatment of Cancer Using Drug Delivery Systems. Pharmaceutics 2017, 9, 46. [Google Scholar] [CrossRef] [Green Version]
  134. John, J.V.; Chung, C.-W.; Johnson, R.P.; Jeong, Y.-I.; Chung, K.-D.; Kang, D.H.; Suh, H.; Chen, H.; Kim, I. Dual Stimuli-Responsive Vesicular Nanospheres Fabricated by Lipopolymer Hybrids for Tumor-Targeted Photodynamic Therapy. Biomacromolecules 2015, 17, 20–31. [Google Scholar] [CrossRef]
  135. Zhao, C.; Lu, X.; Li, N.; Yang, G. Natural radioactivity measurements of building materials in Baotou, China. Radiat. Prot. Dosim. 2012, 152, 434–437. [Google Scholar] [CrossRef]
Pharmaceutics 15 00109 g001 550
Figure 1. A general application of photodynamic therapy on solid tumors. Once the actively targeted nanoparticles enter the blood circulation, they are transported to the specific site of the tumor. The laser light irradiates the photosensitizer and activates the actively targeted nanoparticles in the tumor. Then, the photosensitizer molecules produce the singlet oxygen to kill the cancer cells by the mechanisms of apoptosis, autophagy, and necrosis, depending on the location of the photosensitizer in the tumor.
Figure 1. A general application of photodynamic therapy on solid tumors. Once the actively targeted nanoparticles enter the blood circulation, they are transported to the specific site of the tumor. The laser light irradiates the photosensitizer and activates the actively targeted nanoparticles in the tumor. Then, the photosensitizer molecules produce the singlet oxygen to kill the cancer cells by the mechanisms of apoptosis, autophagy, and necrosis, depending on the location of the photosensitizer in the tumor.
Pharmaceutics 15 00109 g001
Pharmaceutics 15 00109 g002 550
Figure 2. All the cellular organelles are depicted in this image. Upon irradiation, the PS molecules become activated and result in phototoxicity or death to the tumor tissue or cells through different mechanisms such as apoptosis, autophagy, and necrosis, depending on the internalization and localization of PS molecules into tumor tissues.
Figure 2. All the cellular organelles are depicted in this image. Upon irradiation, the PS molecules become activated and result in phototoxicity or death to the tumor tissue or cells through different mechanisms such as apoptosis, autophagy, and necrosis, depending on the internalization and localization of PS molecules into tumor tissues.
Pharmaceutics 15 00109 g002
Table
Table 1. Represents the clinical trials and approval status of various photosensitizers [30,31,32,33,34,35,36,37,38,39,40,41,42,43,44].
Table 1. Represents the clinical trials and approval status of various photosensitizers [30,31,32,33,34,35,36,37,38,39,40,41,42,43,44].
Sr. NoPhotosensitizer with Generic Name Chemical Structure Activation Wavelength Clinical Outcomes References
1Porfimer Sodium (Photofrin)Pharmaceutics 15 00109 i001630 nm Approved for bladder cancer, endobronchial cancer, esophageal cancer, lung cancer, and cervical cancer
In clinical trial-brain cancer diagnosis		[30,31,37]
25-Aminolevulinic acid (Levulan and Ameluz)Pharmaceutics 15 00109 i002635 nm Approved for non-melanoma skin cancers
In clinical trial-brain cancer diagnosis 		[38,39,40]
3Hexaminolevulinate hydrochloride (Hexvix®)Pharmaceutics 15 00109 i003635 nm Bladder cancer diagnosis[41,42]
45,10,15,20-Tetrakis(3-hydroxyphenyl) chlorin/Temoporfin (Foscan)Pharmaceutics 15 00109 i004652 nm Approved for head and neck cancer, prostate, and pancreatic cancer[43,44]
52-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH)
(PhotoChlor)		Pharmaceutics 15 00109 i005665 nm In clinical trial-basal cell carcinoma, esophagus, mouth, and throat cancers, cervical intraepithelial neoplasia[32,33]
6Aluminum phthalocyanine tetrasulfonate chloride (Photosens)Pharmaceutics 15 00109 i006676 nm Approved—Russia
In clinical trials-stomach, skin, oral, and breast cancers		[34,35]
7Palladium-Bacteriopheophorbde (WST09)/Padoporfin (Tookad)Pharmaceutics 15 00109 i007763 nm Approved for prostate cancer in Mexico, Israel and 31 countries of the European Union[36]
Table
Table 2. Examples of recent major outcomes on nanoparticles-mediated photosensitizer delivery to the tumor by utilizing the overexpressed receptors site and their ligand.
Table 2. Examples of recent major outcomes on nanoparticles-mediated photosensitizer delivery to the tumor by utilizing the overexpressed receptors site and their ligand.
Nanocarriers SystemPhotosensitizerTumor over
Expression
Receptor		Cancer Cell Lines/
Tumor Model		Major OutcomesRef
Methoxypoly(ethylene glycol)-poly(dl-lacticacid) (mPEG-b-PLA)
Polymeric micelles		Chlorin e6 EGFR Receptor A431 squamous carcinoma cell line
& Xenografted mice model		Enhanced PDT effect and uptake with a targeting moiety, percentage of tumor growth inhibition (%TGI) was found to be (84%).[76]
Poly(D,L-Lactide-co-glycolide
(PLGA) & carboxymethyl
chitosan (CMC)
nanoparticle		Hypocrellin A (HA)Transferrin-receptor A549 human lung adenocarcinoma
cell line & A549 tumor-bearing model
Transferrin-receptor (TFR) positive		The tumor inhibition rate was found to be 63% for 15 days of Photodynamic therapy (PDT) treatment in tumor bearing mouse model.[77]
Polymeric micellesMeta-tetrahydroxyphenyl
chlorin (m-THPC)		Folic acid receptorKB oral cancer cell line & Xenografted animal modelm-THPC-loaded micelles were prepared by using a poly (2-ethyl-2-oxazoline)- b -poly(d, l -lactide) (PEOz-PLA) copolymer.
A single dose of m-THPC with folic acid attached to polymeric micelles has shown antitumor effect against KB oral cancer cell line.
% TGI rate was found to be 92% and an enhanced PDT effect was observed.		[78]
Porphyrin-lipid
(porphysomes)		Porphyrin moleculeFolate receptor 1
(FOLR 1)		A549 & SBC5 lung cancer cells &
mouse lung orthotopic tumor
models		Porphyrin molecule lipid-based active targeted nanoparticle was prepared to enhance the efficacy and specificity of PDT by using FOLR 1. Folate-based porphysomes PDT significantly inhibited cell proliferation in lung cancer. [79]
Gold Nanoparticles
(Smart Cu(II)-aptamer complexes-based gold) 		Chlorin e6 Specific targeting
aptamers-TLS11a		Hepatocellular carcinoma
cell line HepG2 and xenografted mouse model		These smart gold nanoparticles were fabricated for the programable synergistic targeted PDT therapy/Phototheramal therapy (PTT)/chemotherapy functionalities, to provide a synergistic effect for the treatment of hepatocellular carcinoma. [80]
Titania Coated Upconversion NP Titanium dioxide (TiO2) poly ethylene glycol (PEG)up conversionChlorin e6 EGFR ReceptorCAL-27 oral squamous cell
carcinoma (OSCC) & xenograft
oral cancer tumor mouse model		Anti-EGFR-PEG-TiO2- upconversion nanoparticles as NIR PDT agents were fabricated for oral cancer. Enhanced intratumoral delivery and penetration to the deep thick tumor of head and neck cancer.[81]
Polymeric NPChlorin e6 and Indocyanine green Folic acid receptor and cyclic Arginyl-glycyl-aspartic acid (cRGD) targeting peptides MCF-7 human breast cancer cell lines The combination of PDT and Photothermal therapy has been proved to have the potential for tumor inhibition. Tumor apoptosis was found to be 85.9%.[82]
Thermosensitive
liposomes (TSL) 		Chlorin e6Folic acid receptorHuman cervical carcinoma (HeLa)
cells & tumor mouse model		Thermosensitive dual drug-loaded nanocarrier for PDT with Photothermal therapy were prepared to utilize copper sulfide (CuS) and chlorin e6. Enhanced PDT effect and cellular uptake along with the controlled release of PS were observed.
Higher phototoxicity and tumor inhibition was found.		[83]
Cationic
dipeptide nanoparticle 		Rose Bengal (RB) and bis(pyrene) (BP)Cationic dipeptide (H-Phe-Phe-NH2_HCl,CDP)MCF-7 breast cancer(BP-CDPNP-RB) cationic dipeptide was fabricated for the one or two-photon-induced PDT therapy. Biocompatible and exhibit higher penetrability in tissue and enhances cellular uptake.[84]
Chitosan/tripolyphosphate (TTP)CurcuminEGFR receptorMKN45 human gastric cancer cellsEnhanced PDT effect, Curcumin nanoparticles were quickly taken up by the EGFR-overexpression cells. [85]
Gold–Photoactive Polymer Nanoparticles
(Gold acrylic copolymer
with imidazole groups)		Spiropyran (SP) Folic acid receptorRat brain C6 glioma cancer cell linePhoto responsive gold-decorated polymer nanoparticles (PGPNPs) were fabricated for improved PDT therapy and targeted efficiency towards rat brain cancer cell lines along with improved cellular uptake by 71.8%.[86]
Polyacrylamide NPMethylene blue (MB)F3 peptidesGS-9L & F98 rat glioma &
MDA-MB-435 human breast
carcinoma cell lines		Tumor targeting MB-conjugated polyacrylamide nanoparticles were fabricated and used for active targeting, Results shows, that enhanced targeting effect and PDT efficacy with increasing dose and irradiation time.[87]
Silica-basedChlorin e6Folic acid receptorHuman breast MDA-MB-231
cancer cells		Silica NPs were fabricated and coated with chlorin e6 and folic acid as a targeting agent. Results show that PDT and cellular uptake have been enhanced.[88]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Jain, R.; Mohanty, S.; Sarode, I.; Biswas, S.; Singhvi, G.; Dubey, S.K. Multifunctional Photoactive Nanomaterials for Photodynamic Therapy against Tumor: Recent Advancements and Perspectives. Pharmaceutics 2023, 15, 109. https://doi.org/10.3390/pharmaceutics15010109

AMA Style

Jain R, Mohanty S, Sarode I, Biswas S, Singhvi G, Dubey SK. Multifunctional Photoactive Nanomaterials for Photodynamic Therapy against Tumor: Recent Advancements and Perspectives. Pharmaceutics. 2023; 15(1):109. https://doi.org/10.3390/pharmaceutics15010109

Chicago/Turabian Style

Jain, Rupesh, Shambo Mohanty, Ila Sarode, Swati Biswas, Gautam Singhvi, and Sunil Kumar Dubey. 2023. "Multifunctional Photoactive Nanomaterials for Photodynamic Therapy against Tumor: Recent Advancements and Perspectives" Pharmaceutics 15, no. 1: 109. https://doi.org/10.3390/pharmaceutics15010109

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop