Polymeric Nanomicelles for Cancer Nanomedicine—Review ^†

Abstract

Cancer is a serious risk to human life. Some predictions show a considerable increase in new cases and deaths by 2050. Chemotherapy and other conventional treatments encounter issues with a lack of specificity, leading to severe side effects on healthy tissues and drug resistance. Nanotechnology with targeted drug delivery shows improved diagnostics and personalized treatments. Biocompatible and biodegradable self-assembling amphiphilic polymeric micelles are attractive vehicles for targeted drug delivery in cancer treatment, increasing the bioavailability and solubility of anticancer drugs in water. However, the transition to market applications faces some difficulties, mainly focused on patients’ predisposition to develop drug allergies. Intensive studies are a paradigm for resolving all challenges and facilitating the translation of innovative nanotechnologies into everyday clinical practice. This review paper highlights the importance of applying organic polymeric nanocarriers in cancer nanomedicine.

1. Introduction

Cancer is a disease usually characterized by the rapid proliferation of abnormal cells attacking nearby tissues and spreading to other organs. This process is known as metastasis and is the primary cause of death [1].

Globally, cancer stands as a significant contributor to mortality, with roughly 9.75 million deaths out of about 20 million cases of cancer in 2022. Prognoses predict an increase in new cancer diseases to approximately 24 million, with around 11.9 million fatalities by 2030, with a further rise to around 33 million new cases and about 18 million mortalities by 2050. Estimations are that the percentage of deaths from around 49% of new cancer cases in 2022 will rise to approximately 55% in 2050. Early detection is pivotal in reducing cancer-related mortality, comprising two key components: early diagnosis (screening) and treatment [2].

As projected by the International Agency for Research on Cancer [2], the most frequent cancer sites/types are the lungs, trachea and bronchus, breasts, colorectum, prostate, and non-melanoma skin cancer [2].

Cancer treatment strategies used in the past, implementing cytostatic agents, affected only highly proliferative tumor cells without considering their significant heterogeneity. Bulk cancer cells and a small subset known as cancer stem cells (CSCs) contribute to this heterogeneity, including the tumor microenvironment (TME) consisting of non-cancerous cells producing factors and proteins that facilitate the cancer cell growth [3]. This diversity poses a significant challenge, limiting the therapeutic effectiveness of many drugs and contributing to the severity of the disease [3]. Many efforts [4,5,6,7] have been undertaken to comprehend these complex scenarios and devise precise and efficient therapies that target different components, aiming to enhance the overall clinical impact of cancer treatments. These forms of treatment include targeting cancer stem cells in TME [4,5], targeting tumor stroma in TME [6], and targeting metastasis-initiating cells [7].

After cancer diagnosis, a conventional treatment involves the use of combined therapies, starting with surgery, followed by chemotherapy and/or radiotherapy, targeted therapy, immunotherapy, and hormone therapy [8]. Chemotherapy and/or radiotherapy with X-rays are the most recommended conventional approaches [9].

Traditional cancer therapy still faces the challenges of achieving optimal results [9]. Conventional chemotherapeutic drugs do not possess selectivity toward cells and spread throughout the body without differentiating between healthy and damaged tissues. This lack of specificity leads to the development of severe and undesirable side effects, but the emergence of multiple drug resistances can also occur [3].

Nanotechnology provides a means to specifically target therapies to cancerous cells and neoplasms, guide the surgical removal of tumors, and enhance the effectiveness of radiation-based treatments [10]. It also offers a unique set of tools to overcome drug resistance and facilitate the use of novel immunotherapies. Together, these advancements reduce the patient’s risk and increase the likelihood of successful treatment [11].

Numerous researchers are actively developing nanomaterial-based delivery platforms to enhance the efficacy of chemotherapy while mitigating its toxicity [12,13]. For instance, a tailored strategy for photodynamic therapy designed for bone marrow application is under development [14]. This is especially significant in areas typically inaccessible to external radiation sources. On the other hand, to advance cancer diagnostics and therapeutics, others are focused on the determination of the fundamental interactions between nanomaterials and biological systems [15]. This involves a specific focus on nanoparticle-driven drug delivery systems capable of overcoming physiological barriers to attain targeted access to specific tumors [11] and reducing harm to healthy tissues [16]. However, for the utilization of the maximal system potential, the concern related to drug resistance must be addressed [12]. Scientists are actively exploring strategies to overcome drug resistance and enhance the effectiveness of these systems. Combination therapies involve the simultaneous delivery of multiple drugs using nanoparticle-based systems, targeting diverse pathways and mechanisms of drug resistance [17]. Engineered nanoparticles release drugs in a controlled manner providing sustained drug levels bypassing the drug resistance within cancer cells, enabling the selective targeting of cancer cells while sparing healthy tissues and, at the same time, stimulating the optimal therapeutic effects [12,18]. This presents an encouraging avenue for developing more personalized and effective cancer treatments in the future [13]. In this regard, one of the most promising nanoparticles achieving the satisfactory functions of the nanocarriers are polymeric nanomicelles [19]. Therefore, further discussion will focus on current and future research related to nanoparticles and their application in cancer nanomedicine, centering on polymeric micelles. Yet, the implications they can trigger and the restrictions of their application in clinical trials will also be elaborated. This review focused mainly on articles published between 2019 and 2024, using PubMed, ScienceOpen, Scopus, Science Direct, and Science Citation Index (SCI), applying a systematic literature review, and selecting the keywords related to the drug delivery, polymeric nanomicells, nanocarriers, and cancer treatment.

2. Organic Nanoparticles in Cancer Nanomedicine

Many pharmaceutically important compounds face challenges such as insolubility in water solutions, chemical and physiological instability, or toxicity. Innovative approaches such as nanoparticles improve efficacy and minimize the side effects of drug therapies. The encapsulation of drugs within nanoparticles aims to protect them from degradation and deliver them directly to the intended site and allow their controlled release, thereby maximizing therapeutic effects. This transformative progress in nanomedicine has revolutionized drug delivery, offering considerable potential for enhancing patient outcomes [20]. Thus, nanoparticles loaded with chemotherapy drugs can precisely target tumor cells while saving healthy ones and reducing the toxic side effects associated with the drug [10].

Based on their structure and composition, the main types of nanoparticles recognized are of organic and inorganic origin.

Inorganic nanoparticles are easier to control and functionalize [21], while biocompatibility, biodegradability, and tailored properties related to drug encapsulation and/or linking active species to their surface directing specific biological targets make organic nanoparticles (Figure 1) worthy of their application in cancer nanomedicine [22].

Organic nanoparticle systems with multifunctional characters, serving as drug carriers of insoluble drugs, are effective noninvasive therapeutic techniques used in cancer treatments. Compared to traditional therapies, these systems show that due to their many advantages, including higher delivery efficacy, decreased toxicity, and use of external stimuli like pH changes, ultrasound, or heat, the tailored release of medicaments is achieved. This controlled-release feature minimizes premature drug dissociation from the nanoshell, reducing drug accumulation in healthy tissues and organs and lowering systemic toxicity [20,24].

One key benefit of nanocarriers is their ability to target tumor sites. They can be modified by cancer-specific molecules, facilitating specific binding to target receptors on cancer cells. These targeted deliveries result in higher cellular drug uptake and increased anti-tumor activity while minimizing systemic toxicity and potentially life-threatening side effects [13].

Various strategies concerning organic nanoparticles have been developed to address problems related to traditional cancer medicine [25]. Carriers, such as liposomes, lipid-based nanoparticles, and nanomicelles, particularly polymer-based ones with self-assembling properties (Figure 1), have emerged as promising and efficient materials for developing novel drug delivery systems (DDSs) [25].

Self-assembly properties refer to the spontaneous organization of disordered molecular units into structured arrangements driven by specific local interactions among the components themselves [26].

Supramolecular assemblies of hydrophilic (polar) and hydrophobic (nonpolar) structures, known as nanomicelles, are classified into three main classes [27], including polyion complex (PIC) nanomicelles, surfactant nanomicelles, and polymeric nanomicelles, which are the focus of research in this study.

3. Polymeric Nanomicelles in Cancer Nanomedicine

Polymers applied for nanomicelles preparation are amphiphilic di-/tri- block or graft copolymers [28], containing the balanced length of the hydrophobic and hydrophilic blocks, which create two functional domains in the micelle, i.e., the inner core and an outer shell [29]. Hydrophobic copolymer blocks create the micelle core, and the hydrophilic counterparts create the shell.

Hydrophilic polymers used in the synthesis of biocompatible and biodegradable block copolymers for nanomicelles preparation usually include the following:

• Poly(ethylene glycol) (PEG), synthesized mainly by the ring-opening polymerization (ROP) of ethylene oxide, shows high chain flexibility and good biocompatibility [30];
• Hydrophilic poly(2-oxazoline)s (POx), embracing poly(2-methyl-2-oxazoline) (PMeOx) and poly(2-ethyl-2-oxazoline) (PEtOx), prepared by living cationic ring-opening polymerization, are biocompatible, prevent biological fouling (accumulation of microorganisms or biological small species in undesired places) and allow enhanced penetrating in the mucus systems [31];
• Poly(amino acid)s, such as poly(aspartic acid) P(Asp)) [32], poly(glutamic acid) (P(Glu)) [33], and poly(sarcosine) [34], are synthesized by anionic ROP, and they prevent biofouling.

Anionic and ring-opening polymerization [35,36,37,38,39,40,41] are the most common methods of synthesis of hydrophobic polymers with varying molecular weights, i.e., lengths. These polymers, conjugated to the hydrophilic block, have low toxicity and good biocompatibility [42]. A longer hydrophobic block of a higher length forms a larger hydrophobic core, allowing hydrophobic drug encapsulation. On the other hand, micelles of smaller sizes allow more efficient penetration into tumors and improve the drug’s anticancer activity. Hydrophobic blocks of copolymers involved in micelles formation encounter following polymers:

• Polyesters, commonly poly(lactic acid) (PLA), poly(ε-caprolactone) (PCL), poly(lactic-co-glycolic acid) (PLGA), are synthesized by ring-opening polymerization of cyclic esters, obtaining high molecular weight biodegradable polyesters of narrow polydispersity [36,37,38];
• Polyethers with low polydispersity index, obtained by ring-opening anionic polymerization of alkenes, involve poly(propylene oxide) (PPO), poly(butylene oxide) (PBO), poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) copolymers [35,39];
• Poly(L-amino acid) (PAA),like poly(L-aspartic acid) (polyAsp), poly(L-lysine)(polyLis), poly(L-glutamic acid) (polyGlut) is synthesized by the living polymerization of N-carboxyanhydride of α-amino acids. These polymer systems exhibit sensitivity to pH [40];
• PEG-distearoylphosphatidylethanolamine (DSPE) belonging to the group of PEG-conjugated phospholipids which is characterized by the long circulation in the bloodstream [41].

The smallest capillary in the body is 5 to 6 mm in diameter, allowing the nanomicelles, usually sized between 10 and 100 nm, to be administered intravenously in the body. In this way, embolism during drug delivery in the blood vessels does not occur [35].

The size and shape of nanomicelles depend on the preparation technique, i.e., preparation conditions.

One of the techniques for polymeric nanomicelles preparation is the method of direct dissolution, which is used for moderately hydrophobic block copolymers. After the dissolution of the drug and copolymer in an aqueous solution and heating the system, the formation of nanomicelles is initiated. Due to dehydration, the core of the micelles is formed [27,35].

The solvent casting methods include oil-in-water (o/w) emulsion, dialysis, and solution casting [27,35]. The approaches applying the oil-in-water (o/w) emulsion allow physical encapsulation of pharmaceutics. Polymer and drug are dissolved in an immiscible organic solvent and a small amount of water. The organic phase is dispersed as droplets in an aqueous medium, creating a nanoemulsion. This nanoemulsion is stabilized by surfactants such as Tween 80, poloxamer, lecithin, or their combination. The size of nanoscopic droplets formed ranges between 20 and 200 nm. Oil droplets made from fatty acid esters, saturated and unsaturated fatty acids, soybean oils, etc., serve as the reservoir for hydrophobic drugs. Solvents are removed by evaporation, initiating the encapsulation of the drug in the nanomicelles core.

In the cases of solvents with a high boiling point, dialysis is a suitable solution. Both the polymer and the drug are dissolved in the appropriate organic solvent, which is miscible with water. The organic solvent is removed with dialysis against water for more than 12 h, initiating the formation of loaded drug micelles. The characteristic of this technique is the low efficiency of drug encapsulation [27,35].

The typical architecture of polymeric micelles consists of a hydrophobic core and a hydrophilic shell that enables the encapsulation of anticancer hydrophobic drugs, e.g., paclitaxel, doxorubicin, camptothecin, etc. [43]. Being enclosed within the micelle core, the hydrophilic outer shell additionally shields the drugs from unanticipated interactions and biodegradation when exposed in the in vivo surroundings, by the outer shell. The core–shell structure provides stability to nanomicelles, improving the drug accumulation at targeted cancer sites, which leads to their extended half-life, longer circulation time in the body [35], boosted effectiveness [44], and, at the same time, minimizing the adverse effects on noncancerous tissues [27]. In addition, these nanocarriers improve the bioavailability and solubility of drugs in water [35]. In addition, these nano-systems have excellent biocompatibility and biodegradability, by being decomposed into non-toxic low molecular weight byproducts and can be removed from the body as normal metabolites [35].

Nanomicelles can participate in passive and active cancer targeting. Passive accumulation of drugs in tumor tissues is achieved through the enhanced permeability and retention (EPR) effect [45]. Active targeting occurs with the conjugation of the micelle surface with specific moieties of different sizes, such as peptides and nucleic acids directed to a complementary receptor in a tissue, as shown in Figure 2 [46]. It results in optimal delivery with minimal side effects. For example, platinum-loaded nanomicelles conjugated with a fragment of antibody can target tumorxenografts of pancreatic cancer [36]. The system developed between the block of polyacid from the poly(glycolic acid)-b-poly(glutamic acid) (PEG-b-P(Glu)) [47] and poly(ethylene glycol)–poly(aspartic acid) (PEG-b-P(Asp)) [34] and the metal from the drugs dichloro(1,2-diaminocyclohexane) platinum(II) (DACHPt) and cis-dichlorodiammine platinum(II) (cisplatin) is an example of active targeting. The interaction between ligands and targeted cells facilitates the release of the drug from the micelles [27,47].

Combining various functionalities within the core or on the surface, multifunctional nanoparticles offer the additional advantage of enhancing antitumor activity. With a combination of drugs and targets, such as small molecule drugs, antigenic proteins, aptamer sequences, and molecules like DNA, siRNA, shRNA, and miRNA [44], one can experience the integration of their activities. This possibility makes them different from the monofunctional nanoparticles delivering a single payload. This approach aligns with the recognition that successful therapeutic regimens often involve a combination of drugs and targets, as evidenced by ongoing clinical trials exploring diverse treatment combinations for optimal results in cancer therapy [48].

Polyethylene glycol phosphatidyl ethanolamine (PEG-PE) micelles conjugated with the MCF-7-specific phage protein and loaded with the anticancer drug paclitaxel displayed better targeting of the cancer cells compared with the nanomicelles that are not conjugated with the specific targeting agent [49]. Sarkar et al. [50] have recently advanced self-assembled amphiphilic micelles of stearic acid-g-polyethyleneimine copolymers conjugated with carbon dots functionalized with folic acid, for simultaneous bio-imaging for the triple-negative breast cancer (TNBC), and, at the same time, for anticancer drug delivery.

The focus of the scientific interest is directed [48] at creating suitable polymeric nanomicellecarriers/drug systems that will address all the requirements occurring during the transition of laboratory and preclinical research into clinical trials. A clinical study of prostate-specific membrane antigen (PSMA)-targeted polymeric nanosystems PSMA-targeted polymeric nanoparticles encapsulating doxorubicin (DOX) has been applied in vitro proving the potential application in prostate cancer treatments [51]. Some clinical trials for the treatment of gynecologic cancer, advanced non-small cell lung cancer, and advanced ovarian and pancreatic cancers have taken the Genexol-PM/Paclitaxel/PEG-PLA system [52].

The acidic environment in tumors serves as a signal to activate the drug release from the micelle. Poly(d,l-lactide)-graft-poly(N-isopropyl acrylamide-co-methacrylic acid), showing self-assembling properties, was used to prepare nanomicells with a core–shell structure. The micelles are sensitive to the pH changes, which enable the control of the release of the encapsulated drug [53]. The typical pH of normal tissue is approximately 7.4. Within tumor cells, anaerobic glycolysis induced by oxygen deficiency generates lactic acid. However, the absence of a proper vascular system in tumor cells prevents the complete flow of lactic acid, resulting in an acidic environment [54], allowing for the selective release of the therapeutic agent. The explanation of this phenomenon offers two mechanisms. The first includes nanomicelles with ionizable groups based on the protonation/deprotonation of polymers. The second approach covers nanomicelles having acid-sensitive bonds that release the therapeutic agent from the micelle core as a result of the hydrolysis [55].

Despite the progress in the development of nanocarriers for cancer diagnosis and treatment, the translation process from clinical development to their market applications faces significant obstacles that are mainly related to the following difficulties [48]:

Anticipating susceptibility of the patient to allergic reactions.

Predicting a definitive pattern or behavior among patients, even those receiving the same dose of medicine proves challenging. While the mechanisms of action observed during clinical studies in diverse patient populations may produce reactions, the drug can exhibit unexpected and contradictory side effects when administered to the broader global population [48].

Contamination with endotoxin and its quantification.

The primary components on the surface of Gram-negative bacteria are endotoxins that the inborn immune system recognizes as a threat and triggers a robust immune reaction in response to their presence. Endotoxins may cause a significant inflammatory reaction. When the immune system eliminates Gram-negative bacteria, fragments of their membrane containing endotoxins are released into the bloodstream, potentially causing symptoms such as fever and diarrhea. Intense endotoxemia can progress to sepsis, ultimately posing a threat to life [48].

The internalization of the drug into cellular structures.

Endocytosis and intracellular trafficking depend on the interaction of nanoparticle-cell membrane, which, on the other hand, is influenced by factors such as the type of nanocarrier, lipophilicity, surface charge, particle size, and shape, as well as the type of cells involved in internalization [56].

Typically, a drug circulates and accumulates at the targeted site before the internalization into the cell starts. Due to the challenge of the effective introduction of the drug to tumor cells, this step is a critical bottleneck in the chemotherapeutic nanomedicine [48,57].

Complementary to all these challenges, additional concerns are introduced with the intelligent multidrug-loaded polymeric micelles. First, the anticancer effect is restricted to solid tumors only and does not take nonsolid ones, like leukemia, into account. Secondly, the difficulty is directed toward the stability of the micelles. After their administration in vivo, a dilution decreases the concentration of the amphiphilic copolymers below the value of the critical micelle concentration, disintegrating the micellar structure [51].

Taking promising nanomedicine formulations from preclinical testing to actual clinical applications involves a thorough process of testing, optimization, and regulatory approval. The successful shift in cancer nanomedicine “from the bench to the bedside” requires the provision of systems with satisfactory safety, effectiveness, and scalability, framed in the regulations and legal requirements [48].

Intensive interdisciplinary partnerships involving chemists, material scientists, biologists, pharmacists, physicians, and regulatory bodies, and extensive studies are vital to fast-track the translation of innovative nanotechnologies into everyday clinical practice. This approach, rooted in patient-centered research, becomes indispensable in unlocking the full potential of nanomedicine, especially in the realm of personalized cancer care [48].

4. Conclusions

Cancer has become one of the biggest threats to human health. Researchers predict a severe increase in new cases of cancer and fatal outcomes by 2050. Early detection methods combined with multiple strategic approaches are critical for the reduction in the mortality rates from cancer diseases. Conventional cancer treatments attack not only tumor cells but healthy tissues as well, alongside adverse side effects. Nanotechnology provides precise drug delivery and customized therapy options. Thus, advanced therapeutic solutions related to polymeric micelles enhance cancer treatment through effective drug delivery systems for reaching cancer cells. Facing many challenges in translating these innovations into practice, the application of intensive research is essential for overcoming obstacles and implementing innovative nanotechnologies in clinical settings. This paper highlights the importance of organic nanocarriers, emphasizing polymeric micelles for cancer nanomedicine applications.