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Therapeutic Polymers for Drug Delivery

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Materials Science".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 39062

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Special Issue Editors

Dr. Catarina Pinto Reis

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Guest Editor

Faculty of Pharmacy/iMed.ULisboa and IBEB/FCUL, University of Lisboa, Lisboa, Portugal
Interests: development of new drug delivery systems; therapeutic polymers for drug delivery; methods of micro- and nanoencapsulation of drugs; medical devices; food supplements; cosmetics; drug dissolution; absorption; metabolism and elimination studies; targeted therapies; in vivo efficacy and safety assessments using animal models; preclinical toxicity assessment; regulatory affairs
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Dr. Maria Manuela Gaspar

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iMed.ULisboa, Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal
Interests: drug delivery systems; 2D and 3D in vitro models; establishment of murine models and alternative routes of administration; pharmacokinetic and biodistribution studies; bacterial infections; melanoma; breast cancer; inflammation; colon cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Polymeric materials have been applied for decades in therapeutic applications such as drug delivery and tissue regeneration, mainly due to their biocompatibility and suitable mechanical properties. Polymeric therapeutics encompass, at the same time, drug–polymer conjugates, polymer–protein conjugates and supramolecular drug-delivery systems based on well-defined multivalent and dendritic polymers. In case of polymer–drug conjugates, they have been used as bioactive pharmaceuticals owing to their increased drug efficacy, solubility, and target specificity. On the other hand, several polymer–protein conjugates made by anchoring enzymes or biologically relevant proteins to polyethylene glycol components have demonstrated a significant improvement in stability and pharmacokinetic properties.

An overview of polymeric therapeutics in drug delivery will be herein presented, with a focus on key concepts, polymerization methods, new approaches that have been applied to improve the control of polymer structure and examples that characterize the relevant features of these novel drug-delivery systems. This Special Issue will cover a variety of polymer-based therapeutics in greater detail, including noncovalent and covalent polymeric delivery vehicles (nanoparticles, liposomes, dendrimers), polymer sequestrants, and polymerized drugs, and the recent advances in this emerging area.

Prof. Catarina Pinto Reis
Dr. Maria Manuela Gaspar
Guest Editors

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Keywords

Drug-polymer conjugates
Polymer-protein conjugates
Supramolecular drug-delivery system
Polymer chemistry
Molecular biology
Proteins
Enzymes
In vitro and in vivo studies
Efficacy and safety assessment

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Published Papers (9 papers)

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Research

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18 pages, 4804 KiB

Open AccessArticle

Highly Branched Betulin Based Polyanhydrides for Self-Assembled Micellar Nanoparticles Formulation

by Daria Niewolik, Barbara Bednarczyk-Cwynar, Piotr Ruszkowski, Grzegorz Dzido and Katarzyna Jaszcz

Int. J. Mol. Sci. 2022, 23(19), 11462; https://doi.org/10.3390/ijms231911462 - 28 Sep 2022

Cited by 1 | Viewed by 1850

Abstract

Polyanhydrides based on betulin are promising materials for use in controlled drug delivery systems. Due to the broad biological activity of betulin derivatives and lack of toxicity in vitro and in vivo, these polymers can be used both as polymeric prodrug and as carriers of other biologically active compounds. In this study, we develop a novel amphiphilic branched polyanhydrides synthesized by the two-step melt polycondensation of betulin disuccinate (DBB) and a tricarboxylic derivative of poly(ethylene glycol) (PEG_COOH). DBB and PEG_COOH were used as the hydrophobic and hydrophilic segments, respectively. The content of DBB in copolymers was from 10 to 95 wt%. Copolymers were assessed for their cytostatic activity against various cancer cell lines. Compared to linear DBB and PEG-based polyanhydrides, the branched polyanhydrides exhibited higher anticancer activity. The obtained polymers were able to self-assemble in water to form micelles with hydrodynamic diameters from 144.8 to 561.8 nm. and are stable over a concentration range from 12.5 µg/mL to 6.8 mg/mL. The formed micelles were found to be spherical in shape using a scanning electron microscope. It was found that the structure and composition of polyanhydrides affected the hydrodynamic diameter of the micelles. The branched betulin-based polyanhydrides have the potential to serve as biodegradable polymer prodrugs or carriers for other bioactive compounds. Full article

(This article belongs to the Special Issue Therapeutic Polymers for Drug Delivery)

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17 pages, 6473 KiB

Open AccessArticle

Enhanced Anti-Tumor Activity in Mice with Temozolomide-Resistant Human Glioblastoma Cell Line-Derived Xenograft Using SN-38-Incorporated Polymeric Microparticle

by Tao-Chieh Yang, Shih-Jung Liu, Wei-Lun Lo, Shu-Mei Chen, Ya-Ling Tang and Yuan-Yun Tseng

Int. J. Mol. Sci. 2021, 22(11), 5557; https://doi.org/10.3390/ijms22115557 - 24 May 2021

Cited by 5 | Viewed by 4066

Abstract

Glioblastoma multiforme (GBM) has remained one of the most lethal and challenging cancers to treat. Previous studies have shown encouraging results when irinotecan was used in combination with temozolomide (TMZ) for treating GBM. However, irinotecan has a narrow therapeutic index: a slight dose increase in irinotecan can induce toxicities that outweigh its therapeutic benefits. SN-38 is the active metabolite of irinotecan that accounts for both its anti-tumor efficacy and toxicity. In our previous paper, we showed that SN-38 embedded into 50:50 biodegradable poly[(d,l)-lactide-co-glycolide] (PLGA) microparticles (SMPs) provides an efficient delivery and sustained release of SN-38 from SMPs in the brain tissues of rats. These properties of SMPs give them potential for therapeutic application due to their high efficacy and low toxicity. In this study, we tested the anti-tumor activity of SMP-based interstitial chemotherapy combined with TMZ using TMZ-resistant human glioblastoma cell line-derived xenograft models. Our data suggest that treatment in which SMPs are combined with TMZ reduces tumor growth and extends survival in mice bearing xenograft tumors derived from both TMZ-resistant and TMZ-sensitive human glioblastoma cell lines. Our findings demonstrate that combining SMPs with TMZ may have potential as a promising strategy for the treatment of GBM. Full article

(This article belongs to the Special Issue Therapeutic Polymers for Drug Delivery)

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20 pages, 9733 KiB

Open AccessArticle

Mesoporous Silica-Bioglass Composite Pellets as Bone Drug Delivery System with Mineralization Potential

by Adrian Szewczyk, Adrianna Skwira, Agnieszka Konopacka, Rafał Sądej and Magdalena Prokopowicz

Int. J. Mol. Sci. 2021, 22(9), 4708; https://doi.org/10.3390/ijms22094708 - 29 Apr 2021

Cited by 15 | Viewed by 3436

Abstract

For decades, local bone drug delivery systems have been investigated in terms of their application in regenerative medicine. Among them, inorganic polymers based on amorphous silica have been widely explored. In this work, we combined two types of amorphous silica: bioglass and doxycycline-loaded mesoporous silica MCM-41 into the form of spherical granules (pellets) as a bifunctional bone drug delivery system. Both types of silica were obtained in a sol-gel method. The drug adsorption onto the MCM-41 was performed via adsorption from concentrated doxycycline hydrochloride solution. Pellets were obtained on a laboratory scale using the wet granulation-extrusion-spheronization method and investigated in terms of physical properties, drug release, antimicrobial activity against Staphylococcus aureus, mineralization properties in simulated body fluid, and cytotoxicity towards human osteoblasts. The obtained pellets were characterized by satisfactory mechanical properties which eliminated the risk of pellets cracking during further investigations. The biphasic drug release from pellets was observed: burst stage (44% of adsorbed drug released within the first day) followed by prolonged release with zero-order kinetics (estimated time of complete drug release was 19 days) with maintained antimicrobial activity. The progressive biomimetic apatite formation on the surface of the pellets was observed. No cytotoxic effect of pellets towards human osteoblasts was noticed. Full article

(This article belongs to the Special Issue Therapeutic Polymers for Drug Delivery)

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18 pages, 10297 KiB

Open AccessArticle

Development of a Topical Insulin Polymeric Nanoformulation for Skin Burn Regeneration: An Experimental Approach

by Maria Quitério, Sandra Simões, Andreia Ascenso, Manuela Carvalheiro, Ana Paula Leandro, Isabel Correia, Ana Silveira Viana, Pedro Faísca, Lia Ascensão, Jesús Molpeceres, Maria Manuela Gaspar and Catarina Pinto Reis

Int. J. Mol. Sci. 2021, 22(8), 4087; https://doi.org/10.3390/ijms22084087 - 15 Apr 2021

Cited by 8 | Viewed by 3813

Abstract

Insulin is a peptide hormone with many physiological functions, besides its use in diabetes treatment. An important role of insulin is related to the wound healing process—however, insulin itself is too sensitive to the external environment requiring the protective of a nanocarrier. Polymer-based nanoparticles can protect, deliver, and retain the protein in the target area. This study aims to produce and characterize a topical treatment for wound healing consisting of insulin-loaded poly-DL-lactide/glycolide (PLGA) nanoparticles. Insulin-loaded nanoparticles present a mean size of approximately 500 nm and neutral surface charge. Spherical shaped nanoparticles are observed by scanning electron microscopy and confirmed by atomic force microscopy. SDS-PAGE and circular dichroism analysis demonstrated that insulin preserved its integrity and secondary structure after the encapsulation process. In vitro release studies suggested a controlled release profile. Safety of the formulation was confirmed using cell lines, and cell viability was concentration and time-dependent. Preliminary safety in vivo assays also revealed promising results. Full article

(This article belongs to the Special Issue Therapeutic Polymers for Drug Delivery)

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21 pages, 5986 KiB

Open AccessArticle

Fabrication and Characterisation of a Photo-Responsive, Injectable Nanosystem for Sustained Delivery of Macromolecules

by Pakama Mahlumba, Pradeep Kumar, Lisa C. du Toit, Madan S. Poka, Philemon Ubanako and Yahya E. Choonara

Int. J. Mol. Sci. 2021, 22(7), 3359; https://doi.org/10.3390/ijms22073359 - 25 Mar 2021

Cited by 6 | Viewed by 2802

Abstract

The demand for biodegradable sustained release carriers with minimally invasive and less frequent administration properties for therapeutic proteins and peptides has increased over the years. The purpose of achieving sustained minimally invasive and site-specific delivery of macromolecules led to the investigation of a photo-responsive delivery system. This research explored a biodegradable prolamin, zein, modified with an azo dye (DHAB) to synthesize photo-responsive azoprolamin (AZP) nanospheres loaded with Immunoglobulin G (IgG). AZP nanospheres were incorporated in a hyaluronic acid (HA) hydrogel to develop a novel injectable photo-responsive nanosystem (HA-NSP) as a potential approach for the treatment of chorio-retinal diseases such as age-related macular degeneration (AMD) and diabetic retinopathy. AZP nanospheres were prepared via coacervation technique, dispersed in HA hydrogel and characterised via infrared spectroscopy (FTIR), X-ray diffraction (XRD) and thermogravimetric analysis (TGA). Size and morphology were studied via scanning electron microscopy (SEM) and dynamic light scattering (DLS), UV spectroscopy for photo-responsiveness. Rheological properties and injectability were investigated, as well as cytotoxicity effect on HRPE cell lines. Particle size obtained was <200 nm and photo-responsiveness to UV = 365 nm by decreasing particle diameter to 94 nm was confirmed by DLS. Encapsulation efficiency of the optimised nanospheres was 85% and IgG was released over 32 days up to 60%. Injectability of HA-NSP was confirmed with maximum force 10 N required and shear-thinning behaviour observed in rheology studies. In vitro cell cytotoxicity effect of both NSPs and HA-NSP showed non-cytotoxicity with relative cell viability of ≥80%. A biocompatible, biodegradable injectable photo-responsive nanosystem for sustained release of macromolecular IgG was successfully developed. Full article

(This article belongs to the Special Issue Therapeutic Polymers for Drug Delivery)

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20 pages, 3524 KiB

Open AccessArticle

Bioactive Betulin and PEG Based Polyanhydrides for Use in Drug Delivery Systems

by Daria Niewolik, Barbara Bednarczyk-Cwynar, Piotr Ruszkowski, Tomasz R. Sosnowski and Katarzyna Jaszcz

Int. J. Mol. Sci. 2021, 22(3), 1090; https://doi.org/10.3390/ijms22031090 - 22 Jan 2021

Cited by 15 | Viewed by 3381

Abstract

In the course of this study, a series of novel, biodegradable polyanhydrides based on betulin disuccinate and dicarboxylic derivatives of poly(ethylene glycol) were prepared by two-step polycondensation. These copolymers can be used as carriers in drug delivery systems, in the form of microspheres. Betulin and its derivatives exhibit a broad spectrum of biological activity, including cytotoxic activity, which makes them promising substances for use as therapeutic agents. Microspheres that were prepared from betulin based polyanhydrides show promising properties for use in application in drug delivery systems, including inhalation systems. The obtained copolymers release the active substance—betulin disuccinate—as a result of hydrolysis under physiological conditions. The use of a poly(ethylene glycol) derivative as a co-monomer increases the solubility and bioavailability of the obtained compounds. Microspheres with diameters in the range of 0.5–25 µm were prepared by emulsion solvent evaporation method and their physicochemical and aerodynamic properties were analyzed. The morphological characteristics of the microspheres depended on the presence of poly(ethylene glycol) (PEG) segment within the structure of polyanhydrides. The porosity of the particles depended on the amount and molecular weight of the PEG used and also on the speed of homogenization. The most porous particles were obtained from polyanhydrides containing 20% wt. of PEG 600 by using a homogenization speed of 18,000 rpm. Full article

(This article belongs to the Special Issue Therapeutic Polymers for Drug Delivery)

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28 pages, 3924 KiB

Open AccessArticle

A Step Forward in Breast Cancer Research: From a Natural-Like Experimental Model to a Preliminary Photothermal Approach

by Eduardo Costa, Tânia Ferreira-Gonçalves, Miguel Cardoso, João M. P. Coelho, Maria Manuela Gaspar, Pedro Faísca, Lia Ascensão, António S. Cabrita, Catarina Pinto Reis and Isabel V. Figueiredo

Int. J. Mol. Sci. 2020, 21(24), 9681; https://doi.org/10.3390/ijms21249681 - 18 Dec 2020

Cited by 16 | Viewed by 6198

Abstract

Breast cancer is one of the most frequently diagnosed malignancies and common causes of cancer death in women. Recent studies suggest that environmental exposures to certain chemicals, such as 7,12-Dimethylbenzanthracene (DMBA), a chemical present in tobacco, may increase the risk of developing breast cancer later in life. The first-line treatments for breast cancer (surgery, chemotherapy or a combination of both) are generally invasive and frequently associated with severe side effects and high comorbidity. Consequently, novel approaches are strongly required to find more natural-like experimental models that better reflect the tumors’ etiology, physiopathology and response to treatments, as well as to find more targeted, efficient and minimally invasive treatments. This study proposes the development and an in deep biological characterization of an experimental model using DMBA-tumor-induction in Sprague-Dawley female rats. Moreover, a photothermal therapy approach using a near-infrared laser coupled with gold nanoparticles was preliminarily assessed. The gold nanoparticles were functionalized with Epidermal Growth Factor, and their physicochemical properties and in vitro effects were characterized. DMBA proved to be a very good and selective inductor of breast cancer, with 100% incidence and inducing an average of 4.7 tumors per animal. Epigenetic analysis showed that tumors classified with worst prognosis were hypomethylated. The tumor-induced rats were then subjected to a preliminary treatment using functionalized gold nanoparticles and its activation by laser (650–900 nm). The treatment outcomes presented very promising alterations in terms of tumor histology, confirming the presence of necrosis in most of the cases. Although this study revealed encouraging results as a breast cancer therapy, it is important to define tumor eligibility and specific efficiency criteria to further assess its application in breast cancer treatment on other species. Full article

(This article belongs to the Special Issue Therapeutic Polymers for Drug Delivery)

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Review

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18 pages, 34502 KiB

Open AccessReview

Stimuli-Responsive Polymeric Nanomaterials for the Delivery of Immunotherapy Moieties: Antigens, Adjuvants and Agonists

by Raveena Nagareddy, Reju George Thomas and Yong Yeon Jeong

Int. J. Mol. Sci. 2021, 22(22), 12510; https://doi.org/10.3390/ijms222212510 - 19 Nov 2021

Cited by 8 | Viewed by 2466

Abstract

Immunotherapy has been investigated for decades, and it has provided promising results in preclinical studies. The most important issue that hinders researchers from advancing to clinical studies is the delivery system for immunotherapy agents, such as antigens, adjuvants and agonists, and the activation of these agents at the tumour site. Polymers are among the most versatile materials for a variety of treatments and diagnostics, and some polymers are reactive to either endogenous or exogenous stimuli. Utilizing this advantage, researchers have been developing novel and effective polymeric nanomaterials that can deliver immunotherapeutic moieties. In this review, we summarized recent works on stimuli-responsive polymeric nanomaterials that deliver antigens, adjuvants and agonists to tumours for immunotherapy purposes. Full article

(This article belongs to the Special Issue Therapeutic Polymers for Drug Delivery)

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37 pages, 5147 KiB

Open AccessReview

Exosomes Engineering and Their Roles as Therapy Delivery Tools, Therapeutic Targets, and Biomarkers

by Nika Kučuk, Mateja Primožič, Željko Knez and Maja Leitgeb

Int. J. Mol. Sci. 2021, 22(17), 9543; https://doi.org/10.3390/ijms22179543 - 2 Sep 2021

Cited by 93 | Viewed by 9418

Abstract

Exosomes are becoming increasingly important therapeutic biomaterials for use in a variety of therapeutic applications due to their unique characteristics, especially due to the ineffectiveness and cytotoxicity of some existing therapies and synthetic therapeutic nanocarriers. They are highly promising as carriers of drugs, genes, and other therapeutic agents that can be incorporated into their interior or onto their surface through various modification techniques to improve their targeting abilities. In addition, they are biocompatible, safe, and stable. The review focuses on different types of exosomes and methods of their preparation, including the incorporation of different kinds of cargo, especially for drug delivery purposes. In particular, their importance and effectiveness as delivery vehicles of various therapeutic agents for a variety of therapeutic applications, including different diseases and disorders such as cancer treatment, cardiovascular and neurodegenerative diseases, are emphasized. Administration routes of exosomes into the body are also included. A novelty in the article is the emphasis on global companies that are already successfully developing and testing such therapeutic biomaterials, with a focus on the most influential ones. Moreover, a comparison of the advantages and disadvantages of the various methods of exosome production is summarized for the first time. Full article

(This article belongs to the Special Issue Therapeutic Polymers for Drug Delivery)

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