Polymer-based Delivery Systems Research Articles

Polymers for mRNA Delivery.

mRNA delivery has emerged as a transformative approach in biotechnology and medicine, offering a versatile platform for the development of novel therapeutics. Unlike traditional small molecule drugs or protein-based biologics, mRNA therapeutics have the unique ability to direct cells to generate therapeutic proteins, allowing for precise modulation of biological processes. The delivery of mRNA into target cells is a critical step in realizing the therapeutic potential of this technology. In this review, our focus is on the latest advancements in designing functional polymers to achieve efficient mRNA delivery. Biodegradable polymers and low molecular weight polymers in addressing the balance in mRNA binding and release are summarized. Benefiting from the excellent performance of lipid nanoparticles in mRNA delivery, polymer/lipid hybrid nanostructures are also included. Finally, the challenges and future prospects in the development of polymer-based mRNA delivery systems are discussed.

Non-viral gene therapy for Leber's congenital amaurosis: progress and possibilities.

Leber's congenital amaurosis (LCA) represents a set of rare and pervasive hereditary conditions of the retina that cause severe vision loss starting in early childhood. Targeted treatment intervention has become possible thanks to recent advances in understanding LCA genetic basis. While viral vectors have shown efficacy in gene delivery, they present challenges related to safety, low cargo capacity, and the potential for random genomic integration. Non-viral gene therapy is a safer and more flexible alternative to treating the underlying genetic mutation causing LCA. Non-viral gene delivery methods, such as inorganic nanoparticles, polymer-based delivery systems, and lipid-based nanoparticles, bypass the risks of immunogenicity and genomic integration, potentially offering a more versatile and personalized treatment for patients. This review explores the genetic background of LCA, emphasizing the mutations involved, and explores diverse non-viral gene delivery methods being developed. It also highlights recent studies on non-viral gene therapy for LCA in animal models and clinical trials. It presents future perspectives for gene therapy, including integrating emerging technologies like CRISPR-Cas9, interdisciplinary collaborations, personalized medicine, and ethical considerations.

Smart Polymer-Based Delivery Systems for Curcumin in Colon Cancer Therapy: A Review.

Curcumin, a well-known bioactive component, has profound effects against colon cancer. However, the limitations are poor systemic absorption, off-target distribution, chemical instability, short half-life, and less concentration reaching tumor tissues. Several drug delivery systems have been evaluated so far to deliver effective concentrations of curcumin to the malignant tissues. This review aims to explore the role of smart polymers in overcoming limitations in curcumin delivery against colon cancer. Literature of the past 10 years was collected from Scopus, PubMed/Medline, Google Scholar, and Science Direct using specific keywords. Several preclinical and clinical studies of curcumin against colon cancer with the inclusion of smart polymers were screened using keywords like "FDA-approved biomaterials," "stimuli-responsive polymer," "smart biomaterial," and so forth. Smart polymer phrase is used to describe all the mentioned polymers in the manuscript. Stimuli-responsive polymers, including poly-lactic-co-glycolic acid (PLGA), polyethylene glycol (PEG), Eudragit, cyclodextrin, and chitosan, have emerged as promising candidates for curcumin delivery against colon cancer. These polymers facilitate controlled drug release in response to stimuli such as temperature, pH, and enzymes, while offering biocompatibility, biodegradability, and safety. The five selected FDA-approved smart polymers exhibit the potential for enhancing curcumin delivery against colon cancer.

Poly(β-amino ester) polymer library with monomer variation for mRNA delivery

Non-viral vectors for mRNA delivery primarily include lipid nanoparticles (LNPs) and polymers. While LNPs are known for their high mRNA delivery efficiency, they can induce excessive immune responses and cause off-target effects, potentially leading to side effects. In this study, we aimed to explore polymer-based mRNA delivery systems as a viable alternative to LNPs, focusing on their mRNA delivery efficiency and potential application in mRNA vaccines. We created a library of poly(β-amino ester) (PBAE) polymers by combining various amine monomers and acrylate monomers. Through screening this polymer library, we identified specific polymer nanoparticles (PNPs) that demonstrated high mRNA expression efficiency, with sustained mRNA expression for up to two weeks. Furthermore, the PNPs showed mRNA expression only at the injection site and did not exhibit liver toxicity. Additionally, when assessing immune activation, the PNPs significantly induced T-cell immune activation and were effective in the plaque reduction neutralization test. These results suggest that polymer-based mRNA delivery systems not only hold potential for use in mRNA vaccines but also show promise for therapeutic applications.

Macromolecular Polymer Based Complexes: A Diverse Strategy for the Delivery of Nucleotides.

This review explores the burgeoning field of macromolecular polymer-based complexes, highlighting their revolutionary potential for the delivery of nucleotides for therapeutic applications. These complexes, ingeniously crafted from a variety of polymers, offer a unique solution to the challenges of nucleotide delivery, including protection from degradation, targeted delivery, and controlled release. The focus of this report is primarily on the design principles, encapsulation strategies, and biological interactions of these complexes, with an emphasis on their biocompatibility, biodegradability, and ability to form diverse structures, such as nanoparticles and micelles. Significant attention is paid to the latest advancements in polymer science that enable the precise tailoring of these complexes for specific nucleotides, such as DNA, RNA, and siRNA. The review discusses the critical role of surface modifications and the incorporation of targeting ligands in enhancing cellular uptake and ensuring delivery to specific tissues or cells, thereby reducing off-target effects and improving therapeutic efficacy. Clinical applications of these polymer-based delivery systems are thoroughly examined with a focus on their use in treating genetic disorders, cancer, and infectious diseases. The review also addresses the challenges and limitations currently faced in this field, such as scalability, manufacturing complexities, and regulatory hurdles. Overall, this review provides a comprehensive overview of the current state and future prospects of macromolecular polymer-based complexes in nucleotide delivery. It underscores the significance of these systems in advancing the field of targeted therapeutics and their potential to reshape the landscape of medical treatment for a wide range of diseases.

Tumor Microenvironment-Responsive Polymer-Based RNA Delivery Systems for Cancer Treatment.

Ribonucleic acid (RNA) therapeutics offer a broad prospect in cancer treatment. However, their successful application requires overcoming various physiological barriers to effectively deliver RNAs to the target sites. Currently, a number of RNA delivery systems based on polymeric nanoparticles are developed to overcome these barriers in RNA delivery. This work provides an overview of the existing RNA therapeutics for cancer gene therapy, and particularly summarizes those that are entering the clinical phase. This work then discusses the core features and latest research developments of tumor microenvironment-responsive polymer-based RNA delivery carriers which are designed based on the pathological characteristics of the tumor microenvironment. Finally, this work also proposes opportunities for the transformation of RNA therapies into cancer immunotherapy methods in clinical applications.

Permeability: The Driving Force That Influences the Mechanical Behavior of Polymers Used for Hydrogen Storage and Delivery

This article explores the main mechanisms that can generate damage in polymers and polymer-based materials used for hydrogen storage and distribution infrastructures. All of these mechanisms are driven by the permeability process that is enhanced by the operating temperature and pressure conditions. Hydrogen storage and delivery systems typically work under high pressure and a relatively wide range of temperatures, especially during the filling and emptying processes. Therefore, it is of great interest to better understand how this phenomenon can influence the integrity of polymer-based hydrogen infrastructures in order to avoid catastrophic events and to better design/investigate new optimized solutions. The first part of this paper discusses the main storage and delivery solutions for gas and liquid hydrogen. Then, the physics of the permeability is investigated with a focus on the effect of pressure and temperature on the integrity of polymers working in a hydrogen environment. Finally, the main mechanisms that mostly induce damage in polymers operating in a hydrogen environment and that influence their mechanical properties are explored and discussed. Particular focus was placed on the rapid gas decompression and aging phenomena. In addition, some of the limits that still exist for a reliable design of polymer-based storage and delivery systems for hydrogen are pointed out.

Advancements of Polymer-Based Transdermal Drug Delivery Systems in Drug Bioavailability and Patient Compliance in United States

Transdermal drug delivery system (TDDS) helps in overcoming drug molecule barriers such as particle size, lipophilicity, permeability, and transports the medication directly to the blood circulation by employing physical and chemical penetration enhancers using polymers. The use of skin as a drug delivery route is challenging due to the stratum corneum's barrier properties that restrict the therapeutic bioavailability of the medications. Both, natural and synthetic polymers are used in TDDS to transport the medication into circulation via diffusion, and swelling control. TDDS is generally achieved by using transdermal patches containing one or more pharmaceutical active entities that are placed on unbroken skin for delivering active entities directly to the bloodstream by crossing the skin barrier. TDDS is the trendiest -delivery system as it is painless, non-invasive, self-administrative, avoids hepatic first-pass metabolism, and delivers poorly soluble drugs and increases the bioavailability. An overview of TDDS is provided in this review article, including its advantages over traditional dosage forms, limitations, different components of transdermal patches, modern techniques as well as transdermal products available in US market.

Three-Dimensional Hydrogel Bioprinting Technology as a Scaffold of Novel Drug Delivery and Biomedical Devices: A Comprehensive Review

Polymer hydrogel used as computer-aided, non-biological arsenal utilize as a drug delivery vehicle overthe past few years.New advances in three-dimensional (3D) bioprinting technology have created new opportunitiesfor the use of hydrogel polymer-based medication delivery systems. 3D printing can deliver the ideal shapes or changecapabilities under specific circumstances which have a better adaptation to physiological function. The accuracy of 3Dprinting technology was significantly higher than that of conventional production techniques.A model bioink acquireproper physicochemical characteristics (mechanical and rheological) and biological properties important for proper functioning.It acts as additive manufacturing with complex spatial structure in biomedical research. In this review, we outlined the currentdevelopments in 3D printed polymer hydrogels as delivery and other platforms.

Rational design of polymer-based mRNA delivery systems for cancer treatment

This review introduces the basic design principles and recent advances in polymeric mRNA therapeutics, highlighting strategies to realize cancer-selective, organ-targeted, and tissue-penetrating mRNA delivery.

Recent advances in polymeric microparticle-based drug delivery systems for knee osteoarthritis treatment.

Due to the poor bioavailability and high joint clearance of drugs, sustained delivery of therapeutic agents has proven difficult in the treatment of osteoarthritis (OA). Intra-articular (IA) drug delivery strategy is an attractive option for enhancing OA patients' prognosis, for which various polymer materials have been used as drug carriers due to their attractive delivery properties, to slow or even reverse the progress of OA by prolonging the duration of therapeutic agent residence in the joint. This article focuses on the recent developments in natural and synthetic polymer-based microsphere drug delivery systems for treating knee osteoarthritis. It evaluates the translational potential of some novel formulations for clinical application.

NANOENCAPSULATION OF LUTEOLIN: ENHANCING BIOAVAILABILITY AND MEDICINAL BENEFITS

Luteolin is a naturally occurring chemical widely found in plants ranging from Bryophyta to Magnoliophyta. It can be obtained from several dietary sources such as carrots, olive oil, celery, spinach, oregano, and, fossils of some organisms such as Celtis and Ulmus dating back 36 to 25 million years. It is synthesized by the Shikimate pathway. The major qualities and therapeutic benefits of luteolin include cytoprotective abilities, Antioxidant, Anti-inflammatory, Anticancer, Antidepressant, Antidiabetic, Antiallergic, Reactive Oxygen Species Scavenging and High radical scavenging. The antioxidant and Reactive Oxygen Species scavenging activity of luteolin aids in treating and curing inflammatory skin processes. It has been proven to act as a therapeutic drug with a wide spectrum of scope in the prevention and treatment of a vast range of malignant and benign cancers, extending from bladder cancer to breast cancer and from oral cancer to glioblastoma, which is achieved by its anticancer, antioxidant properties and cytoprotective abilities. Apart from its anticancer properties, it has a great scope in the restoration from neuropsychiatric disease and high-level fatigue due to Long COVID syndrome-associated brain fog and Chemo fog. The poor solubility and low bioavailability of luteolin limit its use in food and medicine. Synthetic and Natural polymer-based delivery systems have been developed to improve its stability and bioavailability. This review will highlight recent research on its nanoencapsulation and provide more information on luteolin to help readers have a better grasp of the compound's medicinal benefits.

Polymer-Based Self-Assembled Drug Delivery Systems for Glaucoma Treatment: Design Strategies and Recent Advances.

Glaucoma has become the world's leading cause of irreversible blindness, and one of its main characteristics is high intraocular pressure. Currently, the non-surgical drug treatment scheme to reduce intraocular pressure is a priority method for glaucoma treatment. However, the complex and special structure of the eye poses significant challenges to the treatment effect and safety adherence of this drug treatment approach. To address these challenges, the application of polymer-based self-assembled drug delivery systems in glaucoma treatment has emerged. This review focuses on the utilization of polymer-based self-assembled structures or materials as important functional and intelligent carriers for drug delivery in glaucoma treatment. Various drug delivery systems, such as eye drops, hydrogels, and contact lenses, are discussed. Additionally, the review primarily summarizes the design strategies and methods used to enhance the treatment effect and safety compliance of these polymer-based drug delivery systems. Finally, the discussion delves into the new challenges and prospects of employing polymer-based self-assembled drug delivery systems for the treatment of glaucoma.

Development and Statistical Optimization of Polymer-Based Nanoparticulate Delivery System for Enhancing Cytarabine Efficacy in Leukemia Treatment

Development and Statistical Optimization of Polymer-Based Nanoparticulate Delivery System for Enhancing Cytarabine Efficacy in Leukemia Treatment

Unraveling the in vivo biological fate of mPEG2000-PDLLA2500-COOH diblock copolymers by LC-MS/MS based on CID in source technique

Methoxy poly (ethylene glycol)-poly(D, L-lactic acid) (mPEG-PDLLA) is a biocompatible and amphiphilic diblock copolymer composed of a hydrophilic poly(ethylene glycol) block and a hydrophobic poly(D, L-lactic acid) block, which can self-assemble into micelles in aqueous solution. It is one of the most widely used diblock copolymers for drug delivery, drug solubilization and drug encapsulation. Fully characterizing the in vivo fate of mPEG-PDLLA diblock copolymers is important to promote the further development of polymer-based nanocarrier drug delivery systems. However, to date, a bioanalysis assay for simultaneous quantification of mPEG-PDLLA and mPEG has not been reported. In this study, we developed such a novel LC-MS/MS assay based on CID in source technique and used it to study the multiple-dose pharmacokinetic, tissue distribution and excretion of mPEG2000-PDLLA2500-COOH and mPEG2000 in rat after intravenous administration. The results indicate that mPEG2000-PDLLA2500-COOH and mPEG2000 are mainly distributed to the liver, lung, spleen and kidney after intravenous administration. mPEG2000-PDLLA2500-COOH is mostly excreted via the renal route in the form of mPEG2000. Overall, the results of this study provide a comprehensive and clear picture of the in vivo fate of mPEG2000-PDLLA2500-COOH which will be useful in evaluating the efficiency and safety of polymer-based nanocarrier drug delivery systems.

Advances in Natural Polymer-Based Transdermal Drug Delivery Systems for Tumor Therapy.

As an alternative to traditional oral and intravenous injections with limited efficacy, transdermal drug delivery (TDD) has shown great promise in tumor treatment. Over the past decade, natural polymers have been designed into various nanocarriers due to their excellent biocompatibility, biodegradability, and easy availability, providing more options for TDD. In addition, surface functionalization modification of the rich functional groups of natural polymers, which in turn are developed into targeted and stimulus-responsive functional materials, allows precise delivery of drugs to tumor sites and release of drugs in response to specific stimuli. It not only improves the treatment efficiency of tumor but also reduces the toxic and side effects to normal tissues. Therefore, the development of natural polymer-based TDD (NPTDD) systems has great potential in tumor therapy. In this review, the mechanism of NPTDD systems such as penetration enhancers, nanoparticles, microneedles, hydrogels and nanofibers prepared from hyaluronic acid, chitosan, sodium alginate, cellulose, heparin and protein, and their applications in tumor therapy are overviewed. This review also outlines the future prospects and current challenges of NPTDD systems for local treatment tumors.

Polymer-Based mRNA Delivery Strategies for Advanced Therapies.

Messenger RNA (mRNA)-based therapies offer great promise for the treatment of a variety of diseases. In 2020, two FDA approvals of mRNA-based vaccines have elevated mRNA vaccines to global recognition. However, the therapeutic capabilities of mRNA extend far beyond vaccines against infectious diseases. They hold potential for cancer vaccines, protein replacement therapies, gene editing therapies, and immunotherapies. For realizing such advanced therapies, it is crucial to develop effective carrier systems. Recent advances in materials science have led to the development of promising nonviral mRNA delivery systems. In comparison to other carriers like lipid nanoparticles, polymer-based delivery systems often receive less attention, despite their unique ability to carefully tune their chemical features to promote mRNA protection, their favorable pharmacokinetics, and their potential for targeting delivery. In this review, the central features of polymer-based systems for mRNA delivery highlighting the molecular design criteria, stability, and biodistribution are discussed. Finally, the role of targeting ligands for the future of RNA therapies is analyzed.

Electrospun polymer fibers modified with FK506 for the long-term treatment of acute cardiac allograft rejection in a heart transplantation model.

FK506, a first-line immunosuppressant, is routinely administered orally and intravenously following heart transplantation. However, frequent administration can result in a substantial psychological burden to patients, resulting in non-adherence to medication. The purpose of our study is to overcome the disadvantages of systemic drug administration by developing a polymer-based delivery system that is tunable and biodegradable and that can release highly hydrophobic FK506 over extended periods to treat or prevent acute cardiac allograft rejection. Using an electrospinning method, long-acting microfibers were prepared, and FK506 appeared to be continuously released for up to 14 days based on the in vitro release profiles. After implanting the microfiber subcutaneously into the abdominals of transplanted rats, it was found that the infiltration of T cells and macrophages and the secretion of interleukin-2 (IL-2) and IL-1β were significantly reduced compared with those of the free FK506 groups. More importantly, the mean survival time (MST) of the PCL-FK506 group was significantly extended in comparison with that of untreated control recipients and free FK506 (MST of untreated control recipients, free FK506, and PCL-FK506 was 8, 26.1, and 37, respectively). In conclusion, we propose that this drug delivery approach would be suitable for developing long-lasting immunomodulatory agents that prolong cardiac graft survival safely and effectively.

Chemical Approaches to Synthetic Drug Delivery Systems for Systemic Applications.

Poor water solubility and low bioavailability of active pharmaceutical ingredients (APIs) are major causes of friction in the pharmaceutical industry and represent a formidable hurdle for pharmaceutical drug development. Drug delivery remains the major challenge for the application of new small-molecule drugs as well as biopharmaceuticals. The three challenges for synthetic delivery systems are: (i) controlling drug distribution and clearance in the blood; (ii) solubilizing poorly water-soluble agents, and (iii) selectively targeting specific tissues. Although several polymer-based systems have addressed the first two demands and have been translated into clinical practice, no targeted synthetic drug delivery system has reached the market. This Review is designed to provide a background on the challenges and requirements for the design and translation of new polymer-based delivery systems. This report will focus on chemical approaches to drug delivery for systemic applications.

Targeted Transposition of Minicircle DNA Using Single-Chain Antibody Conjugated Cyclodextrin-Modified Poly (Propylene Imine) Nanocarriers.

Simple SummaryGene therapy for the treatment of malignancies is an emerging and promising area of particular interest. Therefore, it is imperative to develop effective delivery systems for the specific transfer of nucleic acids into tumors. In comparison to viral vectors, non-viral delivery systems tend to be simple to manufacture, show lower immunogenicity, and are associated with fewer regulatory issues when translated into clinical settings. The aim of our study was to develop single-chain antibody conjugated cyclodextrin-modified poly(propylene imine) (PPI) nanocarriers, comprising β-cyclodextrin-modified PPI, mono-biotinylated, maltose-modified PPI, neutravidin and mono-biotinylated prostate stem cell antigen (PSCA)-specific single-chain antibodies for the targeted transposition of minicircle DNA into PSCA-positive tumor cells. Remarkably, we achieved long-term expression of a therapeutic p53 gene in PSCA-positive tumor cells by combining our tumor-specific hybrid polyplexes with the Sleeping Beauty transposon system in minicircle format.Among non-viral vectors, cationic polymers, such as poly(propylene imine) (PPI), play a prominent role in nucleic acid delivery. However, limitations of polycationic polymer-based DNA delivery systems are (i) insufficient target specificity, (ii) unsatisfactory transgene expression, and (iii) undesired transfer of therapeutic DNA into non-target cells. We developed single-chain antibody fragment (scFv)-directed hybrid polyplexes for targeted gene therapy of prostate stem cell antigen (PSCA)-positive tumors. Besides mono-biotinylated PSCA-specific single-chain antibodies (scFv(AM1-P-BAP)) conjugated to neutravidin, the hybrid polyplexes comprise β-cyclodextrin-modified PPI as well as biotin/maltose-modified PPI as carriers for minicircle DNAs encoding for Sleeping Beauty transposase and a transposon encoding the gene of interest. The PSCA-specific hybrid polyplexes efficiently delivered a GFP gene in PSCA-positive tumor cells, whereas control hybrid polyplexes showed low gene transfer efficiency. In an experimental gene therapy approach, targeted transposition of a codon-optimized p53 into p53-deficient HCT116p53−/−/PSCA cells demonstrated decreased clonogenic survival when compared to mock controls. Noteworthily, p53 transposition in PTEN-deficient H4PSCA glioma cells caused nearly complete loss of clonogenic survival. These results demonstrate the feasibility of combining tumor-targeting hybrid polyplexes and Sleeping Beauty gene transposition, which, due to the modular design, can be extended to other target genes and tumor entities.