Challenges in Biomaterial-Based Drug Delivery Approach for the Treatment of Neurodegenerative Diseases: Opportunities for Extracellular Vesicles

Biomaterials have been the subject of numerous studies to pursue potential therapeutic interventions for a wide variety of disorders and diseases. The physical and chemical properties of various materials have been explored to develop natural, synthetic, or semi-synthetic materials with distinct advantages for use as drug delivery systems for the central nervous system (CNS) and non-CNS diseases. In this review, an overview of popular biomaterials as drug delivery systems for neurogenerative diseases is provided, balancing the potential and challenges associated with the CNS drug delivery. As an effective drug delivery system, desired properties of biomaterials are discussed, addressing the persistent challenges such as targeted drug delivery, stimuli responsiveness, and controlled drug release in vivo. Finally, we discuss the prospects and limitations of incorporating extracellular vesicles (EVs) as a drug delivery system and their use for biocompatible, stable, and targeted delivery with limited immunogenicity, as well as their ability to be delivered via a non-invasive approach for the treatment of neurodegenerative diseases.     

Mutual Prodrugs of 5-Fluorouracil: From a Classic Chemotherapeutic Agent to Novel Potential Anticancer Drugs

The development of potent antitumor agents with a low toxicological profile against healthy cells is still one of the greatest challenges facing medicinal chemistry. In this context, the “mutual prodrug” approach has emerged as a potential tool to overcome undesirable physicochemical features and mitigate the side effects of approved drugs. Among broad-spectrum chemotherapeutics available for clinical use today, 5-fluorouracil (5-FU) is one of the most representative, also included in the World Health Organization model list of essential medicines. Unfortunately, severe side effects and drug resistance phenomena are still the primary limits and drawbacks in its clinical use. This review describes the progress made over the last ten years in developing 5-FU-based mutual prodrugs to improve the therapeutic profile and achieve targeted delivery to cancer tissues.     

Stimuli-Responsive Prodrug Chemistries for Cancer Therapy

Prodrugs are pharmacologically inactive, chemically modified derivatives of active drugs, which, following in vivo administration, are converted to the parent drugs through chemical or enzymatic cleavage. The prodrug approach holds tremendous potential to create the enhanced version of an existing pharmacological agent and leverage those improvements to augment the drug molecules′ bioavailability, targeting ability, therapeutic efficacy, safety, and marketability. Especially in cancer therapy, prodrug application has received substantial attention. A prodrug can effectively broaden the therapeutic window of its parent drug by enhancing its release at targeted tumor sites while reducing its access to healthy cells. The spatiotemporally controlled release can be achieved by manipulating the chemical, physical, or biological stimuli present at the targeted tumor site. The critical strategy comprises drug-carrier linkages that respond to physiological or biochemical stimuli in the tumor milieu to yield the active drug form. This review will focus on the recent advancements in the development of various fluorophore-drug conjugates that are widely used for real-time monitoring of drug delivery. The use of different stimuli-cleavable linkers and the mechanisms of linker cleavage will be discussed. Finally, the review will conclude with a critical discussion of the prospects and challenges that might impede the future development of such prodrugs.     

Systemically Administered,Target Organ-Specific Therapies for Regenerative Medicine

Growth factors and other agents that could potentially enhance tissue regeneration have been identified, but their therapeutic value in clinical medicine has been limited for reasons such as difficulty to maintain bioactivity of locally applied therapeutics in the protease-rich environment of regenerating tissues. Although human diseases are treated with systemically administered drugs in general, all current efforts aimed at enhancing tissue repair with biological drugs have been based on their local application. The systemic administration of growth factors has been ruled out due to concerns about their safety. These concerns are warranted. In addition, only a small proportion of systemically administered drugs reach their intended target. Selective delivery of the drug to the target tissue and use of functional protein domains capable of penetrating cells and tissues could alleviate these problems in certain circumstances. We will present in this review a novel approach utilizing unique molecular fingerprints (“Zip/postal codes”) in the vasculature of regenerating tissues that allows target organ-specific delivery of systemically administered therapeutic molecules by affinity-based physical targeting (using peptides or antibodies as an “address tag”) to injured tissues undergoing repair. The desired outcome of targeted therapies is increased local accumulation and lower systemic concentration of the therapeutic payload. We believe that the physical targeting of systemically administered therapeutic molecules could be rapidly adapted in the field of regenerative medicine.     

Self-assembled targeted nanoparticles: evolution of technologies and bench to bedside translation

Nanoparticles (NPs) have become an important tool in many industries including healthcare. The use of NPs for drug delivery and imaging has introduced exciting opportunities for the improvement of disease diagnosis and treatment. Over the past two decades, several first-generation therapeutic NP products have entered the market. Despite the lack of controlled release and molecular targeting properties in these products, they improved the therapeutic benefit of clinically validated drugs by enhancing drug tolerability and/or efficacy. NP-based imaging agents have also improved the sensitivity and specificity of different diagnostic modalities. The introduction of controlled-release properties and targeting ligands toward the development of next-generation NPs should enable the development of safer and more effective therapeutic NPs and facilitate their application in theranostic nanomedicine. Targeted and controlled-release NPs can drastically alter the pharmacological characteristics of their payload, including their pharmacokinetic and, in some cases, their pharmacodynamic properties. As a result, these NPs can improve drug properties beyond what can be achieved through classic medicinal chemistry. Despite their enormous potential, the translation of targeted NPs into clinical development has faced considerable challenges. One significant problem has been the difficulty in developing targeted NPs with optimal biophysicochemical properties while using robust processes that facilitate scale-up and manufacturing. Recently, efforts have focused on developing NPs through self-assembly or high-throughput processes to facilitate the development and screening of NPs with these distinct properties and the subsequent scale-up of their manufacture. We have also undertaken parallel efforts to integrate additional functionality within therapeutic and imaging NPs, including the ability to carry more than one payload, to respond to environmental triggers, and to provide real-time feedback. In addition, novel targeting approaches are being developed to enhance the tissue-, cell-, or subcellular-specific delivery of NPs for a myriad of important diseases. These include the selection of internalizing ligands for enhanced receptor-mediated NP uptake and the development of extracellular targeting ligands for vascular tissue accumulation of NPs. In this Account, we primarily review the evolution of marketed NP technologies. We also recount our efforts in the design and optimization of NPs for medical applications, which formed the foundation for the clinical translation of the first-in-man targeted and controlled-release NPs (BIND-014) for cancer therapy.     

Nucleic Acid Aptamer‐Mediated Drug Delivery for Targeted Cancer Therapy

Aptamers are emerging as promising therapeutic agents and recognition elements. In particular, cell‐SELEX ( s ystematic e volution of l igands by ex ponential enrichment) allows in vitro selection of aptamers selective to whole cells without prior knowledge of the molecular signatures on the cell surface. The advantage of aptamers is their high affinitiy and binding specificity towards the target. This Minireview focuses on single‐stranded (ss) oligonucleotide (DNA or RNA)‐based aptamers as cancer therapeutics/theranostics. Specifically, aptamer–nanomaterial conjugates, aptamer–drug conjugates, targeted phototherapy and targeted biotherapy are covered in detail. In reviewing the literature, the potential of aptamers as delivery systems for therapeutic and imaging applications in cancer is clear, however, major challenges remain to be resolved, such as the poorly understood pharmacokinetics, toxicity and off‐target effects, before they can be fully exploited in a clinical setting.     

Shear-Responsive Platelet Mimetics for Targeted Drug Delivery

Most targeted drug delivery approaches utilize molecular targets or regional variations in chemical or structural properties of the tissue microenvironment to localize drug at disease sites. Here we briefly describe a novel nanotherapeutic drug delivery platform that relies upon local mechanical activation by high fluid shear stresses to selectively target drugs to sites of vascular obstruction. This strategy is based on the use of microscale aggregates of nanoparticles that are shear sensitive and break up into individual nanoscale components that adhere to the surface of stenotic vessels in regions of abnormally high fluid shear stress, much as natural platelets do. This biomimetic approach to targeted drug delivery offers a potential new therapeutic approach for treatment of pulmonary embolism, stroke, atherosclerosis, and other hemodynamic-related disorders that are caused by vascular clots, stenosis or obstruction.     

Quercetin-encapsulated magnetoliposomes: Fabrication,optimization, characterization,and antioxidant studies

Quercetin (QU) faces challenges in its therapeutic efficacy due to its hydrophobic nature and limited oral bioavailability. Using a Box–Behnken design (BBD) approach, we developed QU-loaded magnetoliposomes (QMLs) to address these limitations. By encapsulating QU within iron oxide nanoparticles (IONPs) and liposomes (LPs), we enhanced its hydrophilicity and improved its potential for drug delivery. Through systematic adjustments of phosal, polyvinyl alcohol, and magnetic/IONPs, we optimized the particle size, zeta potential, and iron content of the QMLs. The formulations underwent comprehensive structural characterization using techniques, such as Fourier transform infrared spectroscopy, X-Ray diffraction, differential scanning calorimetry–thermogravimetric analysis, and energy-dispersive X-ray analysis, whereas their morphology was examined through field emission scanning electron microscopy. Furthermore, we evaluated the in vitro drug release of the QMLs and antioxidant activity of QU, QU-loaded LPs, and QMLs using DPPH, 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid), and H₂O₂ scavenging assays, enabling us to compare their antioxidant potential and the efficiency of QU encapsulation within the magneto LPs. Practical Applications: This research holds significant practical implications, particularly in targeted drug delivery using magnetic liposomes. The developed system shows promise in enhancing cancer therapy, providing localized treatment for inflammation-related conditions, delivering drugs to the brain to address neurological disorders, promoting wound healing, and incorporating quercetin into skincare products for its antioxidant and antiaging benefits.     

Study of the Expression and Function of Calcium-Sensing Receptor in Human Skeletal Muscle

Skeletal muscle has an outstanding capacity for regeneration in response to injuries, but there are disorders in which this process is seriously impaired, such as sarcopenia. Pharmacological treatments to restore muscle trophism are not available, therefore, the identification of suitable therapeutic targets that could be useful for the treatment of skeletal reduced myogenesis is highly desirable. In this in vitro study, we explored the expression and function of the calcium-sensing receptor (CaSR) in human skeletal muscle tissues and their derived satellite cells. The results obtained from analyses with various techniques of gene and protein CaSR expression and of its secondary messengers in response to calcium (Ca²⁺) and CaSR drugs have demonstrated that this receptor is not present in human skeletal muscle tissues, neither in the established satellite cells, nor during in vitro myogenic differentiation. Taken together, our data suggest that, although CaSR is a very important drug target in physiology and pathology, this receptor probably does not have any physiological role in skeletal muscle in normal conditions.     

Carbohydrate-based Biomedical Copolymers for Targeted Delivery of Anticancer Drugs

A variety of strategies and carrier molecules have been used to direct therapeutic agents to tumor sites. The incorporation of a specific targeting moiety to drug carrier may result in active drug uptake by malignant cells. Carbohydrates are important mediators of cell–cell recognition events and have been implicated in related processes such as cell signaling regulation, cellular differentiation, and immune response. The biocompatibility of carbohydrates and their ability to be specifically recognized by cell-surface receptors indicate their potential utility as ligands in targeted drug delivery for therapeutic applications. Yet, carbohydrates are not ideal targeting ligands because they are difficult to synthesize, bind weakly to carbohydrate receptors, and are prone to suffer from enzyme degradation due to labile glycosidic linkages. This review describes the design and development of HPMA-based biomedical copolymers to facilitate the selective delivery of drugs to tumor tissues via carbohydrate–endogenous lectin interactions. Various carbohydrate-decorated HPMA copolymer–drug conjugates are presented and the application of the copolymers for drug delivery is discussed. Current efforts to increase the affinity of carbohydrate ligands for their target receptors through multivalent display are also discussed. These novel HPMA copolymer carbohydrate conjugates hold promise as clinically relevant drug delivery systems for cancer therapy.     

A RNA-DNA Hybrid Aptamer for Nanoparticle-Based Prostate Tumor Targeted Drug Delivery

The side effects of radio- and chemo-therapy pose long-term challenges on a cancer patient’s health. It is, therefore, highly desirable to develop more effective therapies that can specifically target carcinoma cells without damaging normal and healthy cells. Tremendous efforts have been made in the past to develop targeted drug delivery systems for solid cancer treatment. In this study, a new aptamer, A10-3-J1, which recognizes the extracellular domain of the prostate specific membrane antigen (PSMA), was designed. A super paramagnetic iron oxide nanoparticle-aptamer-doxorubicin (SPIO-Apt-Dox) was fabricated and employed as a targeted drug delivery platform for cancer therapy. This DNA RNA hybridized aptamer antitumor agent was able to enhance the cytotoxicity of targeted cells while minimizing collateral damage to non-targeted cells. This SPIO-Apt-Dox nanoparticle has specificity to PSMA⁺ prostate cancer cells. Aptamer inhibited nonspecific uptake of membrane-permeable doxorubic to the non-target cells, leading to reduced untargeted cytotoxicity and endocytic uptake while enhancing targeted cytotoxicity and endocytic uptake. The experimental results indicate that the drug delivery platform can yield statistically significant effectiveness being more cytotoxic to the targeted cells as opposed to the non-targeted cells.     

Theranostic nanomedicine

Nanomedicine formulations aim to improve the biodistribution and the target site accumulation of systemically administered (chemo)therapeutic agents. Many different types of nanomedicines have been evaluated over the years, including for instance liposomes, polymers, micelles and antibodies, and a significant amount of evidence has been obtained showing that these submicrometer-sized carrier materials are able to improve the balance between the efficacy and the toxicity of therapeutic interventions. Besides for therapeutic purposes, nanomedicine formulations have in recent years also been increasingly employed for imaging applications. Moreover, paralleled by advances in chemistry, biology, pharmacy, nanotechnology, medicine and imaging, several different systems have been developed in the last decade in which disease diagnosis and therapy are combined. These so-called (nano) theranostics contain both a drug and an imaging agent within a single formulation, and they can be used for various different purposes. In this Account, we summarize several exemplary efforts in this regard, and we show that theranostic nanomedicines are highly suitable systems for monitoring drug delivery, drug release and drug efficacy. The (pre)clinically most relevant applications of theranostic nanomedicines relate to their use for validating and optimizing the properties of drug delivery systems, and to their ability to be used for pre-screening patients and enabling personalized medicine. Regarding the former, the combination of diagnostic and therapeutic agents within a single formulation provides real-time feedback on the pharmacokinetics, the target site localization and the (off-target) healthy organ accumulation of nanomedicines. Various examples of this will be highlighted in this Account, illustrating that by non-invasively visualizing how well carrier materials are able to deliver pharmacologically active agents to the pathological site, and how well they are able to prevent them from accumulating in potentially endangered healthy tissues, important information can be obtained for optimizing the basic properties of drug delivery systems, as well as for improving the balance between the efficacy and the toxicity of targeted therapeutic interventions. Regarding personalized medicine, it can be reasoned that only in patients which show high levels of target site accumulation, and which respond well to the first couple of treatment cycles, targeted therapy should be continued, and that in those in which this is not the case, other therapeutic options should be considered. Based on these insights, we expect that ever more efforts will be invested in developing theranostic nanomedicines, and that these systems and strategies will contribute substantially to realizing the potential of personalized medicine.     

Monoclonal antibody‐targeted polymeric nanoparticles for cancer therapy – future prospects

Although combination therapy for cancer utilising monoclonal antibodies in conjunction with chemotherapeutic drugs has resulted in increases in 5 year survivals, there nevertheless remains significant morbidity and mortality associated with systemic delivery of cytotoxic drugs. The advent of living radical polymerisation has resulted in complex and elegant nanoparticle structures that can be engineered to passively target a drug payload for cancer treatment. This presents a therapeutic modality whereby biodistribution and consequently systemic toxicity can be reduced, while focusing drug delivery to the tumour site. Nanoparticle delivery can be enhanced by attachment of a targeting monoclonal antibody fragment to facilitate tumour cell uptake through endocytosis, and so increase therapeutic efficacy. In this way, monoclonal antibodies can be supercharged by carrying a payload consisting of a cocktail of conventional chemotherapeutic drugs and siRNA. This review will focus on antibody‐targeted polymeric nanoparticles to cancer cells, and methods and technologies for synthesising such antibody‐targeted nanoparticles. The review is confined to polymeric‐based nanoparticles as these offer some advantages over liposomal nanoparticles and may circumvent some of the pitfalls in nanomedicine. Development of these antibody based polymeric nanoparticles and future directions for therapy are highlighted in this review. © 2014 Society of Chemical Industry     

Drug Conjugates Such as Antibody Drug Conjugates (ADCs), Immunotoxins and Immunoliposomes Challenge Daily Clinical Practice

Drug conjugates have been studied extensively in preclinical in vitro and in vivo models but to date only a few compounds have progressed to the clinical setting. This situation is now changing with the publication of studies demonstrating a significant impact on clinical practice and highlighting the potential of this new class of targeted therapies. This review summarizes the pharmacological and molecular background of the main drug conjugation systems, namely antibody drug conjugates (ADCs), immunotoxins and immunoliposomes. All these compounds combine the specific targeting moiety of an antibody or similar construct with the efficacy of a toxic drug. The aim of this strategy is to target tumor cells specifically while sparing normal tissue, thus resulting in high efficacy and low toxicity. Recently, several strategies have been investigated in phase I clinical trials and some have entered phase III clinical development. This review provides a detailed overview of various strategies and critically discusses the most relevant achievements. Examples of the most advanced compounds include T-DM1 and brentuximab vedotin. However, additional promising strategies such as immunotoxins and immunoliposmes are already in clinical development. In summary, targeted drug delivery by drug conjugates is a new emerging class of anti-cancer therapy that may play a major role in the future.     

Clinical Application of Novel Therapies for Coronary Angiogenesis: Overview,Challenges, and Prospects

Cardiovascular diseases continue to be the leading cause of death worldwide, with ischemic heart disease as the most significant contributor. Pharmacological and surgical interventions have improved clinical outcomes, but are unable to ameliorate advanced stages of end-heart failure. Successful preclinical studies of new therapeutic modalities aimed at revascularization have shown short lasting to no effects in the clinical practice. This lack of success may be attributed to current challenges in patient selection, endpoint measurements, comorbidities, and delivery systems. Although challenges remain, the field of therapeutic angiogenesis is evolving, as novel strategies and bioengineering approaches emerge to optimize delivery and efficacy. Here, we describe the structure, vascularization, and regulation of the vascular system with particular attention to the endothelium. We proceed to discuss preclinical and clinical findings and present challenges and future prospects in the field.     

Progress and Challenges in Developing Aptamer-Functionalized Targeted Drug Delivery Systems

Aptamers, which can be screened via systematic evolution of ligands by exponential enrichment (SELEX), are superior ligands for molecular recognition due to their high selectivity and affinity. The interest in the use of aptamers as ligands for targeted drug delivery has been increasing due to their unique advantages. Based on their different compositions and preparation methods, aptamer-functionalized targeted drug delivery systems can be divided into two main categories: aptamer-small molecule conjugated systems and aptamer-nanomaterial conjugated systems. In this review, we not only summarize recent progress in aptamer selection and the application of aptamers in these targeted drug delivery systems but also discuss the advantages, challenges and new perspectives associated with these delivery systems.     

Nanocarriers,Progenitor Cells,Combinational Approaches,and New Insights on the Retinal Therapy

Progenitor cells derived from the retinal pigment epithelium (RPECs) have shown promise as therapeutic approaches to degenerative retinal disorders including diabetic retinopathy, age-related macular degeneration and Stargardt disease. However, the degeneration of Bruch’s membrane (BM), the natural substrate for the RPE, has been identified as one of the major limitations for utilizing RPECs. This degeneration leads to decreased support, survival and integration of the transplanted RPECs. It has been proposed that the generation of organized structures of nanofibers, in an attempt to mimic the natural retinal extracellular matrix (ECM) and its unique characteristics, could be utilized to overcome these limitations. Furthermore, nanoparticles could be incorporated to provide a platform for improved drug delivery and sustained release of molecules over several months to years. In addition, the incorporation of tissue-specific genes and stem cells into the nanostructures increased the stability and enhanced transfection efficiency of gene/drug to the posterior segment of the eye. This review discusses available drug delivery systems and combination therapies together with challenges associated with each approach. As the last step, we discuss the application of nanofibrous scaffolds for the implantation of RPE progenitor cells with the aim to enhance cell adhesion and support a functionally polarized RPE monolayer.     

Application of magnetic nanoparticles to gene delivery

Nanoparticle technology is being incorporated into many areas of molecular science and biomedicine. Because nanoparticles are small enough to enter almost all areas of the body, including the circulatory system and cells, they have been and continue to be exploited for basic biomedical research as well as clinical diagnostic and therapeutic applications. For example, nanoparticles hold great promise for enabling gene therapy to reach its full potential by facilitating targeted delivery of DNA into tissues and cells. Substantial progress has been made in binding DNA to nanoparticles and controlling the behavior of these complexes. In this article, we review research on binding DNAs to nanoparticles as well as our latest study on non-viral gene delivery using polyethylenimine-coated magnetic nanoparticles.     

ncRNAs in Therapeutics: Challenges and Limitations in Nucleic Acid-Based Drug Delivery

Non-coding RNAs (ncRNAs) are emerging therapeutic tools but there are barriers to their translation to clinical practice. Key issues concern the specificity of the targets, the delivery of the molecules, and their stability, while avoiding “on-target” and “off-target” side effects. In this “ncRNA in therapeutics” issue, we collect several studies of the differential expression of ncRNAs in cardiovascular diseases, bone metabolism-related disorders, neurology, and oncology, and their potential to be used as biomarkers or therapeutic targets. Moreover, we review recent advances in the use of antisense ncRNAs in targeted therapies with a particular emphasis on their basic biological mechanisms, their translational potential, and future trends.     

pH and magnetic field responsive protein-inorganic nanohybrid conjugated with biotin: A biocompatible carrier system targeting lung cancer cells

Multi-stimuli responsive carrier systems, specifically targeting tumor cells are of high significance to improve the efficacy of cancer chemotherapy. In the present study, we have developed, characterized, and biologically evaluated magnetic casein-calcium ferrite hybrid biopolymeric carrier conjugated with biotin for targeted delivery of cinnamaldehyde to lung carcinoma. The dual stimuli-responsive carrier was successfully synthesized with small size, good stability, and high drug encapsulation efficiency. Natural drug cinnamaldehyde was encapsulated in the hybrid carrier, on which biotin was conjugated to facilitate selective cellular uptake. The prepared drug-carrier system exhibited pH-responsive drug release behavior with a higher release rate under acidic conditions, which can be effectively applied in targeted cancer chemotherapy. The superparamagnetic nature of calcium ferrite enabled magnetically-modulated drug delivery with faster drug release, reaching 85.5% within 4 h, in response to magnetic field stimulus. Kinetic modeling of drug release projected the diffusion-controlled release mechanism. Cell viability assay performed on L929 fibroblast and A549 lung cancer cells verified the biocompatibility and cytotoxicity of the developed formulation, respectively. The nanohybrid carrier significantly increased the anticancer potential of cinnamaldehyde with an 18-fold reduction in the IC₅₀ value, signifying the biotin-functionalized protein-inorganic nanohybrid as an efficient multifunctional platform for targeted drug delivery.