Long-acting therapeutic delivery systems for the treatment of gliomas.

Despite the emergence of cutting-edge therapeutic strategies and tremendous progress in research, a complete cure of glioma remains elusive. The heterogenous nature of tumor, immunosuppressive state and presence of blood brain barrier are few of the major obstacles in this regard. Long-acting depot formulations such as injectables and implantables are gaining attention for drug delivery to brain owing to their ease in administration and ability to elute drug locally for extended durations in a controlled manner with minimal toxicity. Hybrid matrices fabricated by incorporating nanoparticulates within such systems help to enhance pharmaceutical advantages. Utilization of long-acting depots as monotherapy or in conjunction with existing strategies rendered significant survival benefits in many preclinical studies and some clinical trials. The discovery of novel targets, immunotherapeutic strategies and alternative drug administration routes are now coupled with several long-acting systems with an ultimate aim to enhance patient survival and prevent glioma recurrences.

Nucleic acid therapies for CNS diseases: Pathophysiology, targets, barriers, and delivery strategies.

Nucleic acid therapeutics have emerged as one of the very advanced and efficacious treatment approaches for debilitating health conditions, including those diseases affecting the central nervous system (CNS). Precise targeting with an optimal control over gene regulation confers long-lasting benefits through the administration of nucleic acid payloads via viral, non-viral, and engineered vectors. The current review majorly focuses on the development and clinical translational potential of non-viral vectors for treating CNS diseases with a focus on their specific design and targeting approaches. These carriers must be able to surmount the various intracellular and extracellular barriers, to ensure successful neuronal transfection and ultimately attain higher therapeutic efficacies. Additionally, the specific challenges associated with CNS administration also include the presence of blood-brain barrier (BBB), the complex pathophysiological and biochemical changes associated with different disease conditions and the existence of non-dividing cells. The advantages offered by lipid-based or polymeric systems, engineered proteins, particle-based systems coupled with various approaches of neuronal targeting have been discussed in the context of a variety of CNS diseases. The possibilities of rapid yet highly efficient gene modifications rendered by the breakthrough methodologies for gene editing and gene manipulation have also opened vast avenues of research in neuroscience and CNS disease therapy. The current review also underscores the extensive scientific efforts to optimize specialized, efficacious yet non-invasive and safer administration approaches to overcome the therapeutic delivery challenges specifically posed by the CNS transport barriers and the overall obstacles to clinical translation.

Differential Drug Release Kinetics from Paclitaxel-Loaded Polydioxanone Membranes and Capsules.

BACKGROUND: Drug laden implantable systems can provide drug release over several hours to years, which eventually aid in the therapy of both acute and chronic diseases. The present study focuses on a fundamental evaluation of the influence of implant properties such as morphology, architecture, porosity, surface area, and wettability in regulating the drug release kinetics from drug-loaded polymeric matrices. METHODS: For this, Polydioxanone (PDS) was selected as the polymer and Paclitaxel (Ptx) as the model drug. Two different forms of the matrix implants, viz., reservoir type capsules developed by dip coating and matrix type membranes fabricated by phase inversion and electrospinning, were utilized for the study. Drug release from all the four different matrices prepared by simple techniques was evaluated in vitro in PBS and ex vivo in peritoneal wash fluid for ~4 weeks. The drug release profiles were thereafter correlated with the physicochemical parameters of the polymeric implants. RESULTS: Reservoir-type capsules followed a slow and steady zero-order kinetics, while matrix-type electrospun and phase inversion membranes displayed typical biphasic kinetics. CONCLUSION: It was inferred that the slow degradation rate of PDS polymer as well as the implant properties like porosity and wettability play an important role in controlling the drug release rates.

Traumatic brain injury and the development of parkinsonism: Understanding pathophysiology, animal models, and therapeutic targets.

The clinical translation of therapeutic approaches to combat debilitating neurodegenerative conditions, such as Parkinson's disease (PD), remains as an urgent unmet challenge. The strong molecular association between the pathogenesis of traumatic brain injury (TBI) and the development of parkinsonism in humans has been well established. Therefore, a lot of ongoing research aims to investigate this pathology overlap in-depth, to exploit the common targets of TBI and PD for development of more effective and long-term treatment strategies. This review article intends to provide a detailed background on TBI pathophysiology and its established overlap with PD with an additional emphasis on the recent findings about their effect on perivascular clearance. Although, the traditional animal models of TBI and PD are still being considered, there is a huge focus on the development of combinatory hybrid animal models coupling concussion with the pre-established PD models for a better recapitulation of the human context of PD pathogenesis. Lastly, the therapeutic targets for TBI and PD, and the contemporary research involving exosomes, DNA vaccines, miRNA, gene therapy and gene editing for the development of potential candidates are discussed, along with the recent development of lesser invasive and promising central nervous system (CNS) drug delivery strategies.

Osmotic core-shell polymeric implant for sustained BDNF AntagoNAT delivery in CNS using minimally invasive nasal depot (MIND) approach.

The development of drug delivery strategies for efficacious therapeutic administration directly into the central nervous system (CNS) in a minimally invasive manner remains a major obstacle hindering the clinical translation of biological disease-modifying therapeutics. A novel direct trans-nasal delivery method, termed 'Minimally-Invasive Nasal Depot' (MIND), has proved to be successful in providing high CNS uptake and brain distribution of blood-brain barrier (BBB) impermeant therapeutics via direct administration to the olfactory submucosal space in a rodent model. The present study describes the engineering of custom-made implants with a unique architecture of an "osmotically-active core" entrapping the therapeutic and a "biodegradable polymeric shell" to enable long-acting delivery using the MIND procedure. The MIND-administered implant provided sustained CNS delivery of brain derived neurotrophic factor (BDNF) AntagoNATs for up to 4 weeks in Sprague Dawley rats resulting in significant endogenous BDNF protein upregulation in several brain tissues. The biocompatibility of such core-shell implants coupled with their substantial pharmacokinetic advantages and safety of the MIND procedure highlights the practical utility and translational potential of this synergistic approach for treatment of chronic age-related neurodegenerative diseases.

Minimally Invasive Nasal Depot (MIND) technique for direct BDNF AntagoNAT delivery to the brain.

The limitations of central nervous system (CNS) drug delivery conferred by the blood-brain barrier (BBB) have been a significant obstacle in the development of large molecule therapeutics for CNS disease. Though significantly safer than direct CNS administration via intrathecal (IT) or intracerebroventricular (ICV) injection, the topical intranasal delivery of CNS therapeutics has failed to become clinically useful due to a variety of practical and physiologic drawbacks leading to high dose variability and poor bioavailability. This study describes the minimally invasive nasal depot (MIND) technique, a novel method of direct trans-nasal CNS drug delivery which overcomes the dosing variability and efficiency challenges of traditional topical trans-nasal, trans-olfactory strategies by delivering the entire therapeutic dose directly to the olfactory submucosal space. We found that the implantation of a depot containing an AntagoNAT (AT) capable of de-repressing brain derived neurotrophic factor (BDNF) expression enabled CNS distribution of ATs with significant and sustained upregulation of BDNF with efficiencies approaching 40% of ICV delivery. As the MIND technique is derived from common outpatient rhinological procedures routinely performed in Ear, Nose and Throat (ENT) clinics, our findings support the significant translational potential of this novel minimally invasive strategy as a reliable therapeutic delivery approach for the treatment of CNS diseases.

Extracellular vesicle-mediated nucleic acid transfer and reprogramming in the tumor microenvironment.

Extracellular vesicles (EVs) have garnered much attention as key mediators of intercellular communication within the tumor microenvironment (TME) as well as at distinct metastatic sites. Nucleic acid molecules are the important components of the EV cargo. Characterizing EVs and strategies for modulating the nucleic acid content to promote anti-tumoral functions has led to the emerging role of EVs as potential novel targets for cancer therapy. Recent approaches of engineering the EVs to reach targeted sites have bought this to the forefront for nucleic acid delivery. In this article, we discuss EV biology with recent methods to analyze their nucleic acid contents. We emphasize the role of EV-mediated nucleic acid transfer in the TME assisting in tumor progression and metastasis and further review the strategies for modulating the nucleic acid content in EV for suppressing tumor growth and immune activation. The article further discusses the recent developments in generating EV mimics as nucleic acid delivery systems.

Critical quality attributes in the development of therapeutic nanomedicines toward clinical translation.

Nanomedicine is a rapidly emerging field with several breakthroughs in the therapeutic drug delivery application. The unique properties of the nanoscale delivery systems offer huge advantages to their payload such as solubilization, increased bioavailability, and improved pharmacokinetics with an overall goal of enhanced therapeutic index. Nanomedicine has the potential for integrating and enabling new therapeutic modalities. Several nanoparticle-based drug delivery systems have been granted approval for clinical use based on their outstanding clinical outcomes. Nanomedicine faces several challenges that hinder the realization of its full potential. In this review, we discuss the critical formulation- and biological-related quality features that significantly influence the performance of nanoparticulate systems in vivo. We also discuss the quality-by-design approach in the pharmaceutical manufacturing and its implementation in the nanomedicine. A deep understanding of these nanomedicine quality checkpoints and a systematic design that takes them into consideration will hopefully expedite the clinical translation process. Graphical abstract.

Delivery of neurotrophic factors in the treatment of age-related chronic neurodegenerative diseases.

Introduction: Neurodegenerative diseases are those wherein the neurons in the brain or peripheral nervous system lose their function, eventually culminating in neuronal death. Aging acts as the predominant factor here due to the reduced protein turnover rate in aging cells. As neurotrophic factors possess imperative roles in protecting the neurons and restoring their functionality, design of different modalities to deliver them to the brain would significantly enhance the therapeutic benefits.Areas covered: This review covers the various mechanisms of neurodegeneration, its molecular link with aging, different neurotrophic factor classes and their potentials, current treatment strategies, the challenges associated with the delivery of neurotrophic factors, administration routes, design of different delivery vehicle design, alternative modalities of delivery, and the clinical translational challenges of these strategies.Expert opinion: A deeper molecular level understanding about the complexity of neurodegeneration, discovery of potential biomarkers, which helps identifying the right targets, finding the accurate animal model completely recapitulating the human scenario, and a validated design of clinical trials would immensely help in overcoming the present challenges. The substantial developments in the field of gene therapy, usage of small molecules and peptide mimetics, combinatory approaches, etc. definitely give brighter hopes.

Nanofibrous Polydioxanone Depots for Prolonged Intraperitoneal Paclitaxel Delivery.

BACKGROUND: Prolonged chemodrug delivery to the tumor site is a prerequisite to maintaining its localised therapeutic concentrations for effective treatment of malignant solid tumors. OBJECTIVE: The current study aims to develop implantable polymeric depots through conventional electrospinning for sustained drug delivery, specifically to the peritoneum. METHODS: Non-woven electrospun mats were fabricated by simple electrospinning of Polydioxanone solution loaded with the chemodrug, Paclitaxel. The implants were subjected to the analysis of morphology, mechanical properties, degradation and drug release in phosphate buffer and patient-derived peritoneal drain fluid samples. In vivo studies were conducted by surgical knotting of these implants to the peritoneal wall of healthy mice. RESULTS: Non-woven electrospun mats with a thickness of 0.65±0.07 mm, weighing ~ 20 mg were fabricated by electrospinning 15 w/v% polymer loaded with 10 w/w% drug. These implants possessing good mechanical integrity showed a drug entrapment efficiency of 87.82±2.54 %. In vitro drug release studies in phosphate buffer showed a sustained profile for ~4 weeks with a burst of 10 % of total drug content, whereas this amounted to >60% in patient samples. Mice implanted with these depots remained healthy during the study period. The biphasic drug release profile obtained in vivo showed a slow trend, with peritoneal lavage and tissues retaining good drug concentrations for a sustained period. CONCLUSION: The results indicate that non-woven electrospun mats developed from biodegradable Polydioxanone polymer can serve as ideal candidates for easily implantable drug depots to address the challenges of peritoneal metastasis in ovarian cancer.

Enhanced anti-tumor efficacy and safety with metronomic intraperitoneal chemotherapy for metastatic ovarian cancer using biodegradable nanotextile implants.

The objective of this study was to evaluate intraperitoneal (IP) metronomic chemotherapy using sustained release paclitaxel (PTX) delivery from electrospun biodegradable polymeric yarns woven into suturable nanotextiles. Following confirmation of in vitro PTX efficacy in ID8-VEGF epithelial ovarian cancer cells, in vivo studies were performed upon surgical peritoneal implantation of nanotextile implants in orthotopic, syngeneic ID8-VEGF tumor-bearing C57BL/6 mice. In comparison to the clinical PTX-solution, there was a significant enhancement of anti-tumor efficacy and safety with PTX-nanotextiles. After 35-days, the peritoneum of tumor-bearing mice with PTX-nanotextiles was completely devoid of tumor nodules and ascitic fluid. Additionally, VEGF levels measured in peritoneal lavage fluid were 300-fold lower compared to PTX-solution and 600-fold lower as compared to untreated tumor-bearing animals. PTX-solution treated group also developed severe metastatic lesions and progressive ascitic fluid buildup. More importantly, no signs of systemic/ organ toxicity were observed in PTX-nanotextile implanted mice, unlike the systemic toxic effects induced by PTX-solution. Collectively, our results show the therapeutic and safety advantages offered by combining clinically translatable metronomic low-dose chemotherapy and IP pharmacokinetics using biodegradable nanotextile implants in addressing the challenges of late-stage ovarian cancer.

Long-term drug delivery using implantable electrospun woven polymeric nanotextiles.

A woven nanotextile implant was developed and optimized for long-term continuous drug delivery for potential oncological applications. Electrospun polydioxanone (PDS) nanoyarns, which are twisted bundles of PDS nanofibres, were loaded with paclitaxel (PTX) and woven into nanotextiles of different packing densities. A mechanistic modeling of in vitro drug release proved that a combination of diffusion and matrix degradation controlled the slow PTX-release from a nanoyarn, emphasizing the role of nanostructure in modulating release kinetics. Woven nanotextiles, through variations in its packing density and thereby architecture, demonstrated tuneable PTX-release. In vivo PTX-release, pharmacokinetics and biodistribution were evaluated in healthy BALB/c mice by suturing the nanotextile to peritoneal wall. The slow and metronomic PTX-release for 60 days from the loosely woven implant was extremely effective in enhancing its residence in peritoneum, in contrast to intraperitoneal injections. Such an implantable matrix offers a novel platform for therapy of solid tumors over prolonged durations.

Intraperitoneal chemotherapy for ovarian cancer using sustained-release implantable devices.

INTRODUCTION: Epithelial ovarian cancer (EOC) remains to be the most lethal of all gynecological malignancies mainly due to its asymptomatic nature. The late stages are manifested with predominant metastases confined to the peritoneal cavity. Although there has been a substantial progress in the treatment avenue with different therapeutic interventions, the overall survival rate of patients remain poor due to relapse and drug resistance. AREAS COVERED: The pharmacokinetic advantages offered by intraperitoneal (IP) chemotherapy due to peritoneal-plasma barrier can be potentially exploited for EOC relapse treatment. The ability to retain high concentrations of chemo-drugs with high AUC peritoneum/plasma for prolonged durations in the peritoneal cavity can be utilized effectively through the clinical adoption of drug delivery systems (DDSs) which obviates the need for indwelling catheters. The metronomic dosing strategy could enhance anti-tumor efficacy with a continuous, low dose of chemo-drugs providing minimal systemic toxicity. EXPERT OPINION: The development of a feasible, non-catheter based, IP DDS, retaining the peritoneal-drug levels, with less systemic levels could offer significant survival advantages as a patient-compliant therapeutic strategy. Suturable-implantable devices based on metronomic dosing, eluting drug in a sustained manner at low doses, could be implanted surgically post-debulking for treatment of refractory EOC patients.

Electrospun Polymeric Core-sheath Yarns as Drug Eluting Surgical Sutures.

Drug-coated sutures are widely used as delivery depots for antibiotics and anti-inflammatory drugs at surgical wound sites. Although drug-laden coating provides good localized drug concentration, variable loading efficiency and release kinetics limits its use. Alternatively, drug incorporation within suture matrices is hampered by the harsh fabrication conditions required for suture-strength enhancement. To circumvent these limitations, we fabricated mechanically robust electrospun core-sheath yarns as sutures, with a central poly-l-lactic acid core, and a drug-eluting poly-lactic-co-glycolic acid sheath. The electrospun sheath was incorporated with aceclofenac or insulin to demonstrate versatility of the suture in loading both chemical and biological class of drugs. Aceclofenac and insulin incorporated sutures exhibited 15% and 4% loading, and release for 10 and 7 days, respectively. Aceclofenac sutures demonstrated reduced epidermal hyperplasia and cellularity in skin-inflammation animal model, while insulin loaded sutures showed enhanced cellular migration in wound healing assay. In conclusion, we demonstrate an innovative strategy of producing mechanically strong, prolonged drug-release sutures loaded with different classes of drugs.