Rohit Bisht

Polymeric micelles for ocular drug delivery: From structural frameworks to recent preclinical studies

Abstract Effective intraocular drug delivery poses a major challenge due to the presence of various elimination mechanisms and physiological barriers that result in low ocular bioavailability after topical application. Over the past decades, polymeric micelles have emerged as one of the most promising drug delivery platforms for the management of ocular diseases affecting the anterior (dry eye syndrome) and posterior (age‐related macular degeneration, diabetic retinopathy and glaucoma) segments of the eye. Promising preclinical efficacy results from both in‐vitro and in‐vivo animal studies have led to their steady progression through clinical trials. The mucoadhesive nature of these polymeric micelles results in enhanced contact with the ocular surface while their small size allows better tissue penetration. Most importantly, being highly water soluble, these polymeric micelles generate clear aqueous solutions which allows easy application in the form of eye drops without any vision interference. Enhanced stability, larger cargo capacity, non‐toxicity, ease of surface modification and controlled drug release are additional advantages with polymeric micelles. Finally, simple and cost effective fabrication techniques render their industrial acceptance relatively high. This review summarizes structural frameworks, methods of preparation, physicochemical properties, patented inventions and recent advances of these micelles as effective carriers for ocular drug delivery highlighting their performance in preclinical studies. Graphical abstract Figure. No Caption available.

Light-responsive in situ forming injectable implants for effective drug delivery to the posterior segment of the eye

ABSTRACT Introduction: Frequent intravitreal injections are currently the preferred treatment method for diseases affecting the posterior segment of the eye. However, these repeated injections have been associated with pain, risk of infection, hemorrhages, retinal detachment and high treatment costs. To overcome these limitations, light-responsive in situ forming injectable implants (ISFIs) may emerge as novel systems providing site-specific controlled drug delivery to the retinal tissues with great accuracy, safety, minimal invasiveness and high cost efficiency. Area covered: Complex ocular barriers, routes for drug delivery, types of injectable implants, ocular application of light and benefits of light-responsive systems are discussed with regards to challenges and strategies employed for effective drug delivery to the posterior segment of the eye. In particular, we have highlighted photoresponsive moieties, photopolymerization mechanisms and different development strategies with their limitations as well as recent advancements in the field. Expert opinion: Biodegradable light-responsive ISFIs are promising drug delivery systems that have shown a high degree of biocompatibility with sustained drug release in a number of applications. However, their use in intravitreal drug delivery is still in the very early stages. Issues related to the biocompatibility of the photoinitiator and the elimination of photo-degraded by-products from the ocular tissues need careful consideration, not only from a chemistry standpoint, but also from a biological perspective to improve the suitability of these systems for clinical applications.

Nanocarrier mediated retinal drug delivery: overcoming ocular barriers to treat posterior eye diseases

Effective drug delivery to the retina still remains a challenge due to ocular elimination mechanisms and complex barriers that selectively limit the entry of drugs into the eye. To overcome these barriers, frequent intravitreal injections are currently used to achieve high drug concentrations in vitreous and retina. However, these repetitive injections may result in several side effects. Recent advancements in the field of nanoparticle-based drug delivery could overcome some of these unmet needs and various preclinical studies conducted to date have demonstrated promising results of nanotherapies in the treatment of retinal diseases. Compared to the majority of commercially available ocular implants, the biodegradable nature of most nanoparticles (NPs) avoids the need for surgical implantation and removal after the release of the payload. In addition, the sustained drug release from NPs over an extended period of time reduces the need for frequent intravitreal injections and the risk of associated side effects. The nanometer size and highly modifiable surface properties make NPs excellent candidates for targeted ocular drug delivery. Studies have shown that nanocarriers enhance the intravitreal half-life and thus bioavailability of a number of drugs including proteins and peptides. In addition, they have shown promising results in delivering genetic material to the retinal tissues by protecting it from possible intravitreal degradation. This review covers the various challenges associated with drug delivery to the posterior segment of the eye, particularly the retina, and highlights the application of nanocarriers to overcome these challenges in context with recent advances in preclinical studies. WIREs Nanomed Nanobiotechnol 2018, 10:e1473. doi: 10.1002/wnan.1473 This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Implantable Materials and Surgical Technologies > Nanomaterials and Implants.

PLGA nanoparticles for intravitreal peptide delivery: statistical optimization, characterization and toxicity evaluation

Abstract Frequent intravitreal injections are currently used to overcome the ocular barriers and provide sufficient drug to the posterior eye segment. However, intravitreal injections have been associated with a number of complications and high treatment costs. To overcome these limitations, peptide-loaded poly(d,l-lactic-co-glycolic acid) nanoparticles (PLGA NPs) were developed using the nanoprecipitation technique and were optimized via Box–Behnken Design (BBD) and Response Surface Methodology (RSM). Developed NPs were evaluated for potential toxicity and cell apoptosis using the zebrafish embryo toxicity (ZET) model with titanium dioxide NPs and ethanol (1% v/v) serving as positive controls. Developed NPs had a size of 75.6–153.8 nm, a polydispersity index between 0.11 and 0.25 and a zeta potential of −9.4 to −46.0 mV. Loaded peptide was found to be stable under various experimental conditions tested. BBD and RSM were validated through the characterization of optimized formulations. Survival and hatching rates of NP-treated zebrafish 0–144 h post-fertilization were found to be normal with no significant malformations. Cellular apoptosis studies also endorsed the non-cytotoxic nature of the NPs. The overall results indicate that optimized PLGA nanoparticles could be a promising platform for efficient peptide delivery to the posterior segment of the eye.

Topical formulation of self-assembled antiviral prodrug nanomicelles for targeted retinal delivery

Topical drug administration for back of the eye delivery is extremely challenging due to the presence of protection mechanisms and physiological barriers. Self-assembled polymeric nanomicelles have emerged as promising vehicles for drug delivery. Apart from serving as an inert nanocarrier for therapeutic agents, polymeric nanomicelles are known to bypass mononuclear phagocytic system (MPS) and efflux transporters thereby improving drug bioavailability. In this investigation, a highly efficacious biotinylated lipid prodrug of cyclic cidofovir (B-C12-cCDF) was formulated within polymeric nanomicelles as a carrier for targeted retinal delivery. Polymeric nanomicelles were prepared from polyoxyethylene hydrogenated castor oil 40 (HCO-40) and octoxynol 40 (OC-40). In vitro release studies revealed that B-C12-cCDF-loaded nanomicelles released B-C12-cCDF at a faster rate in stimulated tear fluid (STF) in comparison to PBST. MTT and LDH assays demonstrated negligible cytotoxicity of B-C12-cCDF-loaded nanomicelles relative to CDF and B-C12-cCDF in HRPE (human retinal pigment epithelial, D407), HCE-T (human corneal epithelial), and CCL 20.2 (human conjunctival epithelial) cells. Confocal laser scanning microscopy and flow cytometry analyses indicated that B-C12-cCDF-loaded nanomicelles were efficiently internalized into D407 and HCE-T cells in contrast to CDF and B-C12-cCDF. Moreover, little B-C12-cCDF was also observed in the nuclei after 24 h of incubation. Polymeric nanomicelles carrying the transporter targeted prodrug did not produce any cytotoxic effects and were internalized into the cells effectively. Permeability experiments across HCE-T cells further confirmed significant transport of prodrug loaded nanomicelles and their subsequent uptake into D407 cells. These findings indicate that HCO-40/OC-40 based polymeric nanomicelles could become a promising topical delivery system for ocular administration of antiviral agents.

Development of a novel stability indicating RP-HPLC method for quantification of Connexin43 mimetic peptide and determination of its degradation kinetics in biological fluids

Connexin43 mimetic peptide (Cx43MP) has been intensively investigated for its therapeutic effect in the management of inflammatory eye conditions, spinal cord injury, wound healing and ischemia-induced brain damage. Here, we report on a validated stability–indicating reversed-phase high performance liquid chromatography (RP-HPLC) method for the quantification of Cx43MP under stress conditions. These included exposure to acid/base, light, oxidation and high temperature. In addition, the degradation kinetics of the peptide were evaluated in bovine vitreous and drug-free human plasma at 37 °C. Detection of Cx43MP was carried out at 214 nm with a retention time of 7.5 min. The method showed excellent linearity over the concentration range of 0.9–250 µg/mL (R2 ≥ 0.998), and the limits of detection (LOD) and quantification (LOQ) were found to be 0.90 and 2.98 μg/mL, respectively. The accuracy of the method determined by the mean percentage recovery at 7.8, 62.5 and 250 µg/mL was 96.79%, 98.25% and 99.06% with a RSD of < 2.2%. Accelerated stability studies revealed that Cx43MP was more sensitive to basic conditions and completely degraded within 24 h at 37 °C (0% recovery) and within 12 h at 80 °C (0.34% recovery). Cx43MP was found to be more stable in bovine vitreous (t1/2slow= 171.8 min) compared to human plasma (t1/2slow = 39.3 min) at 37 °C according to the two phase degradation kinetic model. These findings are important for further pre-clinical development of Cx43MP.

Diagnosis and Drug Delivery to the Brain: Novel Strategies

For decades, tremendous efforts have been made by biomedical and pharmaceutical researchers to treat diseases affecting the central nervous system (CNS). The blood–brain barrier effectively protects the brain, but poses a formidable challenge to drug delivery. Many conventional drugs cannot cross the BBB in therapeutic concentrations (less than 1%). As a result proper treatments of various CNS diseases such as Alzheimer, brain tumors, and human immunodeficiency virus infection are compromised. Due to the failure of most treatments for CNS disorders, development of novel drug delivery systems appears to be highly challenging. Nanotechnology has paved a way for new therapies for CNS drug delivery. In particular, multifunctional nanoscaled carriers with a variety of imaging options have revolutionized drug delivery platforms, diagnosis, monitoring, and treatment of brain disorders. In this chapter, an attempt has been made to provide an overview of various novel drug delivery and diagnosis strategies to treat brain disorders.Abstract For decades, tremendous efforts have been made by biomedical and pharmaceutical researchers to treat diseases affecting the central nervous system (CNS). The blood–brain barrier effectively protects the brain, but poses a formidable challenge to drug delivery. Many conventional drugs cannot cross the BBB in therapeutic concentrations (less than 1%). As a result proper treatments of various CNS diseases such as Alzheimer, brain tumors, and human immunodeficiency virus infection are compromised. Due to the failure of most treatments for CNS disorders, development of novel drug delivery systems appears to be highly challenging. Nanotechnology has paved a way for new therapies for CNS drug delivery. In particular, multifunctional nanoscaled carriers with a variety of imaging options have revolutionized drug delivery platforms, diagnosis, monitoring, and treatment of brain disorders. In this chapter, an attempt has been made to provide an overview of various novel drug delivery and diagnosis strategies to treat brain disorders.

Micro- and Nanotechnology-Based Implantable Devices and Bionics

Abstract Over the years, the medical device industry based on micro- and nanotechnology systems has been growing at a very fast rate and having immense opportunity for effective management of wide pathophysiological conditions. This chapter provides a brief introduction on the structural framework of various micro- and nanotechnology-based implantable devices and bionics including micro- and nanoelectromechanical systems. These devices are designed to mimic biological systems and natural intelligence. The biocompatibility issues with these devices are described in this chapter. This chapter also covers biocompatibility issues with such devices before describing their application as biosensors, diagnostics, and drug delivery systems. Advancements in implantable devices and bionics are also discussed. Finally, challenges and opportunities regarding control over the drug release profiles and interactions with various biological components are highlighted.