Vibhuti Agrahari

Novel delivery approaches for cancer therapeutics.

Currently, a majority of cancer treatment strategies are based on the removal of tumor mass mainly by surgery. Chemical and physical treatments such as chemo- and radiotherapies have also made a major contribution in inhibiting rapid growth of malignant cells. Furthermore, these approaches are often combined to enhance therapeutic indices. It is widely known that surgery, chemo- and radiotherapy also inhibit normal cells growth. In addition, these treatment modalities are associated with severe side effects and high toxicity which in turn lead to low quality of life. This review encompasses novel strategies for more effective chemotherapeutic delivery aiming to generate better prognosis. Currently, cancer treatment is a highly dynamic field and significant advances are being made in the development of novel cancer treatment strategies. In contrast to conventional cancer therapeutics, novel approaches such as ligand or receptor based targeting, triggered release, intracellular drug targeting, gene delivery, cancer stem cell therapy, magnetic drug targeting and ultrasound-mediated drug delivery, have added new modalities for cancer treatment. These approaches have led to selective detection of malignant cells leading to their eradication with minimal side effects. Lowering multi-drug resistance and involving influx transportation in targeted drug delivery to cancer cells can also contribute significantly in the therapeutic interventions in cancer.

Nanocarrier fabrication and macromolecule drug delivery: challenges and opportunities

Macromolecules (proteins/peptides) have the potential for the development of new therapeutics. Due to their specific mechanism of action, macromolecules can be administered at relatively low doses compared with small-molecule drugs. Unfortunately, the therapeutic potential and clinical application of macromolecules is hampered by various obstacles including their large size, short in vivo half-life, phagocytic clearance, poor membrane permeability and structural instability. These challenges have encouraged researchers to develop novel strategies for effective delivery of macromolecules. In this review, various routes of macromolecule administration (invasive/noninvasive) are discussed. The advantages/limitations of novel delivery systems and the potential role of nanotechnology for the delivery of macromolecules are elaborated. In addition, fabrication approaches to make nanoformulations in different shapes and sizes are also summarized.

Composite Nanoformulation Therapeutics for Long-Term Ocular Delivery of Macromolecules

The purpose of this investigation is to design and synthesize novel pentablock (PB) copolymer (PB-1: PCL-PLA-PEG-PLA-PCL) based nanoformulations suspended in a thermosensitive gelling copolymer (PB-2: mPEG-PCL-PLA-PCL-PEGm) termed as composite nanoformulation. The composite nanoformulation was prepared to provide a sustained delivery of macromolecules over a longer duration with negligible burst release effect. The delivery system was designed to be utilized for the treatment of posterior segment ocular diseases such as age-related (wet) macular degeneration, diabetic retinopathy, and diabetic macular edema. The novel PB copolymers were characterized for their functional groups by Fourier transform infrared spectroscopy, molecular weight and purity by (1)H NMR spectroscopy, and gel permeation chromatography. X-ray diffraction analysis was used to determine the crystallinity of copolymers. The size distribution of PB-1 nanoparticles (NPs) prepared using emulsification-solvent evaporation method was found to be ∼150 nm analyzed by nanoparticle tracking analysis. The % encapsulation efficiency and % drug loading were found to be 66.64% w/w ± 1.75 and 18.17% w/w ± 0.39, respectively, (n = 3). Different weight percentages (15 and 20 wt %) of the PB-2 copolymer have been utilized for in vitro release studies of IgG-Fab from composite nanoformulation. A negligible burst release with continuous near zero-order release has been observed from the composite nanoformulation analyzed up to 80 days. In vitro cell viability and biocompatibility studies performed on ocular (human corneal epithelial and retinal pigment epithelium) and mouse macrophage (RAW 264.7) cell lines showed that the synthesized PB copolymer based composite nanoformulations were safe for clinical applications. On the basis of the results observed, it is concluded that PB copolymer based composite nanoformulations can serve as a platform for ocular delivery of therapeutic proteins. In addition, the composite nanoformulation may provide minimal side effects associated with frequent intravitreal injections.

A comprehensive insight on ocular pharmacokinetics.

The eye is a distinctive organ with protective anatomy and physiology. Several pharmacokinetics compartment models of ocular drug delivery have been developed for describing the absorption, distribution, and elimination of ocular drugs in the eye. Determining pharmacokinetics parameters in ocular tissues is a major challenge because of the complex anatomy and dynamic physiological barrier of the eye. In this review, pharmacokinetics of these compartments exploring different drugs, delivery systems, and routes of administration is discussed including factors affecting intraocular bioavailability. Factors such as precorneal fluid drainage, drug binding to tear proteins, systemic drug absorption, corneal factors, melanin binding, and drug metabolism render ocular delivery challenging and are elaborated in this manuscript. Several compartment models are discussed; these are developed in ocular drug delivery to study the pharmacokinetics parameters. There are several transporters present in both anterior and posterior segments of the eye which play a significant role in ocular pharmacokinetics and are summarized briefly. Moreover, several ocular pharmacokinetics animal models and relevant studies are reviewed and discussed in addition to the pharmacokinetics of various ocular formulations.

Novel Pentablock Copolymer Based Nanoparticles Containing Pazopanib: A Potential Therapy for Ocular Neovascularization

The main aim of this study was to design novel pentablock (PB) (PLA-PCL-PEG-PCL-PLA) polymer to prepare nanoparticles (NP) in order to achieve sustain delivery of pazopanib with minimal burst effect for the treatment of ocular neovascularization. Another purpose was to evaluate the effect of pazopanib loaded NP to bypass drug efflux with the discussion of recent patents. PB copolymer was successfully synthesized using ring opening polymerization reaction mechanism and characterized using 1 H NMR, GPC and XRD analysis. Synthesized PB copolymer was found to non- cytotoxic, non-immunogenic and biocompatible with ocular cell lines. Also, several parameters such as entrapment efficiency, drug loading, in vitro drug release profiling and effect of pazopanib NP in evading efflux transporters were examined. PB copolymer-based NP exhibited continuous release of pazopanib. It can be utilized to achieve continuous first order delivery of pazopanib upto 100 days from nanoparticles without any significant burst effect. Pazopanib loaded NP were successful in evading drug efflux mediated via efflux transporters. This formulation can be employed to circumvent ocular barriers without altering ocular protective mechanisms. Our results indicated that PB copolymer based drug delivery systems can serve as a platform technology for the development of sustained release therapy for the treatment of ocular neovascularization. This drug delivery system can also be applicable for other ocular complications.

How are we improving the delivery to back of the eye? Advances and challenges of novel therapeutic approaches

ABSTRACT Introduction: Drug delivery to the back of the eye requires strategic approaches that guarantee the long-term therapeutic effect with patient compliance. Current treatments for posterior eye diseases suffer from significant challenges including frequent intraocular injections of anti-VEGF agents and related adverse effects in addition to the high cost of the therapy. Areas covered: Treatment challenges and promising drug delivery approaches for posterior segment eye diseases, such as age-related macular degeneration (AMD) are summarized. Advances in the development of several nanotechnology-based systems, including stimuli-responsive approaches to enhance drug bioavailability and overcome existing barriers for effective ocular delivery are discussed. Stem cell transplantation and encapsulated cell technology (ECT) approaches to treat posterior eye diseases are elaborated. Expert opinion: There are several drug delivery systems demonstrating promising results. However, a better understanding of ocular barriers, disease pathophysiology, and drug clearance mechanisms is required for better therapeutic outcomes. The stem cell transplantation strategy and ECT approach provide positive results in AMD therapy, but there are a number of challenges that must be overcome for long-term efficiency. Ultimately, there are numerous multidimensional challenges to cure vision problems and a collaborative approach among scientists is required.

Optimization of novel pentablock copolymer based composite formulation for sustained delivery of peptide/protein in the treatment of ocular diseases

Abstract This manuscript is focussed on the development of pentablock (PB) copolymer based sustained release formulation for the treatment of posterior segment ocular diseases. We have successfully synthesised biodegradable and biocompatible PB copolymers for the preparation of nanoparticles (NPs) and thermosensitive gel. Achieving high drug loading with hydrophilic biotherapeutics (peptides/proteins) is a challenging task. Moreover, small intravitreal injection volume (≤100 μL) requires high loading to develop a long term (six months) sustained release formulation. We have successfully investigated various formulation parameters to achieve maximum peptide/protein (octreotide, insulin, lysozyme, IgG-Fab, IgG, and catalase) loading in PB NPs. Improvement in drug loading can facilitate delivery of larger doses of therapeutic proteins via limited injection volume. A composite formulation comprised of NPs in gel system exhibited sustained release (without burst effect) of peptides and proteins, may serve as a platform technology for the treatment of posterior segment ocular diseases.

Nanoparticle-based topical ophthalmic formulation for sustained release of stereoisomeric dipeptide prodrugs of ganciclovir

Abstract Poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles (NP) of Val-Val dipeptide monoester prodrugs of ganciclovir (GCV) including L-Val-L-Val-GCV (LLGCV), L-Val-D-Val-GCV (LDGCV) and D-Val-L-Val-GCV (DLGCV) were formulated and dispersed in thermosensitive PLGA-PEG-PLGA polymer gel for the treatment of herpes simplex virus type 1 (HSV-1)-induced viral corneal keratitis. Nanoparticles containing prodrugs of GCV were prepared by a double-emulsion solvent evaporation technique using various PLGA polymers with different drug/polymer ratios. Nanoparticles were characterized with respect to particle size, entrapment efficiency, polydispersity, drug loading, surface morphology, zeta potential and crystallinity. Prodrugs-loaded NP were incorporated into in situ gelling system. These formulations were examined for in vitro release and cytotoxicity. The results of optimized entrapment efficiencies of LLGCV-, LDGCV- and DLGCV-loaded NP are of 38.7 ± 2.0%, 41.8 ± 1.9%, and 45.3 ± 2.2%; drug loadings 3.87 ± 0.20%, 2.79 ± 0.13% and 3.02 ± 0.15%; yield 85.2 ± 3.0%, 86.9 ± 4.6% and 76.9 ± 2.1%; particle sizes 116.6 ± 4.5, 143.0 ± 3.8 and 134.1 ± 5.2 nm; and zeta potential −15.0 ± 4.96, −13.8 ± 5.26 and −13.9 ± 5.14 mV, respectively. Cytotoxicity studies suggested that all the formulations are non-toxic. In vitro release of prodrugs from NP showed a biphasic release pattern with an initial burst phase followed by a sustained phase. Such burst effect was completely eliminated when NP were suspended in thermosensitive gels with near zero-order release kinetics. Prodrugs-loaded PLGA NP dispersed in thermosensitive gels can thus serve as a promising drug delivery system for the treatment of anterior eye diseases.

Next generation drug delivery: circulatory cells-mediated nanotherapeutic approaches

Nanocarriers (NCs), such as liposomes, hydrogels, nanoparticles, micelles, fibers, and dendrimers, provide several advantages in delivery applications and have been extensively applied to enhance the therapeutic efficacy of drugs [1–4]. However, the major challenges in NC applications are to transport the therapeutics to the target site without significant degradation, avoid rapid phagocytic clearance, prolonging the circulation time, insufficient targeting, and limited ability to cross biological barriers such as the blood–brain barrier [1–4]. Thus, alternative drug delivery approaches are desirable. One emerging strategy to address the above nanotechnology challenges is to select body’s own circulatory cells as drug carriers [1,4–8]. Circulatory cells have received a significant interest as drug delivery vehicles because of several attractive and distinctive features arise from their unique structures, mechanical properties, and surface functionality [1,4–8]. These properties include high biocompatibility (if immunologically compatible), high mobility, a longer circulation lifespan, inherent biodegradability through known clearance pathways, natural capability of cell/tissue targeting, high drug loading capacity due to their large internal volume, remarkable stability in circulation, and their ability to cross biological barriers [1,4–7]. This editorial article provides an outline of several circulatory cells and their inherent properties (Tables 1) in the design of cell-mediated delivery systems (Figure 1).

Transporter effects on cell permeability in drug delivery

ABSTRACT Introduction: The role of drug transporters as one of the determinants of cellular drug permeability has become increasingly evident. Despite the lipophilicity of a drug molecule as rate-limiting factor for passive diffusion across biological membranes, carrier-mediated and active transport have gained attention over the years. A better understanding of the effects and roles of these influx transporters towards transmembrane permeability of a drug molecule need to be delineated for drug development and delivery. Areas covered: This review focuses on findings relative to role of transporters in drug absorption and bioavailability. Particularly the areas demanding further research have been emphasized. This review will also highlight various transporters expressed on vital organs and their effects on drug pharmacokinetics. Expert opinion: Significant efforts have been devoted to understand the role of transporters, their iterative interplay with metabolizing enzymes through molecular enzymology, binding and structure-activity relationship studies. A few assays such as parallel artificial membrane permeation assay (PAMPA) have been developed to analyze drug transport across phospholipid membranes. Although large web-accessible databases on tissue selective expression profiles at transcriptomic as well as proteomic are available, there is a need to collocate the scattered literature on the role of transporters in drug development and delivery.