Amit Rawat

Targeted brain delivery of AZT via transferrin anchored pegylated albumin nanoparticles

Hydrophilic drugs/peptides have poor cross Blood–brain permeability. Various drug delivery systems with diverse surfacial characteristics have been reported for effective translocation of drugs across Blood–brain barrier. In present investigation, the potential of engineered albumin nanoparticles was evaluated for brain specific delivery after intravenous administration. Long circulatory PEGylated albumin nanoparticles encapsulating water-soluble antiviral drug azidothymidine (AZT) were prepared by ultra-emulsification method using chemical cross-linking by glutaraldehyde. Surface of the PEGylated nanoparticles was modified by anchoring transferrin as a ligand for brain targeting. Nanoparticles were characterized for their size, polydispersity, surfacial charge, drug loading and in vitro drug release. Fluorescence studies revealed the enhanced uptake of transferrin-anchored nanoparticles in the brain tissues when compared with unmodified nanoparticles. In vivo evaluation was carried out on albino rats to evaluate tissue distribution of engineered nanoparticles after intravenous administration. A significant (*P < 0.01) enhancement of brain localization of AZT was observed for transferrin anchored pegylated albumin nanopariticles (Tf-PEG-NPs). Hence, the specific role of transferrin ligand on nanoparticles for brain targeting was confirmed.

Tetanus toxoid‐loaded transfersomes for topical immunization

Topical immunization is a novel immunization strategy by which antigens and adjuvants are applied topically to intact skin to induce potent antibody and cell‐mediated responses. Among various approaches for topical immunization, the vesicular approach is gaining wide attention. Proteineous antigen alone or in combination with conventional bioactive carriers could not penetrate through the intact skin. Hence, specially designed, deformable lipid vesicles called transfersomes were used in this study for the non‐invasive delivery of tetanus toxoid (TT). Transfersomes were prepared and characterized for shape, size, entrapment efficiency and deformability index. Fluorescence microscopy was used to investigate the mechanism of vesicle penetration through the skin. The immune stimulating activity of these vesicles was studied by measuring the serum anti‐tetanus toxoid IgG titre following topical immunization. The immune response was compared with the same dose of alum adsorbed tetanus toxoid (AATT) given intramuscularly, topically administered plain tetanus toxoid solution, and a physical mixture of tetanus toxoid and transfersomes again given topically. The results indicated that the optimal transfersomal formulation had a soya phosphatidylcholine and sodium deoxycholate ratio of 85:15%, w/w. This formulation showed maximum entrapment efficiency (87.34±3.81%) and deformability index (121.5±4.21). An in‐vivo study revealed that topically administered tetanus toxoid‐loaded transfersomes, after secondary immunization, elicited an immune response (anti‐TT‐IgG) comparable with that produced by intramuscular AATT. Fluorescence microscopy revealed the penetration of transfersomes through the skin to deliver the antigen to the immunocompetent Langerhans cells.

Estrogen(s) and Analogs as a Non-Immunogenic Endogenous Ligand in Targeted Drug/DNA Delivery

The maximum therapeutic potentials of pharmacologically active molecules are generally not attained due to their non specific delivery. Ligands associated with drug or delivery system through which it is delivered provide navigation and direction to the carrier system(s) so as to reach and release bioactive(s) at the desired site of action in a optimum therapeutic concentration vis a vis minimizing the undesired side effects associated with non specific delivery. Many ligands employed and implicated in targeted drug delivery have been reportedly found to be mild to strong immunogenic. Hence, their potential utility is considered to be compromised in achieving concept of magic bullet. Therefore endogenous ligand (bio self molecules) based drug/DNA delivery may be a better alternative they being biocomponents so are non-immunogenic and biocompatible per se. Estrogens and their receptors are over expressed in the several pathophysiological conditions including cardiovascular, osteoarthritis and cancer of prostate and ovaries etc. The selective high density of such portal may be utilized for targeting such estrogen receptor rich sites. The several scientific communities from various fields of specialization of science have explored estrogen(s) and their analogs for the purpose of targeting of bioactive(s) either by preparing estrogen-drug conjugates of using estrogens as site-directing ligands attached with various carrier system(s). This review presents an exhaustive account of how hormones especially estrogens and their derivatives could be used for site-specific delivery of bioactive(s), as diagnostic agents and also the future prospects of these bioligands in controlled and targeted clinical pharmacology. Estrogen-drug conjugates and various carrier systems that utilized estrogens as ligands for site-specific delivery have been reviewed and are discussed in detail.

A Needle-Free Approach for Topical Immunization: Antigen Delivery via Vesicular Carrier System(s)

Topical immunization (TI) is novel and needle free strategy involving vaccine delivery through topical application of antigen and adjuvant(s) directly or via a suitable carrier system on intact skin. Anatomy and physiology of skin attracts scientists in developing topical carrier system(s) for enhanced delivery of bioactive(s). Numerous techniques i.e. physical, chemical and vesicular carrier systems have been exploited for topical immunization. The present review discuss various vesicular systems i.e. liposomes, niosomes, transfersomes, vesosomes etc. for the efficient topical delivery of various immunogens along with comparative points of their merit(s) in TI. The mechanism of permeation of bioactive(s) through skin route via these carriers to the immune system for development of both cellular and humeral immunity has also been discussed. Moreover, the effect of composition and type of carrier system on type of immunity induced has also been focused to develop new effective carrier system(s) for topical immunization.

Hepatitis B surface protein docked vesicular carrier for site specific delivery to liver.

The intrinsic liver tropism of liposomes can be augmented by the addition of targeting features such as the incorporation of hepatotropic elements of the hepatitis viruses. Hepatitis B virus is known to infect hepatocytes after viremia by asialoglycoprotein receptor mediated uptake. However, the specificity of hepatitis B virus surface protein (HBsAg) towards hepatocytes has confronting reports. In the present study, we evaluated the functional ability of HBsAg to be employed as a ligand for targeting hepatocytes. We prepared 14C labeled small unilamellar vesicles (SUVs) composed of egg PC/Cholesterol/N-glutarylphosphatidylethanolamine (NGPE) in a 60:30:10 molar ratio. HBsAg was covalently linked to SUVs using a water-soluble carbodiimide (EDC) mediated conjugation with NGPE. In vitro cell binding and uptake studies revealed that bioprotein docked carrier system was efficiently taken up by HepG2 cells by the receptor mediated endocytosis. The biodistribution behaviour of plain and HBsAg coated liposomes was also examined followed by intravenous injection. The study revealed that almost 75% of the radioactivity was recovered in the liver after 4 h of injection that was nearly three-fold greater in magnitude than the plain liposomes. Further, fractionation of liver into liver parenchymal cells (PC) and non-parenchymal cells confirmed the preferential localization of the HBsAg coated liposomal carrier in the parenchymal cells.

Cell-selective mitochondrial targeting: progress in mitochondrial medicine.

Mitochondrion, the energy generating organelle of the cell, is a subject of interest for selective targeting of therapeutic molecules, both Drugs and DNA, since it is found to be involved in numerous disorders like diabetes, neurodegenerative disease and cancer etc. Mitochondrial therapy can be made possible if the bioactive molecule is selectively delivered to the mitochondria of correct cell type, using cell specific ligands and mitochondriotropic molecules in designing of cell selective mitochondria specific carrier system. In this present review we will elaborate the role of mitochondria in human disease, cell specific ligands, mitochondriotropic molecules and their utilization in construction of such cell selective and mitochondria specific delivery systems that will make mitochondrial medicine practically possible.