Neelesh Kumar Mehra

Targeted drug delivery to macrophages

Introduction: Targeted drug delivery to the macrophages appears to be an attractive proposition to improve therapeutic efficacy of enclosed drug. Thus, macrophages can be exploited as Trojan horses for targeted drug delivery. Nanocarriers can migrate across the different membrane barriers and release their drug cargo at sites of infection. Areas covered: This review discusses the current status and utilization of various micro- as well as nanocarriers like microspheres/microparticles, liposomes, nanoparticles, dendrimers, niosomes, and carbon nanotubes for targeted delivery of bioactives to the macrophages. Expert opinion: The design of nanocarriers for cell-mediated drug delivery may differ from those used for conventional drug delivery systems. The literature review shows that nanocarriers could supplement sustained drug delivery to the macrophages, extended duration of action, reduced therapeutic dose, improved patient compliance, and reduced adverse effects of highly toxic, potent drugs. There is still a need to identify more specific receptors that are responsible for macrophage targeting. The identification of such receptors may also facilitate drug targeting to further specific parts of the body containing different types of macrophages.

A review of ligand tethered surface engineered carbon nanotubes.

Carbon nanotubes (CNTs) have emerged as fascinating materials, exhibiting promising potential in receptor based targeting owing to their unique physicochemical properties (cell membrane penetration, high surface area and drug payload, biocompatibility, easy surface modification, photoluminescence property, and non-immunogenicity etc). The hydrophilicity, a major constrain associated with the first generation of CNTs i.e. pristine CNTs, could be overcome using functionalization techniques. In the last two decades variety of functionalized CNTs (f-CNTs) i.e. oxidized, amidated, acylated, surfactant and biopolymer-assisted, and biomolecules modified have been developed and utilized as effective, safe, nano sized, and smart systems to deliver a wide range of bioactives in the biological system. The purpose of this review is to examine the various aspects of conjugation and associated conjugation chemistry of various targeting ligands to CNTs for their respective biomedical applications. The various biomolecules have been easily tethered to CNTs surfaces including proteins and amino acid, enzymes, nucleic acid (DNA and siRNA), aptamers, vitamins, monoclonal antibodies, peptides (NGR, RGD and Aniopep-2) and so on, for targeting purposes.

Receptor-based targeting of therapeutics

Receptor-based targeting of therapeutics may be a fascinating proposition to improve the therapeutic efficacy of encapsulated drugs. The development of safe and effective nanomedicines is a prerequisite in the current nanotechnological scenario. Currently, the surface engineering of nanocarriers has attracted great attention for targeted therapeutic delivery by selective binding of targeting ligand to the specific receptors present on the surface of cells. In this review, we have discussed the current status of various receptors such as transferrin, lectoferrin, lectin, folate, human EGF receptor, scavenger, nuclear and integrin, which are over-expressed on the surface of cancer cells; along with the relevance of targeted delivery systems such as nanoparticles, polymersomes, dendrimers, liposomes and carbon nanotubes. The review also focuses on the effective utilization of receptor-based targeted delivery systems for the management of cancer in effective ways by minimizing the drug-associated side effects and improving the therapeutic efficacy of developed nano-architectures.

Carbon nanotubes and their toxicity

The vital need of studying the toxicological profile of carbon nanotubes (CNTs) has emerged from the rapidly enhancing utility of CNTs in the field of nanobiology and drug delivery. This review highlights the vivid aspect of CNTs’ toxicity comprising of in-vitro to in-vivo toxicological profile vis-à-vis the various potential routes of CNTs exposure. The article also underlines the various surface modifications on carbon nanotubes and its role in imparting biocompatibility to the CNTs, further suggesting their utility as a safer delivery module for bioactives.

Development and characterization of dexamethasone mesylate anchored on multi walled carbon nanotubes.

Dexamethasone conjugated multi wall carbon nanotubes (DEX-MWCNTs) were developed for controlled delivery of a doxorubicin HCl (DOX) with reduced toxicity. The DEX-MWCNTs were prepared by sequential functionalization of MWCNTs. The DOX was physically loaded onto the purified raw MWCNTs and DEX-MWCNTs at pH 7.4 phosphate buffer solutions (PBS) and evaluated for entrapment efficiency, in vitro release, hemolytic toxicity and ex vivo studies on “A-549” lung epithelial cancer cell line. DOX was efficiently loaded into purified raw and DEX-MWCNTs formulation and the highest entrapment of DOX was found to be 92.6 ± 0.5% in the case of DEX-MWCNTS with good dispersion. In-vitro release of DOX was studied from the DOX/DEX-MWCNTs at pH 5.5 and 7.4 (PBS), which displayed an initial faster followed by sustained release up to 200 h. Further, DOX/DEX-MWCNTs were found to be less hemolytic and more cytotoxic as compared to free DOX on “A-549” lung epithelial cancer cell line.

Gemcitabine-loaded smart carbon nanotubes for effective targeting to cancer cells

Abstract Carbon nanotubes (CNTs) are the three-dimensional sp2 hybridized nano-containers that have attracted considerable interest in drug delivery by offering potential advantages such as biocompatibility, non-immunogenicity, high loading efficiency, intrinsic stability and low toxicities. The aim of the present investigation was to assess the potential of gemcitabine-loaded folic acid (FA) conjugated multi-walled CNTs (GEM/FA-NT) for targeting to breast cancer cells. Pristine MWCNTs was functionalized by FA followed by carboxylation, acylation and amidation and characterized by electron microscopy, FT-IR spectroscopy, X-ray diffraction, entrapment efficiency, cytotoxicity and in vivo studies. FDA-approved GEM was loaded to the purified (GEM-NT) and GEM/FA-NT, and % entrapment efficiency was found to be approximately 71.60 ± 0.25 and 79.60 ± 0.45, respectively. The developed formulation GEM/FA-NT was found to have significantly less hemolytic toxicity (8.23 ± 0.65) as compared to free GEM (17.34 ± 0.56). The in vitro release was found to be in sustained pattern at the lysosomal pH, which depicts more cytotoxic response on human breast cancer cell line (MCF-7). It may be interpreted that the GEM/FA-NT formulation is capable to carry drug and deliver it selectively at the tumor site while minimizing side effects and thus holds promise in chemotherapy.

Macrophages targeting of amphotericin B through mannosylated multiwalled carbon nanotubes.

The objective of the present investigation was to assess the potential of polysaccharide (mannose) conjugated engineered multiwalled carbon nanotubes (MWCNTs) bearing Amphotericin B (AmB) formulation for site-specific delivery to macrophages. The mannosylated carbon nanotubes (CNTs) were synthesized and AmB was efficiently loaded using dialysis diffusion method. The synthesized mannosylated MWCNTs were characterized by various physicochemical and physiological parameters such as fourier transform infrared (FTIR) spectroscopy, scanning and transmission electron microscopy (SEM & TEM), drug loading and entrapment efficiency, in-vitro release kinetics, in-vivo study and toxicological investigation. AmB loaded mannosylated MWCNTs (AmBitubes) was found to be nanometric in size (500 nm) with tubular structure and good entrapment efficiency (75.46 ± 1.40%). In-vitro AmB from AmBitubes was found to be released in a controlled manner at pH 4, 7.4 and 10, with enhanced cell uptake and higher disposition in macrophage-rich organs, thereby indicating the site-specific drug delivery. The results suggest that AmBitubes could be employed as efficient nano-carrier for antileishmanial therapy.

Development, characterization and cancer targeting potential of surface engineered carbon nanotubes

Abstract The aim of the present study was to assess the in vitro and in vivo potential of doxorubicin-loaded, folic acid appended engineered multi-walled carbon nanotubes (DOX/FA-PEG-MWCNTs) for efficient tumor targeting. The loading efficiency was determined to be 92.0 ± 0.92 (DOX/FA-PEG-MWCNTs) in phosphate buffer solution (pH 7.4) ascribed to π–π stacking interaction. The developed nanoconjugates were evaluated for in vitro DOX release, erythrocytes toxicity, ex vivo cytotoxicity and cell uptake studies on MCF-7 (breast cancer cell line). The DOX/FA-PEG-MWCNTs nanoconjugate affords higher efficacy in tumor growth suppression due to its stealth nature and most preferentially taken up by the cultured MCF-7 through caveolae-mediated endocytosis as compared to free DOX. The in vivo studies were performed to determine the pharmacokinetics, biodistribution and antitumor efficacy on tumor bearing female Sprague Dawley rats and improved pharmacokinetics confirm the function of FA-PEG conjugated CNTs. The median survival time for tumor bearing rats treated with DOX/FA-PEG-MWCNTs (30 d) was extended very significantly as compared to free DOX (p < 0.001). The results concluded that developed water-soluble nano-conjugates might emerge as “safe and effective” nano-medicine in cancer treatment by minimizing the side effects with and Generally Regarded as Safe prominence.

Potentials and emerging trends in nanopharmacology

Nanopharmacology is a relatively newer branch of pharmacology which investigates interaction of a nanomedicine with living systems at the nanoscale level. Modern medicine is increasingly concerned with various surface modified nanocarriers, such as dendrimers, nanoparticles, carbon based nanomaterials, polymer-drug nanoconjugates, etc., which have immense therapeutic potential by target specific drug delivery, using nanoscaffolding and nanocontainers, owing to the specific physical, chemical and biological properties of these moieties that is related to their nanoscale size range. Nanopharmacology could have potential medical and pharmaceutical benefits via applications of nanotechnology in the delivery of therapeutic and diagnostic agents. Nanomaterials may be expected to find application in the cardiovascular, as well as, renal arena, in the near future.

Hyperbranched dendritic nano-carriers for topical delivery of dithranol

Abstract The purpose of the current investigation was to explore the potential of polypropylene imine (PPI) dendrimers to deliver dithranol (DIT) topically and to evaluate its encapsulation, permeation and skin irritation potential. PPI (5.0 generation, 5.0 G) dendrimers and DIT-loaded PPI (DIT–PPI) were prepared and characterized by spectroscopy and transmission electron microscopy. DIT encapsulation, in vitro skin permeation study, skin irritation studies, fluorescent studies and tape stripping studies were performed. Loading of DIT was found to be pH dependent with maximum encapsulation at acidic pH (1.0 ± 0.02, 17.2 ± 0.56 and 57.1 ± 1.32% at 7.4, 5.5 and 1.2 pH, respectively). DIT–PPI showed significantly enhanced permeation rate constant and lesser skin irritation (11.61 ± 1.80 μg/cm2/h and 1.0, respectively) when compared with the plain DIT solution (2.72 ± 0.31 μg/cm2/h and 2.3, respectively). Skin separation studies and confocal laser scanning microscope images showed that the dye-loaded dendrimers exhibits deposition of dye in pilosebaceous compartment. These studies demonstrate that PPI can be exploited to improve the topical bioavailability of the molecules in a controlled pattern. The enhanced accumulation of DIT via dendrimer carrier within the skin might help optimize targeting of this drug to the epidermal and dermal sites, thus creating new opportunities for well-controlled, modern topical application of DIT for the treatment of psoriasis.