Amarnath Maitra

Polymeric nanoparticle-encapsulated curcumin ("nanocurcumin"): a novel strategy for human cancer therapy.

BackgroundCurcumin, a yellow polyphenol extracted from the rhizome of turmeric (Curcuma longa), has potent anti-cancer properties as demonstrated in a plethora of human cancer cell line and animal carcinogenesis models. Nevertheless, widespread clinical application of this relatively efficacious agent in cancer and other diseases has been limited due to poor aqueous solubility, and consequently, minimal systemic bioavailability. Nanoparticle-based drug delivery approaches have the potential for rendering hydrophobic agents like curcumin dispersible in aqueous media, thus circumventing the pitfalls of poor solubility.ResultsWe have synthesized polymeric nanoparticle encapsulated formulation of curcumin – nanocurcumin – utilizing the micellar aggregates of cross-linked and random copolymers of N-isopropylacrylamide (NIPAAM), with N-vinyl-2-pyrrolidone (VP) and poly(ethyleneglycol)monoacrylate (PEG-A). Physico-chemical characterization of the polymeric nanoparticles by dynamic laser light scattering and transmission electron microscopy confirms a narrow size distribution in the 50 nm range. Nanocurcumin, unlike free curcumin, is readily dispersed in aqueous media. Nanocurcumin demonstrates comparable in vitro therapeutic efficacy to free curcumin against a panel of human pancreatic cancer cell lines, as assessed by cell viability and clonogenicity assays in soft agar. Further, nanocurcumins mechanisms of action on pancreatic cancer cells mirror that of free curcumin, including induction of cellular apoptosis, blockade of nuclear factor kappa B (NFκB) activation, and downregulation of steady state levels of multiple pro-inflammatory cytokines (IL-6, IL-8, and TNFα).ConclusionNanocurcumin provides an opportunity to expand the clinical repertoire of this efficacious agent by enabling ready aqueous dispersion. Future studies utilizing nanocurcumin are warranted in pre-clinical in vivo models of cancer and other diseases that might benefit from the effects of curcumin.

Tumour targeted delivery of encapsulated dextran-doxorubicin conjugate using chitosan nanoparticles as carrier.

Doxorubicin (DXR) commonly used in cancer therapy produces undesirable side effects such as cardiotoxicity. To minimize these, attempts have been made to couple the drug with dextran (DEX) and then to encapsulate this drug conjugate in hydrogel nanoparticles. By encapsulation of the drug conjugate in biodegradable, biocompatible long circulating hydrogel nanoparticles, we further improved the therapeutic efficacy of the conjugate. The size of these nanoparticles as determined by quasi-elastic light scattering, was found to be 100+/-10 nm diameter, which favors the enhanced permeability and retention effect (EPR) as observed in most solid tumors. The antitumor effect of these DEX-DXR nanoparticles, was evaluated in J774A.1 macrophage tumor cells implanted in Balb/c mice. The in vivo efficacy of these nanoparticles as antitumor drug carriers, was determined by tumor regression and increased survival time as compared to drug conjugate and free drug. These results suggest that encapsulation of the conjugate in nanoparticles not only reduces the side effects, but also improves its therapeutic efficacy in the treatment of solid tumors.

Solution behaviour of Aerosol OT in non-polar solvents

Abstract The aggregational behaviour of Aerosol OT in non-polar solvents and the applications of these systems in various areas have been reviewed. Aerosol OT forms reverse micelles in oils without using any cosurfactant and the reverse micellar solution can dissolve large amounts of water with the formation of discrete droplet microemulsion or bicontinuous microemulsions. Due to their simplicity in the sense of the smallest number of components in the reverse micellar systems, these systems have been widely studied and have also been divergently applied. This review gives a detailed account of various aspects of Aerosol OT reverse micelles namely their aggregational, structural, conformational, dynamic and applications reported in the literature to date.

Calcium phosphate nanoparticles as novel non-viral vectors for targeted gene delivery

Calcium phosphate nanoparticles present a unique class of non-viral vectors, which can serve as efficient and alternative DNA carriers for targeted delivery of genes. In this study we report the design and synthesis of ultra-low size, highly monodispersed DNA doped calcium phosphate nanoparticles of size around 80 nm in diameter. The DNA encapsulated inside the nanoparticle is protected from the external DNase environment and could be used safely to transfer the encapsulated DNA under in vitro and in vivo conditions. Moreover, the surface of these nanoparticles could be suitably modified by adsorbing a highly adhesive polymer like polyacrylic acid followed by conjugating the carboxylic groups of the polymer with a ligand such as p-amino-1-thio-beta-galactopyranoside using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride as a coupling agent. We have demonstrated in our studies that these surface modified calcium phosphate nanoparticles can be used in vivo to target genes specifically to the liver.

Preparation, characterization and biodistribution of ultrafine chitosan nanoparticles.

Chitosan nanoparticles cross-linked with glutaraldehyde have been prepared in AOT/n hexane reverse micellar system. The cross-linking in the polymeric network has been confirmed from FTIR data. Because of the adhesive nature of these particles, their sizes, as measured by QELS, have been found dependent on the particle density in aqueous buffer. The particle size has also been found to vary with the amount of cross-linking. The actual particle size of these chitosan nanoparticles with a particular degree of cross-linking has been determined at infinite dilution of particles in water. The particle size at infinite dilution is approximately 30 nm diameter, when 10% of the amine groups in the polymeric chains have been cross-linked and it shoots up to 110 nm diameter when all the amine groups are cross-linked (100% cross-linked). TEM pictures show that these particles are spherical in shape and remain in the form of aggregation. The biodistribution of these particles after intravenous injections in mice showed that these particles readily evade the RES system and remain in the blood for a considerable amount of time. The gamma image of the rabbit after administration of (99m)Technetium (99mTc) tagged chitosan nanoparticles also confirms the above observation, as the blood pool is readily visible even after 2 h. The gamma picture shows distribution of particles in the heart, liver, kidneys, bladder and the vertebral column. Interestingly, the biodistribution studies of the chitosan nanoparticles have indicated that these particles are distributed in the bone marrow also, implying the possibility of using these nanoparticles for bone imaging and targeting purpose.

Concentration-dependent toxicity of iron oxide nanoparticles mediated by increased oxidative stress

Iron oxide nanoparticles with unique magnetic properties have a high potential for use in several biomedical, bioengineering and in vivo applications, including tissue repair, magnetic resonance imaging, immunoassay, drug delivery, detoxification of biologic fluids, cell sorting, and hyperthermia. Although various surface modifications are being done for making these nonbiodegradable nanoparticles more biocompatible, their toxic potential is still a major concern. The current in vitro study of the interaction of superparamagnetic iron oxide nanoparticles of mean diameter 30 nm coated with Tween 80 and murine macrophage (J774) cells was undertaken to evaluate the dose- and time-dependent toxic potential, as well as investigate the role of oxidative stress in the toxicity. A 15–30 nm size range of spherical nanoparticles were characterized by transmission electron microscopy and zeta sizer. MTT assay showed >95% viability of cells in lower concentrations (25–200 μg/mL) and up to three hours of exposure, whereas at higher concentrations (300–500 μg/mL) and prolonged (six hours) exposure viability reduced to 55%–65%. Necrosis-apoptosis assay by propidium iodide and Hoechst-33342 staining revealed loss of the majority of the cells by apoptosis. H2DCFDDA assay to quantify generation of intracellular reactive oxygen species (ROS) indicated that exposure to a higher concentration of nanoparticles resulted in enhanced ROS generation, leading to cell injury and death. The cell membrane injury induced by nanoparticles studied using the lactate dehydrogenase assay, showed both concentration- and time-dependent damage. Thus, this study concluded that use of a low optimum concentration of superparamagnetic iron oxide nanoparticles is important for avoidance of oxidative stress-induced cell injury and death.

Biodistribution of fluoresceinated dextran using novel nanoparticles evading reticuloendothelial system.

The rapid clearance of circulating nanoparticles from the blood stream coupled with their high uptake by liver and spleen has thus far been overcome by reducing the particle size, and by making the particle surface hydrophilic with poloxamers and poloxamines. We have prepared hydrogel nanoparticles of polyvinylpyrrolidone of a size less than 100 nm diameter with precise size distribution. Since the inner cores of these particles are also hydrophilic, these particles are capable of encapsulating water-soluble compounds. Biodistribution of these particles shows practically negligible (<1%) uptake by the macrophages in liver and spleen, and approximately 5-10% of these particles remain in circulation even 8 h after i.v. injection. Increasing the surface hydrophobicity as well as particle size can increase the RES uptake of these particles. Because of longer residence in blood, the hydrogel nanoparticles have potential therapeutic applications particularly in cancer: the water-soluble cytotoxic agents encapsulated in these particles can be targeted to tumors while minimizing the likelihood of toxicity to reticuloendothelial system (RES).

Calcium phosphate nanoparticles: second-generation nonviral vectors in gene therapy

Adverse effects of viral vectors, instability of naked DNA, cytotoxicity and low transfection of cationic lipids, cationic polymers and other synthetic vectors are currently severe limitations in gene therapy. In addition to targeting a specific cell type, an ideal nonviral vector must manifest an efficient endosomal escape, render sufficient protection of DNA in the cytosol and help provide an easy passage of cytosolic DNA to the nucleus. Virus-like size calcium phosphate nanoparticles have been found to overcome many of these limitations in delivering genes to the nucleus of specific cells. This review has focused on some applications of DNA-loaded calcium phosphate nanoparticles as nonviral vectors in gene delivery, and their potential use in gene therapy, as well as highlighting the mechanistic studies to probe the reason for high transfection efficiency of the vector. It has been demonstrated that calcium ions play an important role in endosomal escape, cytosolic stability and enhanced nuclear uptake of DNA through nuclear pore complexes. The special role of exogenous calcium ions to overcome obstacles in practical realization of this field suggests that calcium phosphate nanoparticles are not ‘me too’ synthetic vectors and can be designated as second-generation nonviral vectors for gene therapy.

Preparation of acicular γ-Fe2O3 particles from a microemulsion-mediated reaction

A microemulsion-mediated chemical reaction was used to synthesize acicular particles of γ-Fe2O3 with an equivalent spherical diameter (ESD) of 7–8 run. From a comparison of the measured values of the hydrodynamic diameter of the water-in-oil microemulsion droplets and the ESD of the resulting γ-Fe2O3 particles, we show that each microemulsion droplet gives birth to a single particle of γ-Fe2O3.

Dextran–doxorubicin/chitosan nanoparticles for solid tumor therapy

Chemotherapy is a major therapeutic approach for the treatment of localized and metastasized cancers. Whereas potent chemotherapeutic agents seem promising in the test tube, clinical trials often fail due to unfavorable pharmacokinetics, poor delivery, low local concentrations, and limited accumulation in the target cell. The pathophysiology of the tumor vasculature and stromal compartment presents a major obstacle to effective delivery of agents to solid tumors. Poor perfusion of the tumor, arterio-venous shunting, necrotic and hypoxic areas, as well as a high interstitial fluid pressure work against favorable drug uptake. Thus, targeted drug delivery using long-circulating particulate drug carriers such as hydrogels of controlled size (<100 nm diameter) holds immense potential to improve the treatment of cancer by selectively providing therapeutically effective drug concentrations at the tumor site [through enhanced permeability and retention (EPR) effect] while reducing undesirable side effects. This review focuses on the progress of targeted delivery of nanoparticulated anticancer drug such as doxorubicin chemically conjugated with dextran and encapsulated in chitosan nanoparticles to solid tumor with reduced side effect of drug. Regulated particle size and long circulation of these hydrogel nanoparticles in blood help them accumulate in tumor tissue through EPR effect as evident from the significant regression of the tumor volume. The cardiotoxicity of doxorubicin can be minimized by coupling the drug with dextran and encapsulating it in chitosan nanoparticles.