Dibakar Dhara

Thermal and pH responsive polymer-tethered multifunctional magnetic nanoparticles for targeted delivery of anticancer drug.

Targeted and efficient delivery of therapeutics to tumor cells is one of the key issues in cancer therapy. In the present work, we report a temperature and pH dual responsive core-shell nanoparticles comprising smart polymer shell coated on magnetic nanoparticles as an anticancer drug carrier and cancer cell-specific targeting agent. Magnetite nanoparticles (MNPs), prepared by a simple coprecipitation method, was surface modified by introducing amine groups using 3-aminopropyltriethoxysilane. Dual-responsive poly(N-isopropylacrylamide)-block-poly(acrylic acid) copolymer, synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization, was then attached to the amine-functionalized MNPs via EDC/NHS method. Further, to accomplish cancer-specific targeting properties, folic acid was tethered to the surface of the nanoparticles. Thereafter, rhodamine B isothiocyanate was conjugated to endow fluorescent property to the MNPs required for cellular imaging applications. The nanoparticles were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), selected area electron diffraction (SAED), field emission scanning electron microscopy (FESEM), energy-dispersive X-ray spectroscopy (EDX), thermogravimetric analysis (TGA), zeta potential, vibrating sample magnetometer (VSM), X-ray photoelectron spectroscopy (XPS) measurements, and FTIR, UV-vis spectral analysis. Doxorubicin (DOX), an anticancer drug used for the present study, was loaded into the nanoparticles and its release behavior was subsequently studied. Result showed a sustained release of DOX preferentially at the desired lysosomal pH and temperature condition. The biological activity of the DOX-loaded MNPs was studied by MTT assay, fluorescence microscopy, and apoptosis. Intracellular-uptake studies revealed preferential uptake of these nanoparticles into cancer cells (HeLa cells) compared to normal fibroblast cells (L929 cells). The in vitro apoptosis study revealed that the DOX-loaded nanoparticles caused significant death to the HeLa cells. These nanoparticles were capable of target specific release of the loaded drug in response to pH and temperature and hence may serve as a potential drug carrier for in vivo applications.

Biocompatible mesoporous silica-coated superparamagnetic manganese ferrite nanoparticles for targeted drug delivery and MR imaging applications

Multifunctional mesoporous silica-coated superparamagnetic manganese ferrite (MnFe2O4) nanoparticles (M-MSN) were synthesized and evaluated for targeted drug delivery and magnetic resonance imaging (MRI) applications. MnFe2O4 nanoparticles were prepared by solvothermal route and were silica-coated by surface silylation using sol-gel reactions. Subsequently, silylation was done using (3-aminopropyl)triethoxysilane in presence of a surfactant (CTAB), followed by selective etching of the surfactant molecules that resulted in amine-functionalized superparamagnetic nanoparticles (NH2-MSN). Further modification of the surface of the NH2-MSN with targeting (folate) or fluorescent (RITC) molecules resulted in M-MSN. The formation of the M-MSN was proved by several characterization techniques viz. XRD, XPS, HRTEM, FESEM, VSM, BET surface area measurement, FTIR, and UV-Vis spectroscopy. The M-MSN were loaded with anticancer drug Doxorubicin and the efficacy of the DOX loaded M-MSN was evaluated through in vitro cytotoxicity, fluorescence microscopy, and apoptosis studies. The in vivo biocompatibility of the M-MSN was demonstrated in a mice-model system. Moreover, the M-MSN also acted as superior MRI contrast agent owing to a high magnetization value as well as superparamagnetic behavior at room temperature. These folate-conjugated nanoparticles (FA-MSN) exhibited stronger T2-weighted MRI contrast towards HeLa cells as compared to the nanoparticles without folate conjugation, justifying their potential importance in MRI based diagnosis of cancer. Such M-MSN with a magnetic core required for MRI imaging, a porous shell for carrying drug molecules, a targeting moeity for cancer cell specificity and a fluorescent molecule for imaging, all integrated into a single system, may potentially serve as an excellent material in biomedical applications.

Fabrication of magnetic mesoporous manganese ferrite nanocomposites as efficient catalyst for degradation of dye pollutants

In this study, mesoporous silica encapsulated with magnetic MnFe2O4 nanoparticles is synthesized by a solvothermal method. The synthetic route is feasible and widely applicable. The obtained products have been characterized by an X-ray powder diffraction (XRD) pattern, field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), high-resolution TEM (HRTEM) and nitrogen adsorption–desorption isotherm measurements. The synthesized magnetic mesoporous MnFe2O4 nanoparticles are monodispersed with a mean diameter of 200 nm, and have an obvious mesoporous silica shell of ∼20 nm. The surface area of magnetic mesoporous MnFe2O4 nanocomposites is 423 m2 g−1. The nanoparticles are superparamagnetic in nature at room temperature and can be separated by an external magnetic field. This magnetic mesoporous material is used as a catalyst for the degradation of methyl orange dye. The merits of the effect under different conditions like pH, temperature, light and sonolysis have been evaluated by investigating the degradation of azo dye. The mesoporous MnFe2O4 nanocomposites have effective adsorption of dyes inside the porous network followed by degradation with the central magnetite core and regeneration of the catalyst with the help of a simple magnet for successive uses.

Facile preparation of multifunctional hollow silica nanoparticles and their cancer specific targeting effect

Efficient delivery of therapeutics to tumor cells is one of the key issues in cancer therapy. In the present work, we have established a facile and unique chemical strategy for fabrication of highly biocompatible and water-dispersible multifunctional hollow silica nanoparticles (HSNPs). These mesoporous silica nanoparticles, having ring-like morphology, were fabricated by the sol-gel method followed by selective etching of the inner inorganic core. Further, to accomplish cancer-specific targeting properties, folic acid was tethered to the surface of HSNPs through amide bond formation using the EDC/NHS coupling method. Thereafter, rhodamine B isothiocyanate (RITC) was conjugated to the HSNPs to endow the fluorescent property to the nanoparticles required for biological imaging applications. The successful formation of multifunctional HSNPs was confirmed by XRD, FTIR, zeta potential, TEM, FESEM, and BET surface area measurements. The average particle size of HSNPs was found to be 50 nm to 70 nm from TEM analysis, which is the desired size-range for drug-delivery vehicles. These HSNPs showed good mesoporous behavior and were found to be an excellent candidate for loading and releasing the anticancer drug doxorubicin (DOX). The bioactivity of the HSNPs was verified by biological assay including cell cytotoxicity by MTT assay, intracellular uptake by fluorescence microscopy, cell cycle analysis by fluorescence-activated cell sorting (FACS), and apoptosis study. Besides, the effect of salt concentration on the drug release performance was evaluated. An in vitro biological study revealed that these DOX-loaded folate-targeted HSNPs achieved excellent efficacy for simultaneously targeting and destroying cancer cells.

pH-induced vesicle-to-micelle transition in amphiphilic diblock copolymer: investigation by energy transfer between in situ formed polymer embedded gold nanoparticles and fluorescent dye.

The ability to regulate the formation of nanostructures through self-assembly of amphiphilic block copolymers is of immense significance in the field of biology and medicine. In this work, a new block copolymer synthesized by using reversible addition-fragmentation chain transfer (RAFT) polymerization technique from poly(ethylene glycol) monomethyl ether acrylate (PEGMA) and Boc-l-tryptophan acryloyloxyethyl ester (Boc-l-trp-HEA) was found to spontaneously form pH-responsive water-soluble nanostructures after removal of the Boc group. While polymer vesicles or polymerosomes were formed at physiological pH, the micelles were formed at acidic pH (< 5.2), and this facilitated a pH-induced reversible vesicle-to-micelle transition. Formation of these nanostructures was confirmed by different characterization techniques, viz. transmission electron microscopy, dynamic light scattering, and steady-state fluorescence measurements. Further, these vesicles were successfully utilized to reduce HAuCl4 and stabilize the resulting gold nanoparticles (AuNPs). These AuNPs, confined within the hydrophobic shell of the vesicles, could participate in energy transfer process with fluorescent dye molecules encapsulated in the core of the vesicles, thus forming a nanometal surface energy transfer (NSET) pair. Subsequently, following the efficiency of energy transfer between this pair, it was possible to monitor the process of transition from vesicles to micelles. Thus, in this work, we have successfully demonstrated that NSET can be used to follow the transition between nanostructures formed by amphiphilic block copolymers.

Polymer grafted magnetic nanoparticles for delivery of anticancer drug at lower pH and elevated temperature

Efficient and controlled delivery of therapeutics to tumor cells is one of the important issues in cancer therapy. In the present work, a series of pH- and temperature-responsive polymer grafted iron oxide nanoparticles were prepared by simple coupling of aminated iron oxide nanoparticle with poly(N-isopropylacrylamide-ran-poly(ethylene glycol) methyl ether acrylate)-block-poly(acrylic acid) (P(NIPA-r-PEGMEA)-b-PAA). For this, three water soluble block polymers were prepared via reversible addition fragmentation transfer (RAFT) polymerization technique. At first, three different block copolymers were prepared by polymerizing mixture of NIPA and PEGMEA (with varying mole ratio) in presence of poly(tert-butyl acrylate) (PtBA) macro chain transfer agent. Subsequently, P(NIPA-r-PEGMEA)-b-PAA copolymers were synthesized by hydrolyzing tert-butyl acrylate groups of the P(NIPA-r-PEGMEA)-b-PtBA copolymers. The resulting polymers were then grafted to iron oxide nanoparticles, and these functionalized nanoparticles were thoroughly characterized by X-ray diffraction (XRD), thermogravimetric analysis (TGA), zeta potential measurements, transmission electron microscopy (TEM), field emission scanning electron microscopy (FESEM), vibrating sample magnetometer (VSM) and Fourier transform infrared spectroscopy (FTIR). Doxorubicin (DOX), an anti-cancer drug, was loaded into the polymer coated nanoparticles and its release behavior was subsequently studied at different pH and temperatures. The drug release pattern revealed a sustained release of DOX preferentially at the desired lysosomal pH of cancer cells (pH 5.0) and slightly above the physiological temperature depending upon the composition of the copolymers. The potential anticancer activity of the polymer grafted DOX loaded nanoparticles were established by MTT assay and apoptosis study of cervical cancer ME 180cells in presence of the nanoparticles. Thus, these particles can be utilized for controlled delivery of anticancer drugs at the desired lysosomal pH and/or by slightly heating the cells using magnetic hyperthermia.

Synthesis, photophysical and photochemical properties of photoacid generators based on N-hydroxyanthracene-1,9-dicarboxyimide and their application toward modification of silicon surfaces.

We have introduced a series of nonionic photoacid generators (PAGs) for carboxylic and sulfonic acids based on N-hydroxyanthracene-1,9-dicarboxyimide (HADI). The newly synthesized PAGs exhibited positive solvachromatic emission (λ(max)(hexane) 461 nm, λ(max)(ethanol) 505 nm) as a function of solvent polarity. Irradiation of PAGs in acetonitrile (ACN) using UV light above 410 nm resulted in the cleavage of weak N-O bonds, leading to the generation of carboxylic and sulfonic acids in good quantum and chemical yields. Mechanism for the homolytic N-O bond cleavage for acid generation was supported by time-dependent density functional theory (TD-DFT) calculations. More importantly, using the PAG monomer N-(p-vinylbenzenesulfonyloxy)anthracene-1,9-dicarboxyimide (VBSADI), we have synthesized N-(p-vinylbenzenesulfonyloxy)anthracene-1,9-dicarboxyimide-methyl methacrylate (VBSADI-MMA) and N-(p-vinylbenzenesulfonyloxy)anthracene-1,9-dicarboxyimide-ethyl acrylate (VBSADI-EA) copolymer through atom transfer radical polymerization (ATRP). Finally, we have also developed photoresponsive organosilicon surfaces using the aforementioned polymers.

Functional Group-Dependent Self-Assembled Nanostructures from Thermo-Responsive Triblock Copolymers

The ability to control the formation of nanostructures through self-assembly of amphiphilic block copolymers is of great interest in the field of biology and catalysis. In this work we have studied the self-assembling behavior of a new class of thermo-responsive triblock copolymers containing poly(ethylene glycol), and demonstrated the manner in which the aggregation pattern changed on simple functional group transformation on the copolymers. Two different triblock copolymers, poly(ethylene glycol)-b-poly(N-ispropylacrylamide)-b-poly(t-butyl acrylate) (P1) and poly(ethylene glycol)-b-poly(N-isopropylacrylamide)-b-poly(glycidyl methacrylate) (P2) were synthesized using reversible addition-fragmentation chain transfer (RAFT) technique. It was observed that P1 and P2 displayed different temperature dependent solution properties in water, with P1 forming micelles above the LCST of the PNIPA while P2 showing macroscopic phase separation under similar conditions. Thereafter, the tert-butyl group of P1 was converted to the corresponding acid (P1a) and the epoxy groups of P2 was converted to diols (P2a), thus transforming the hydrophobic blocks to hydrophilic ones. Quite interestingly, such transformations led to significant changes in their self-assembling behavior, as both P1a and P2a were seen to form vesicles beyond the LCST of PNIPA. Changes in the hydrophilic fraction in the block copolymers by subtle changes in the functionality and temperature led to the formation of varied nanostructured assemblies, as evident from dynamic light scattering (DLS), transmisison electron microscopy (TEM), and steady-state fluorescence analysis. Such formation of thermo-responsive vesicles induced by simple structural changes in the copolymers is quite interesting and highly significant in drug delivery applications.

Gold nanorod embedded reduction responsive block copolymer micelle-triggered drug delivery combined with photothermal ablation for targeted cancer therapy.

BACKGROUND Gold nanorods, by virtue of surface plasmon resonance, convert incident light energy (NIR) into heat energy which induces hyperthermia. We designed unique, multifunctional, gold nanorod embedded block copolymer micelle loaded with GW627368X for targeted drug delivery and photothermal therapy. METHODS Glutathione responsive diblock co-polymer was synthesized by RAFT process forming self-assembled micelle on gold nanorods prepared by seed mediated method and GW627368X was loaded on to the reduction responsive gold nanorod embedded micelle. Photothermal therapy was administered using cwNIR laser (808nm; 4W/cm2). Efficacy of nanoformulated GW627368X, photothermal therapy and combination of both were evaluated in vitro and in vivo. RESULTS In response to photothermal treatment, cells undergo regulated, patterned cell death by necroptosis. Combining GW627368X with photothermal treatment using single nanoparticle enhanced therapeutic outcome. In addition, these nanoparticles are effective X-ray CT contrast agents, thus, can help in monitoring treatment. CONCLUSION Reduction responsive nanorod embedded micelle containing folic acid and lipoic acid when treated on cervical cancer cells or tumour bearing mice, aggregate in and around cancer cells. Due to high glutathione concentration, micelles degrade releasing drug which binds surface receptors inducing apoptosis. When incident with 808nm cwNIR lasers, gold nanorods bring about photothermal effect leading to hyperthermic cell death by necroptosis. Combination of the two modalities enhances therapeutic efficacy by inducing both forms of cell death. GENERAL SIGNIFICANCE Our proposed treatment strategy achieves photothermal therapy and targeted drug delivery simultaneously. It can prove useful in overcoming general toxicities associated with chemotherapeutics and intrinsic/acquired resistance to chemo and radiotherapy.

Effect of encapsulation of curcumin in polymeric nanoparticles: how efficient to control ESIPT process?

This paper demonstrates the photophysics of curcumin inside polymeric nanoparticles (NPs), which are being recently used as targeted drug delivery vehicles. For this purpose, we have prepared three polymeric NPs by ultrasonication method from three well-defined water-insoluble random copolymers. These copolymers having various degrees of hydrophobicity were synthesized via reversible addition-fragmentation transfer (RAFT) method using styrene and three different functional monomers, namely, 2-hydroxyethyl acrylate, 4-formylphenyl acrylate, and 4-vinylbenzyl chloride. The photophysics of the curcumin molecules inside the polymeric NPs have been monitored by applying tools like steady state and time-resolved fluorescence spectroscopy. An increase in fluorescence intensity along with an increase in the lifetime values indicated a perturbation of the excited state intramolecular proton transfer (ESIPT) process of curcumin inside the polymeric NPs.