Temperature and pH responsive 3D printed scaffolds.

This study focused on developing novel materials for 3D printed reverse thermo-responsive (RTR) and pH-sensitive structures, using the stereolithography (SLA) technique and demonstrates the double responsiveness of the constructs printed. Methacrylated poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) triblocks are the basic building blocks of the RTR hydrogels, while acrylic acid is responsible for imparting also pH sensitivity to the 3D printed gels. The water absorption behavior and dimensional changes exhibited by the different 3D printed hydrogel constructs, strongly depended on the temperature and pH, varying also as a function of their composition and concentration. All the hydrogels showed a fast and reversible swelling-deswelling response, as they fluctuated between pH 2.0 and pH 7.4 behavior. Structures comprising two different dually responsive hydrogels were 3D printed and their environmentally sensitive dimensional behavior was reported.

Temperature, pH and redox responsive cellulose based hydrogels for protein delivery.

Cellulose based hydrogels are important due to their biocompatibility, non-toxicity and natural origin. In this work, a new set of pH, temperature and redox responsive hydrogels were prepared from carboxymethylcellulose (CMC) and poly(N-isopropylacrylamide). Copolymeric (CP) hydrogels were synthesized by copolymerizing N-isopropylacrylamide (NIPA) and methacrylated carboxymethylcellulose, semi-interpenetrating network (SIPN) hydrogels were prepared by polymerizing NIPA in presence of CMC. Two types of cross-linkers were used viz. N,N'-methylenebisacrylamide (BIS) and N,N'-bis(acryloyl)cystamine (CBA), a redox sensitive cross-linker. The structures of the hydrogels were characterized by FTIR and SEM studies. The CP hydrogels were found to be more porous than corresponding SIPNs which resulted in higher swelling for the CP hydrogels. Swelling for both the hydrogels were found to increase with CMC content. While the swelling of SIPN hydrogels showed discontinuous temperature dependency, CP hydrogels showed gradual decrease in water retention values with increase in temperature. CBA cross-linked hydrogels showed higher swelling in comparison to BIS cross-linked hydrogels. Additionally, lysozyme was loaded in the hydrogels and its in vitro release was studied in various pH, temperature and in presence of a reducing agent, glutathione (GSH). The release rate was found to be maximum at lower temperature, lower pH and in presence of GSH.

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.

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.

Spontaneous formation of vesicles by self-assembly of cationic block copolymer in the presence of anionic surfactants and their application in formation of polymer embedded gold nanoparticles.

Block copolymers (BCPs), synthesized from cationic monomer (3-(methacryloylamino)propyl)trimethylammonium chloride (MAPTAC) and PEG-based monomer poly(ethylene glycol) methyl ether acrylate (PEGMEA), were found to spontaneously form water-soluble vesicles when mixed with a stoichiometric quantity of negatively charged double-tail surfactant, AOT, at room temperature. However, with single-tail anionic surfactant, i.e., SDS, these block copolymers were seen to form water-soluble micelle-like aggregates. Also, cationic random copolymers (RCPs) of similar composition synthesized from the same monomers showed formation of water-soluble micelle-like aggregates when complexed with SDS or AOT. Such self-assembled vesicle formation observed specifically for the BCP/AOT systems was attributed to a sequential arrangement of monomers in the BCP and the higher hydrophobic volume of AOT, that made the packing factor "p" assume a value that favors the formation of vesicles. TEM analysis showed that average diameters of the vesicles were in the range of ∼100 nm. Pyrene fluorescence experiments indicated a high degree of hydrophobicity of vesicle membrane made from BCP/AOT complexes which were even higher than that of the cores of the water-soluble micelle-like aggregates made from BCP/SDS, RCP/AOT, and RCP/SDS systems. Importantly, the vesicles made from these BCP/AOT stoichiometric complexes were successfully utilized to reduce HAuCl4 to gold nanoparticles. TEM analysis revealed that the gold nanoparticles so formed were successively embedded within the hydrophobic bilayer shell of the vesicles.