Rajendran Amarnath Praphakar

Targeted delivery of rifampicin to tuberculosis-infected macrophages: design, in-vitro , and in-vivo performance of rifampicin-loaded poly(ester amide)s nanocarriers

We have developed a nano drug delivery system for the treatment of tuberculosis (TB) using rifampicin (RF) encapsulated in poly(ester amide)s nanoparticles (PEA-RF-NPs), which are biocompatible polymers. In this study, biodegradable amino acid based poly(ester amide)s (PEAs) were synthesized by the poly condensation reaction and RF-loaded NPs were fabricated by the dialysis method. The surface morphology and in-vitro drug release efficiency were examined. The effect of time and temperature on the cellular uptake of PEA-RF-NPs in NR8383 cells was evaluated. Fluorescence microscopic results of PEA-RF-NPs from NR8383 cell lines suggest its potential application in treating TB. The antibacterial activity of RF against Mycobacterium smegmatis was also evaluated. Based on these results, this approach provides a new means for controlled and efficient release of RF using the PEA-NPs delivery system and is promising for the treatment of TB.

Development of extended-voyaging anti-oxidant Linked Amphiphilic Polymeric Nanomicelles for Anti-Tuberculosis Drug Delivery

Amphiphilic chitosan-graft-poly(caprolactone)/(ferulic acid) (CS-g-PCL/FA) multi-co-polymers were fabricated by microwave-assisted ring opening polymerization followed by an 1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide (EDC)-mediated coupling reaction and characterized by Fourier transformed infrared (FTIR) spectroscopy. Graft copolymers self-assembled into nanomicelles, and were able to incorporate rifampicin (RF) into their hydrophobic inner cores. X-ray diffraction (XRD) patterns were applied to characterize the crystal structures of graft polymers and the effects of RF on micelle morphology. Empty and RF-loaded CS-g-PCL/FA nanomicelles underwent swelling and degradation in acidic pH conditions. Scanning electron microscopy, transmission electron microscopy, and dynamic light scattering revealed that the self-assembled, RF-loaded micelles were spherical, with an average size of 100-210nm. An in vitro study conducted at 37°C demonstrated that RF and FA release from micelles at pH 5.3 was much faster than that at pH 7.4. The RF and FA release was significantly accelerated by switching to an acidic pH, owing to swelling of the micelles at lower pH values caused by the rapid degradation of ester and amide bonds present in the micelles. Fluorescence micrographs revealed successful entry of the polymeric micelles into A549cell lines. Thus, graft polymeric micelles have promising potential for delivery of hydrophobic antitubercular drugs and may improve therapeutic approaches for tuberculosis.

Surface functionalization of natural lignin isolated from Aloe barbadensis Miller biomass by atom transfer radical polymerization for enhanced anticancer efficacy

Lignin (LIG), one of the major natural polymers in the biomass is widely used for various industrial and biomedical applications, mainly in its modified form of grafted lignin. The present study focuses on the isolation of lignin from Aloe barbadensis Miller by a microwave extraction technique and its applicability as a medicinal biomass. The isolated lignin was used for the synthesis of a drug carrier by grafting with methacrylate (MA). Lignin grafted methacrylate was synthesised (LIG-g-MA) via atom transfer radical polymerization (ATRP). 5-Fluorouracil (5-FU) was used as a model cancer drug and it was encapsulated on the hollow nanocarrier by the emulsion/solvent evaporation technique. While NMR spectroscopy elucidates the structure of the isolated lignin, FT-IR and XRD techniques address the binding nature and crystalline character of 5-FU loaded carrier. The surface morphology of the isolated lignin, grafted lignin and drug-loaded carrier was confirmed with SEM and TEM techniques. The encapsulation efficiency and in vitro drug release were studied to determine the efficiency of the carrier. The cell viability and cytotoxicity effect of 5-FU loaded on LIG-g-MA and unloaded LIG-g-MA were performed against MCF-7 and VERO cell lines. In short, the modified natural lignin based on LIG-g-MA hollow-nanofibrous material has been shown to be a potentially useful biocompatible nanocarrier in chemotherapy for cancer treatment.

A pH-sensitive guar gum-grafted-lysine-β-cyclodextrin drug carrier for the controlled release of 5-flourouracil into cancer cells

The physiological environment is a crucial factor in biomedical systems, which can be regulated with relative ease both in vitro and in vivo. Control of pH has emerged as a powerful strategy in cancer therapy because pH has a profound effect on the interaction of a polymeric-based drug delivery system with tumor cells. In this regard, the enhancement of pH response capability was demonstrated with a 5-flourouracil (5-FU)-loaded guar gum (GG)-grafted-lysine-β-cyclodextrin (L-β-CD) drug carrier. The size, charge, morphology, and encapsulation efficiency of the 5-FU-loaded polymeric carrier were characterized for the control and sustained release of the drug. In a specific cancer pH environment, 5-FU-loaded GG-g-L-β-CD could rapidly swallow, disassemble, and release 5-FU by accepting or losing electrons. In vitro observations indicate that GG-g-L-β-CD dramatically releases 5-FU in an acidic environment rather than in a basic environment. In vitro antitumor activity tests showed that 5-FU-loaded GG-g-L-β-CD had a higher cytotoxicity against KB cells, with an IC50 value of 1.38 μg ml-1. The reactive oxygen species (ROS) generated by 5-FU in the KB cells showed efficient suppression of tumour cell growth. The Hoechst assay revealed the active nature of 5-FU in the cell nucleus of the KB cells. The potential mitochondrial damage by apoptosis in KB cells greatly increased cell death. Therefore, due to its active nature, the pH-sensitive 5-FU-loaded GG-g-L-β-CD carrier is a potential drug delivery system for safe and effective cancer therapy, and it can be useful for inhibiting tumour cell growth.

Zn2+ cross-linked sodium alginate-g-allylamine-mannose polymeric carrier of rifampicin for macrophage targeting tuberculosis nanotherapy

Our aim was to evaluate the capacity of polymeric nanoparticles (PNPs) to selectively deliver an antituberculosis drug (rifampicin; RF) to alveolar macrophages. Anionic biodegradable copolymer sodium alginate-g-allylamine-mannose (SA-g-AA-M) was synthesized by atom transfer free radical polymerization and direct coupling of the respective conjugates. The fabrication of RF-loaded Zn2+ ion-cross-linked SA-g-AA-M PNPs was conducted by an O/W emulsion method followed by ionotropic gelation. The structural nature of the RF-loaded SA-g-AA-M PNPs was analyzed by Fourier transform infrared (FT-IR) spectroscopy. Meanwhile, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to illustrate the shape and morphology of the nanoparticles. The PNPs were observed as uniform spheres in the nanometer range (<300 nm), with a low polydispersity index, and excellent performance in terms of drug encapsulation and release ability. The PNPs also showed strong antimicrobial activities against Mycobacterium tuberculosis. Cytotoxicity evaluation in VERO cells by an MTT assay suggested that the PNPs have good biocompatibility. Alveolar macrophage targeting was evaluated via cellular uptake by A549 cells. The cellular uptake results revealed that the Zn2+ concentration of the PNPs increases the intracellular concentration of RF and enhances its antitubercular efficiency. Overall, the results suggest that PNPs could lead to the development of a possible mannose-containing carrier for a macrophage-targeting drug delivery system.

Silver nanoparticle functionalized CS-g-(CA-MA-PZA) carrier for sustainable anti-tuberculosis drug delivery

Recently, drug functionalized biodegradable polymers have been appreciated to be imperative to fabricate multi-drug delivery nanosystems for sustainable drug release. In this work, amphiphilic chitosan-grafted-(cetyl alcohol-maleic anhydride-pyrazinamide) (CS-g-(CA-MA-PZA)) was synthesized by multi-step reactions. The incorporation of rifampicin (RF) and entrapment of silver nanoparticles (Ag NPs) on CS-g-(CA-MA-PZA) polymer was carried out by dialysis technique. From the FT-IR experiment, the polymer modification, incorporation of drugs and the entrapment of Ag NPs on micelles were confirmed. The surface morphology of Ag NPs, polymeric system and drug loaded micelles was described by SEM, TEM and AFM techniques. In addition, the controlled release behaviour of CS-g-(CA-MA-PZA) micelles was studied by UV-Vis spectroscopy. In vitro cell viability, cell apoptosis and cellular uptake experiments shows that multi-drug delivery system could enhance the biocompatibility and higher the cytotoxicity effect on the cells. Since the prepared amphiphilic polymeric micelles exhibit spotty features and the system is a promising strategy for a novel candidate for immediate therapeutically effects for alveolar macrophages.

Sericin-chitosan doped maleate gellan gum nanocomposites for effective cell damage in Mycobacterium tuberculosis

Polysaccharides are increasingly used as biodegradable nanocarrier to selectively deliver therapeutic agents to specific cells. In this study, maleate gellan gum (MA-GG) formed by addition of free radical polymerizable groups, which can be polymerized presence of acetone to design biodegradable three-dimensional networks, were synthesized by esterification. Natural silk sericin was grafted over the maleate gellan gum surface. Maleate Gellan Gum- Silk Sericin-Chitosan (MA-GG-SS-CS) nanocomposites loaded with rifampicin (RF) and pyrazinamide (PZA) to overcome the problems associated with Tuberculosis (TB) therapy. The pH responsive behavior of gellan gum nanocomposites was reposed by silk sericin and exhibited sustained release of 79% RF and 82% PZA for 120 h at pH 4.0. The designed formulations shows higher antimycobacterial activity and rapid delivery of drugs at TB infected macrophage. Nanomaterial effectively aggregated and internalized into the bacterial cells and MH-S cells. Dual drug release inside the cells makes damage in the cell membrane. Green nanocomposites studies pave the way for important use of macromolecules in pulmonary delivery TB drugs.