A pH-sensitive guar gum-: Grafted -lysine-?-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-?-cyclodextrin (L-?-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-?-CD could rapidly swallow, disassemble, and release 5-FU by accepting or losing electrons. In vitro observations indicate that GG-g-L-?-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-?-CD had a higher cytotoxicity against KB cells, with an IC50 value of 1.38 ?g 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-?-CD carrier is a potential drug delivery system for safe and effective cancer therapy, and it can be useful for inhibiting tumour cell growth.MR acknowledges the major financial support received from the University Grants Commission (UGC), Government of India, for financial support under the plan of ‘‘UGC-MRP’’ (F. No. 43-187/ 2014) (SR) and Department of Science and Technology, Science and Engineering Research Board (Ref: YSS/2015/001532; New Delhi, India), ‘‘EMEQ’’ (F. No. – SB/EMEQ-241-2014) and also acknowledges the PURSE program for the purchase of SEM and FT-IR and UPE programs for the purchase of TEM.Scopu

Kinase Targets for Mycolic Acid Biosynthesis in Mycobacterium tuberculosis.

Mycolic acids (MAs) are the characteristic, integral building blocks for the mycomembrane belonging to the insidious bacterial pathogen Mycobacterium tuberculosis (M.tb). These C60-C90 long a-alkyl-ß-hydroxylated fatty acids provide protection to the tubercule bacilli against the outside threats, thus allowing its survival, virulence and resistance to the current antibacterial agents. In the post-genomic era, progress has been made towards understanding the crucial enzymatic machineries involved in the biosynthesis of MAs in M.tb in which two discrete fatty acid synthases systems (FAS-I and FAS-II) were discovered. However, gaps still remain in the exact role of the phosphorylation and dephosphorylation regulatory mechanisms within these systems. To date, a total of 11 serine-threonine protein kinases (STPKs) are found in M.tb. Most enzymes implicated in the MAs synthesis were found to be phosphorylated in vitro and/or in vivo. For instance, phosphorylation of KasA, KasB, mtFabH, HadAB/BC, InhA, MabA, FadD32 and PcA downregulated their enzymatic activity, while phosphorylation of VirS increased its enzymatic activity. These observations suggest that the kinases and phosphatases system could play a role in M.tb adaptive responses and survival mechanisms in the human host. As the mycobacterial STPKs do not share a high sequence homology to the human's, there has been some early drug discovery efforts towards developing potent and selective inhibitors as novel antitubercular agents. Recent updates to the kinases and phosphatases involved in the regulation of MAs biosynthesis will be presented in this minireview, including their known small molecule inhibitors