Synergistic effect of p53 gene/DOX intracellular delivery and P-gp inhibition by pullulan thiomers on cancer cells: in vitro and in vivo evaluations.

Numerous reports emphasize the inverse relationship between the mutant p53 protein and P-glycoprotein overexpression, which adversely affects the chemosensitivity of cancer cells. In this study, the cationised pullulan polysaccharide was conjugated with dithiobutyric acid (PPDBA) for the intracellular delivery of doxorubicin and the p53 gene. The transfection efficiency of PPDBA using the apoptotic gene p53 and its ability to modulate efflux pumps in the presence and absence of glutathione and the subsequent drug retention were studied in different cell lines. The percentage cell death mediated by the PPDBA/p53 nanoplex (4 : 1 ratio) was 59%, and by DOX alone a 50% cell death was attained at 3.13 µM in C6 cells, but the percentage cell death mediated by PPDBA/p53 (4 : 1) in combination with 1 µM DOX was as high as 98%. The effect of PPDBA II/p53/DOX nanoplexes on the mouse tumor model was evaluated in BALB/c mice which demonstrated good efficacy when compared with the drug or gene alone.

Recent advances in functionally modified polymers for mucoadhesive drug delivery.

Novel methods for the delivery of drugs other than the conventional method of oral administration have been a thrust area of research for a few decades. Mucoadhesive delivery of drugs opened up a new domain where rapid and patient-friendly delivery of drugs can be achieved. Delivery of drugs through the mucosal sites such as buccal, nasal, ocular, sublingual, rectal and vaginal facilitates bypassing the first-pass metabolism and the drug reaches the systemic circulation directly. This helps to increase the bioavailability of the drug. The study of the chemical characteristics of polymers with mucoadhesive properties and how the molecules or the pharmaceuticals are transported across the mucosa is very much needed for the advancement of research in this field. And at the same time, it is very pertinent to know about the anatomy and the physiology of the mucosal tissue and its variation in different regions of the body. In this review, we try to present a comprehensive understanding of relevant topics of mucoadhesion giving more emphasis on the mechanism of transport of drugs across mucosa, and different possible functional modifications of polymers to enhance the property of mucoadhesion.

Redox sensitive cationic pullulan for efficient gene transfection and drug retention in C6 glioma cells.

Thiolated cationic pullulan was synthesized by conjugating pullulan with polyethyleneimine (PEI) and mercaptosuccinic acid (MSA). The formed conjugate was oxidized to obtain disulfide linked cationic pullulan (PPMSS). PPMSS exhibited good buffering capacity and nanoplexes formulated were of size less than 150nm. Nanoplexes formed with PPMSS are redox sensitive and susceptible to reductive cleavage by dithiothreitol (DTT) ensuring the intracellular release of DNA. In vitro, cytotoxic evaluation studies of polymers in C6 cell lines established its non-toxic nature. The studies using endocytosis inhibitors revealed the uptake pathways of nanoplexes. Further, the plasmid and polymer tracking studies indicated the successful unpacking of DNA from the nanoplexes and its nuclear localization. The gene transfection efficiency was established by the p53 gene expression studies. Furthermore, the ability of the polymer to inhibit efflux pumping in cancer cells has also been elucidated in terms of P-gp inhibition studies and drug retention kinetics using the anticancer drug, doxorubicin (DOX). Our results also suggest that greater retention of DOX was accompanied by the reduction of disulfide linkage by a ubiquitous intracellular stimulus, glutathione. Thus simultaneous gene and drug delivery using redox sensitive cationic polymers may have a promising potential in cancer therapy.