Abstract
Anticancer therapies are often compromised by nonspecific effects and challenged by tumour environments’ inherent physicochemical and biological characteristics. Often, therapeutic effect can be increased by addressing multiple parameters simultaneously. Here we report on exploiting extravasation due to inherent vascular leakiness for the delivery of a pH-sensitive polymer carrier. Tumours’ acidic microenvironment instigates a charge reversal that promotes cellular internalization where endosomes destabilize and gene delivery is achieved. We assess our carrier with an aggressive non-small cell lung carcinoma (NSCLC) in vivo model and achieve >30% transfection efficiency via systemic delivery. Rejuvenation of the p53 apoptotic pathway as well as expression of KillerRed protein for sensitization in photodynamic therapy (PDT) is accomplished. A single administration greatly suppresses tumour growth and extends median animal survival from 28 days in control subjects to 68 days. The carrier has capacity for multiple payloads for greater therapeutic response where inter-individual variability can compromise efficacy.
Highlights
Anticancer therapies are often compromised by nonspecific effects and challenged by tumour environments’ inherent physicochemical and biological characteristics
Zeta potential and size of DNA-complexes were measured by dynamic light scattering and the formation of the DNA-complex was verified by the changes in the surface charge and particle size at various pH values
Comparisons were made to the bPEI25k/DNA-complex as a control, having a 2/1 ratio, which was optimal for the maximum transfection in vitro
Summary
Anticancer therapies are often compromised by nonspecific effects and challenged by tumour environments’ inherent physicochemical and biological characteristics. These pieces of evidence show that ROS and p53 pathways are intertwined; excessive amounts of either pathway may augment the other, leading to cell apoptosis These avenues in the treatment of cancer can be approached with the development of effective gene delivery. The zeta potential of the DNA-complex recovers once the environment returns from acid to neutral pH Such a carrier is highly versatile in its loading as well as effective in being responsive to the ‘targeted’ tumour tissue microenvironment from systemic administration. We simultaneously rejuvenate the p53-mediated apoptosis signalling pathway and enable photoinduced ROS generation; effectively suppressing tumour growth of an aggressive human NSCLC cell line (H1299) in athymic BALB/c nude mice
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