Uday K Sukumar, J. C. B. Rajendran, S. Gambhir
Feb 12, 2020
Citations
1
Influential Citations
26
Citations
Quality indicators
Journal
ACS applied materials & interfaces
Abstract
Gene directed enzyme prodrug therapy (GDEPT) is a promising approach for cancer therapy, but it suffers from poor targeted delivery in vivo. Polyethylenimine (PEI) is a cationic polymer efficient in delivering negatively charged nucleic acids across cell membranes; however, it is highly toxic in vivo. Hence, we efficiently reduced PEI toxicity without compromising its transfection efficiency by conjugating it with PLGA and PEG as a triblock co-polymer through a multistep synthetic process, and synthesized nanoparticles that showed efficient delivery of loaded nucleic acids in mice. We used this nanoparticle to deliver a rationally engineered TK (thymidine kinase)-p53-NTR (nitroreductase) triple therapeutic gene against hepatocellular carcinoma (HCC), where p53 tumor suppressor gene is mutated in more than 85% of cancers. TK-p53-NTR triple gene therapy restores p53 function and potentiates cancer cell response to delivered prodrugs. We used SP94 peptide functionalized PLGA-PEG-PEI nanoparticles for optimal delivery of TK-p53-NTR therapeutic gene in vivo. The nanoparticles prepared from the conjugated polymer showed high loading efficiency for the DNA and markedly enhanced TK-NTR mediated gene therapy upon simultaneous co-expression of p53 by concurrent rescue of the endogenous apoptotic pathway in HCC cells of both p53 mutant and wild-type phenotypes in vitro. In vivo delivery of TK-p53-NTR genes by SP94 targeted PLGA-PEG-PEI NP in mice resulted in a strong expression of suicide genes selectively in tumors, leading to decline in tumor growth, and establishing a superior therapeutic outcome against HCC. We demonstrate a highly efficient approach that exogenously supplements p53 to enable synergy with the outcome of TK-NTR suicide gene therapy against HCC.