Sequentially Site‐Specific Delivery of Apoptotic Protein and Tumor‐Suppressor Gene for Combination Cancer Therapy

Abstract

Nanocarrier‐mediated codelivery of multiple anticancer drugs is a potential strategy for enhanced efficacy of combination cancer treatment by unifying differential pharmacokinetic properties and maintaining an optimal ratio of drug cargoes. However, a programmable codelivery system is highly desired to deliver different therapeutics to their specific sites of action to pursue maximized combinational effect. Herein a liposome‐based nanoassembly (p53/C‐rNC/L‐FA) is developed for intracellular site‐specific delivery of an apoptotic protein cytochrome c (CytoC) and a plasmid DNA encoding tumor‐suppressing p53 protein (p53 DNA). p53/C‐rNC/L‐FA consists of an acid‐activated fusogenic liposomal membrane shell modified with folic acid (L‐FA) and a DNA/protein complex core assembled by the p53 DNA, protamine and CytoC‐encapsulated redox‐responsive nanocapsule (C‐rNC). Intratumoral and intraendosomal acidities promote membrane fusion between liposome and biomembrane, resulting in release of the encapsulated p53/C‐rNC complex into the cytoplasm. The cytoplasmic reduction causes degradation of C‐rNC with release of CytoC that induces tumor cell apoptosis. The p53 DNA is transported into the nucleus by the aid of the cationic protamine and thus generates expression of the p53 protein that enhances apoptosis combined with CytoC. p53/C‐rNC/L‐FA is demonstrated to significantly induce tumor cell apoptosis and inhibit tumor growth in the orthotopic breast tumor mouse model.

Gene Therapy in Cancer Treatment: Why Go Nano?

“…In some cases, to increase the transfection efficacy, DNA-liposome therapy is combined with other mechanic procedures like ultrasounds [22]. Chen and collaborators designed a liposome-based nanoconjugate (p53/C-rNC/L-FA) for site-specific intracellular delivery of an apoptotic protein cytochrome c and a plasmid DNA encoding tumor-suppressing p53 protein [207]. The authors demonstrated that p53/C-rNC/L-FA liposome induce apoptosis in tumor cell lines and inhibited tumor growth in a breast cancer mouse model [207].…”

“…Chen and collaborators designed a liposome-based nanoconjugate (p53/C-rNC/L-FA) for site-specific intracellular delivery of an apoptotic protein cytochrome c and a plasmid DNA encoding tumor-suppressing p53 protein [207]. The authors demonstrated that p53/C-rNC/L-FA liposome induce apoptosis in tumor cell lines and inhibited tumor growth in a breast cancer mouse model [207]. Zuo and collaborators also used liposomes to deliver p53 but in this case for ovarian cancer targeted therapy [208].…”

Delivery of cancer therapies by synthetic and bio-inspired nanovectors

“…The enhanced vectorization potential and intrinsic tumor cytotoxicity of OVs were also exploited to transiently express tumor suppressors at high levels but still lack clinical assessment [129]. Regarding nanoparticles, liposomes containing p53-encoding plasmids are being evaluated against different types of solid cancers [219,220], including in phase I/II clinical trials (NCT02354547, NCT02340156, NCT02340117).…”

Membrane Fusion Models for Bioapplications

“…Similar approaches using ctyC as the model protein have also been undertaken employing DNA-mediated membrane fusion [110] or pH dependent fusion. [111] In some cases, codelivery systems were employed which provided maximized combinational effects, and have been shown to be more effective in preclinical and clinical studies. [112,113]…”