Creatine based polymer for codelivery of bioengineered MicroRNA and chemodrugs against breast cancer lung metastasis

Metastasis is the major cause for breast cancer related mortality. The combination of miRNA-based therapy and chemotherapy represents a promising approach against breast cancer lung metastasis. The goal of this study is to develop an improved therapy that co-delivers a novel bioengineered miRNA prodrug (tRNA-mir-34a) and doxorubicin (DOX) via a multifunctional nanomicellar carrier that is based on a conjugate of amphiphilic copolymer POEG-VBC backbone with creatine, a naturally occurring cationic molecule. Co-delivery of DOX leads to more effective processing of tRNA-mir-34a into mature miR-34a and down-regulation of target genes. DOX + tRNA-mir-34a/POEG-PCre exhibits potent synergistic anti-tumor and anti-metastasis activity in vitro and in vivo. Interestingly, the enhanced immune response contributes to the overall antitumor efficacy. POEG-PCre may represent a safe and effective delivery system for an optimal chemo-gene combination therapy. Amphiphilic POEG-PCre polymer is able to self-assemble with DOX to form DOX-loaded micelles, which is then condensed by tRNA-mir-34a to form more compact and stable nanocomplexes. The multifunctional POEG-PCre micellar system is highly effective in co-delivery of DOX and tRNA-mir-34a to lungs and subsequently to tumor cells, which represents an optimal chemo-gene combination therapy against cancer lung metastasis. [Display omitted]