Chemotherapy drugs derived nanoparticles encapsulating mRNA encoding tumor suppressor proteins to treat triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) is one type of the most aggressive breast cancers with poor prognosis. It is of great urgency to develop new therapeutics for treating TNBC. Based on current treatment guideline and genetic information of TNBC, a combinational therapy platform integrating chemotherapy drugs and mRNA encoding tumor suppressor proteins may become an efficacious strategy. In this study, we developed paclitaxel amino lipid (PAL) derived nanoparticles (NPs) to incorporate both chemotherapy drugs and P53 mRNA. The PAL P53 mRNA NPs showed superior properties compared to Abraxane® and Lipusu® used in the clinic including high paclitaxel loading capacity (24 wt.%, calculated by paclitaxel in PAL), PAL encapsulation efficiency (94.7% ± 6.8%) and mRNA encapsulation efficiency (88.7% ± 0.7%). Meanwhile, these NPs displayed synergetic cytotoxicity of paclitaxel and P53 mRNA in cultured TNBC cells. More importantly, we demonstrated in vivo anti-tumor efficacy of PAL P53 mRNA NPs in an orthotopic TNBC mouse model. Overall, these chemotherapy drugs derived mRNA NPs provide a new platform to integrate chemotherapy and personalized medicine using tumor genetic information, and therefore represent a promising approach for TNBC treatment.

Strategies for Delivering Nanoparticles across Tumor Blood Vessels

“…[ 26 ] The EPR effect has been a longstanding paradigm in cancer nanomedicine, and has been exploited as the main tumor delivery mechanism for different types of nanoparticles, including inorganic (such as noble metal, oxide, upconversion, and carbon‐based nanoparticles) and organic nanoparticles (such as liposomes or lipid‐based nanoparticles, polymeric nanoparticles and dendrimers). [ 25,46–53 ] However, it is not the only pathway for nanoparticles to cross tumor blood vessels, as depicted in Figure . In general, we can differentiate two main nanoparticle transport pathways: i) paracellular transport by diffusion through intercellular gaps; and ii) transcellular nanoparticle transport through tumor endothelial cells.…”

Vitamin lipid nanoparticles enable adoptive macrophage transfer for the treatment of multidrug-resistant bacterial sepsis

“…Compound 1, vitamin B3 derivative, vitamin C derivative, vitamin D derivative, vitamin E derivative, and vitamin H (also called vitamin B7) derivative, were synthesized according to the methods reported previously 25 .…”

“…mRNAs used in this study were constructed by our mRNA platform based on the reported method 25 . The preparation of mRNA LNPs was reported previously 26 .…”

Nanoplatforms for mRNA Therapeutics

“…Cancer [ 218] LPPs triMannose-lipid/lipid 1/lipid 2 + PEG-HpK Ag (MART-1) I.D. APCs Cancer [ 133] EDOPC/DOPE/DSPE-PEG2k+PbAE Ag (OVA) I.V.…”

“…[145,146,217] Restoring tumor suppressor genes can not only induce tumor cell apoptosis, but also sensitize tumor cells to chemotherapy. [218] It has been found that p53 restoration in p53-deficient HCC and NSCLC tumor cells can induce tumor cell apoptosis via PUMA-Cas9/Cas3 pathway and G1-phase cell cycle arrest via p21/CyclinE1 pathway. [219] p53 restoration can also synergize with chemotherapy drugs such as everolimus in cancer cell killing without causing severe toxicity.…”