Natural Particulates Inspired Specific-Targeted Codelivery of siRNA and Paclitaxel for Collaborative Antitumor Therapy

Mol Pharm. 2017 Sep 5;14(9):2999-3012. doi: 10.1021/acs.molpharmaceut.7b00192. Epub 2017 Aug 14.

Abstract

The effective combination of drugs promoting antiangiogenesis and apoptosis effects has proven to be a promising collaborative tumor antidote; and the codelivery of small interfering RNA (siRNA) and chemotherapy agents within one efficient vehicle has gained more attention over single regimen administration. Herein, vascular endothelial growth factor specific siRNA (siVEGF) and paclitaxel (PTX) were introduced as therapeutic companions and coencapsulated into naturally mimic high-density lipoproteins (rHDL/siVEGF-PTX), so that various mechanisms of treatment can occur simultaneously. The terminal nanoparticles share capacity of specific-targeting to tumor cells overexpressed scavenger receptor class B type I (SR-BI) and deliver siVEGF and PTX into cytoplasm by a nonendocytosis mechanism. By exchanging HDL core lipids with hydrophobic therapeutics, rHDL/siVEGF-PTX possessed particle size of ∼160 nm, surface potential of ∼-20 mV, and desirable long-term storage stability. In vitro results confirmed that the parallel activity of siVEGF and PTX displayed enhanced anticancer efficacy. The half-maximal inhibitory concentration (IC50) of rHDL/siVEGF-PTX toward human breast cancer MCF-7 cell is 0.26 μg/mL (PTX concentration), which presents a 14.96-fold increase in cytotoxicity by taking Taxol as comparison. Moreover, in vivo results further demonstrated that rHDL/siVEGF-PTX performed enhanced tumor growth inhibition via natural targeting pathway, accompanied by remarkable inhibition of neovascularization in situ caused by siVEGF silencing in down-regulation of VEGF proteins. On the premise of effective drug codelivery, rHDL/siVEGF-PTX demonstrated high tumor targeting for collaborative antitumor efficacy without side effects after systemic administration, and this bioinspired strategy could open an avenue for exploration of combined anticancer therapy.

Keywords: codelivery of siRNA and paclitaxel; collaborative antitumor efficacy; direct cytosolic delivery; reconstituted high density lipoproteins; vascular endothelial growth factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Line
  • Cell Survival / drug effects
  • Fatty Acids, Monounsaturated / chemistry
  • Female
  • Humans
  • Immunohistochemistry
  • Lipoproteins, HDL / chemistry*
  • MCF-7 Cells
  • Mice, Inbred BALB C
  • Mice, Nude
  • Nanoparticles / chemistry*
  • Paclitaxel / administration & dosage*
  • Paclitaxel / chemistry
  • Paclitaxel / pharmacology
  • Quaternary Ammonium Compounds / chemistry
  • RNA, Small Interfering / administration & dosage*
  • RNA, Small Interfering / genetics
  • Scavenger Receptors, Class B / chemistry
  • Scavenger Receptors, Class B / metabolism
  • Vascular Endothelial Growth Factor A / chemistry

Substances

  • Antineoplastic Agents
  • Fatty Acids, Monounsaturated
  • Lipoproteins, HDL
  • Quaternary Ammonium Compounds
  • RNA, Small Interfering
  • Scavenger Receptors, Class B
  • Vascular Endothelial Growth Factor A
  • 1,2-dioleoyloxy-3-(trimethylammonium)propane
  • Paclitaxel