Mitochondria apoptosis pathway synergistically activated by hierarchical targeted nanoparticles co-delivering siRNA and lonidamine

Biomaterials. 2015 Aug:61:178-89. doi: 10.1016/j.biomaterials.2015.05.027. Epub 2015 May 16.

Abstract

The mitochondria-mediated apoptosis pathway is an effective option for cancer therapy due to the presence of cell-suicide weapons in mitochondria. However, anti-apoptotic proteins that are over-expressed in the mitochondria of many malignant tumors, such as Bcl-2 protein, could allow the cancer cells to evade apoptosis, greatly reducing the efficacy of this type of chemotherapy. Here, we constructed a hierarchical targeted delivery system that can deliver siRNA and chemotherapeutic agents sequentially to tumor cells and mitochondria. In detail, the copolymer TPP-CP-LND (TCPL) was synthesized by the mitochondria-targeting ligand triphenylphosphine (TPP) and therapeutic drug lonidamine (LND) conjugated to the polyethyleneimine in chitosan-graft-PEI (CP), and then complexed with siRNA. Followed, the complexes were coated with poly(acrylic acid)-polyethylene glycol-folic acid (PPF) copolymer to form a hierarchical targeted co-delivery system (TCPL/siRNA/PPF NPs). The TCPL/siRNA/PPF NPs had a neutral surface charge, were stable in plasma and exhibited pH-responsive shell separation. Remarkably, the TCPL/siRNA/PPF NPs simultaneously released siBcl-2 into the cytoplasm and delivered LND to mitochondria in the same cancer cell after FA-directed internalization, and even synergistically activated mitochondria apoptosis pathway. This work demonstrated the potential of RNA-interference and mitochondria-targeted chemotherapeutics to collaboratively stimulate the mitochondria apoptosis pathway for cancer therapy.

Keywords: Co-delivery; Hierarchical targeting; Lonidamine; Mitochondria apoptosis pathway; Multifunctional nanoparticle; siRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / administration & dosage
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins / metabolism*
  • Diffusion
  • HeLa Cells
  • Humans
  • Indazoles / administration & dosage*
  • Indazoles / chemistry
  • Mitochondria / drug effects
  • Mitochondria / physiology*
  • Mitochondrial Proteins / metabolism
  • Nanocapsules / chemistry*
  • Nanocapsules / ultrastructure
  • RNA, Small Interfering / administration & dosage*
  • RNA, Small Interfering / genetics
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Indazoles
  • Mitochondrial Proteins
  • Nanocapsules
  • RNA, Small Interfering
  • lonidamine