Enhancing tumor cell response to chemotherapy through nanoparticle-mediated codelivery of siRNA and cisplatin prodrug

Xiaoyang Xu, Kun Xie, Xue Qing Zhang, Eric M. Pridgen, Ga Young Park, Danica S. Cui, Jinjun Shi, Jun Wu, Philip W. Kantoff, Stephen J. Lippard, Robert Langer, Graham C. Walker, Omid C. Farokhzad

Research output: Contribution to journalArticlepeer-review

230 Scopus citations

Abstract

Cisplatin and other DNA-damaging chemotherapeutics are widely used to treat a broad spectrum of malignancies. However, their application is limited by both intrinsic and acquired chemoresistance. Most mutations that result from DNA damage are the consequence of error-prone translesion DNA synthesis, which could be responsible for the acquired resistance against DNA-damaging agents. Recent studies have shown that the suppression of crucial gene products (e.g., REV1, REV3L) involved in the errorprone translesion DNA synthesis pathway can sensitize intrinsically resistant tumors to chemotherapy and reduce the frequency of acquired drug resistance of relapsed tumors. In this context, combining conventional DNA-damaging chemotherapy with siRNA-based therapeutics represents a promising strategy for treating patients with malignancies. To this end, we developed a versatile nanoparticle (NP) platform to deliver a cisplatin prodrug and REV1/REV3L-specific siRNAs simultaneously to the same tumor cells. NPs are formulated through self-assembly of a biodegradable poly(lactide- coglycolide)-b-poly(ethylene glycol) diblock copolymer and a self-synthesized cationic lipid. We demonstrated the potency of the siRNA-containing NPs to knock down target genes efficiently both in vitro and in vivo. The therapeutic efficacy of NPs containing both cisplatin prodrug and REV1/REV3L-specific siRNAs was further investigated in vitro and in vivo. Quantitative real-time PCR results showed that the NPs exhibited a significant and sustained suppression of both genes in tumors for up to 3 d after a single dose. Administering these NPs revealed a synergistic effect on tumor inhibition in a human Lymph Node Carcinoma of the Prostate xenograft mouse model that was strikingly more effective than platinum monotherapy.

Original languageEnglish (US)
Pages (from-to)18638-18643
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number46
DOIs
StatePublished - Nov 12 2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Chemosensitivity
  • Combination therapy
  • SiRNA delivery

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