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

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

Proceedings of the National Academy of Sciences of the United States of America, 12 November 2013, Vol.110(46), pp.18638-43 [Peer Reviewed Journal]

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  • Title:
    Enhancing tumor cell response to chemotherapy through nanoparticle-mediated codelivery of siRNA and cisplatin prodrug
  • Author: Xu, Xiaoyang ; Xie, Kun ; Zhang, Xue-Qing ; Pridgen, Eric M ; Park, Ga Young ; Cui, Danica S ; Shi, Jinjun ; Wu, Jun ; Kantoff, Philip W ; Lippard, Stephen J ; Langer, Robert ; Walker, Graham C ; Farokhzad, Omid C
  • Subjects: Chemosensitivity ; Combination Therapy ; Sirna Delivery ; Antineoplastic Agents -- Administration & Dosage ; Drug Delivery Systems -- Methods ; Drug Resistance, Neoplasm -- Genetics ; Drug Therapy, Combination -- Methods ; Nanoparticles -- Therapeutic Use ; RNA Interference -- Physiology ; RNA, Small Interfering -- Administration & Dosage
  • Is Part Of: Proceedings of the National Academy of Sciences of the United States of America, 12 November 2013, Vol.110(46), pp.18638-43
  • Description: 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 error-prone 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.
  • Language: English
  • Identifier: E-ISSN: 1091-6490 ; PMID: 24167294 Version:1 ; DOI: 10.1073/pnas.1303958110

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