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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 46; pp. 18638 - 18643
• Main Authors: Xu, Xiaoyang, Xie, Kun, Zhang, Xue-Qing, Pridgen, Eric M., Ga Young Park, Cui, Danica S., Shi, Jinjun, Wu, Jun, Kantoff, Philip W., Lippard, Stephen J., Langer, Robert, Walker, Graham C., Farokhzad, Omid C.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 12.11.2013; NATIONAL ACADEMY OF SCIENCES; National Acad Sciences
• Subjects: animal models; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; biodegradability; Biodegradation; Biological Sciences; Cell Line, Tumor; Cells; Chemotherapy; cisplatin; Cisplatin - administration & dosage; Cisplatin - pharmacology; composite polymers; Copolymers; Deoxyribonucleic acid; DNA; DNA damage; Dosage; Drug Carriers - administration & dosage; Drug Delivery Systems - methods; Drug resistance; Drug Resistance, Neoplasm - genetics; drug therapy; Drug Therapy, Combination - methods; ethylene glycol; Gene Silencing; genes; HeLa cells; Heterologous transplantation; Humans; lipids; Luciferases; lymph nodes; Medical treatment; mutation; nanoparticles; Nanoparticles - therapeutic use; neoplasm cells; patients; Physical Sciences; Platinum; Platinum - pharmacokinetics; Prodrugs; prostatic neoplasms; quantitative polymerase chain reaction; Ribonucleic acid; RNA; RNA Interference - physiology; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - genetics; Small interfering RNA; synergism; Synergistic effect; Tumors; siRNA delivery; chemosensitivity; combination therapy
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1303958110

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- co glycolide)- 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.