title: Enhancing tumor cell response to chemotherapy through nanoparticle-mediated codelivery of siRNA and cisplatin prodrug.
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 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.
authors.affiliation: Laboratory of Nanomedicine and Biomaterials, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Xu
authors.forename: Kun
authors.initials: K
authors.lastname: Xie
authors.forename: Xue-Qing
authors.initials: XQ
authors.lastname: Zhang
authors.forename: Eric M
authors.initials: EM
authors.lastname: Pridgen
authors.forename: Ga Young
authors.initials: GY
authors.lastname: Park
authors.forename: Danica S
authors.initials: DS
authors.lastname: Cui
authors.forename: Jinjun
authors.initials: J
authors.lastname: Shi
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Lippard
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
authors.forename: Graham C
authors.initials: GC
authors.lastname: Walker
authors.forename: Omid C
authors.initials: OC
authors.lastname: Farokhzad
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D004337:Drug Carriers / Q000008:administration & dosage; D016503:Drug Delivery Systems / Q000379:methods*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004359:Drug Therapy, Combination / Q000379:methods*; D020868:Gene Silencing; D006801:Humans; D008156:Luciferases; D053758:Nanoparticles / Q000627:therapeutic use*; D010984:Platinum / Q000493:pharmacokinetics; D034622:RNA Interference / Q000502:physiology*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D034741:RNA, Small Interfering; D010984:Platinum; D008156:Luciferases; D002945:Cisplatin
keywords: chemosensitivity; combination therapy; siRNA delivery