Using an RNAi Signature Assay To Guide the Design of Three-Drug-Conjugated Nanoparticles with Validated Mechanisms, In Vivo Efficacy, and Low Toxicity.
Single-nanoparticle (NP) combination chemotherapeutics are quickly emerging as attractive alternatives to traditional chemotherapy due to their ability to increase drug solubility, reduce off-target toxicity, enhance blood circulation lifetime, and increase the amount of drug delivered to tumors. In the case of NP-bound drugs, that is, NP-prodrugs, the current standard of practice is to assume that the subcellular mechanism of action for each drug released from the NP mirrors that of the unbound, free-drug. Here, we use an RNAi signature assay for the first time to examine the mechanism of action of multidrug-conjugated NP prodrugs relative to their small molecule prodrugs and native drug mechanisms of action. Additionally, the effective additive contribution of three different drugs in a single-NP platform is characterized. The results indicate that some platinum(IV) cisplatin prodrugs, although cytotoxic, may not have the expected mechanism of action for cisplatin. This insight was utilized to develop a novel platinum(IV) oxaliplatin prodrug and incorporate it into a three-drug-conjugated NP, where each drug's mechanism of action is preserved, to treat tumor-bearing mice with otherwise lethal levels of chemotherapy.
Department of Chemistry, and ‡The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
Jonathan C
JC
Barnes
Department of Chemistry, and ‡The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
Peter M
PM
Bruno
Department of Chemistry, and ‡The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
Hung V-T
HV
Nguyen
Department of Chemistry, and ‡The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
Longyan
L
Liao
Department of Chemistry, and ‡The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
Jenny
J
Liu
Department of Chemistry, and ‡The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
Michael T
MT
Hemann
Department of Chemistry, and ‡The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
Jeremiah A
JA
Johnson
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D051379:Mice; D015394:Molecular Structure; D053758:Nanoparticles / Q000737:chemistry*; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D000077150:Oxaliplatin; D011355:Prodrugs / Q000008:administration & dosage; D034622:RNA Interference
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D011355:Prodrugs; D000077150:Oxaliplatin; D004317:Doxorubicin; D002166:Camptothecin