TY - JOUR
T1 - Sequential application of a cytotoxic nanoparticle and a PI3K inhibitor enhances antitumor efficacy
AU - Pandey, Ambarish
AU - Kulkarni, Ashish
AU - Roy, Bhaskar
AU - Goldman, Aaron
AU - Sarangi, Sasmit
AU - Sengupta, Poulomi
AU - Phipps, Colin
AU - Kopparam, Jawahar
AU - Oh, Michael
AU - Basu, Sudipta
AU - Kohandel, Mohammad
AU - Sengupta, Shiladitya
PY - 2014/2/1
Y1 - 2014/2/1
N2 - Nanomedicines that preferentially deploy cytotoxic agents to tumors and molecular targeted therapeutics that inhibit specific aberrant oncogenic drivers are emerging as the new paradigm for the management of cancer. While combination therapies are a mainstay of cancer chemotherapy, few studies have addressed the combination of nanomedicines and molecular targeted therapeutics. Furthermore, limited knowledge exists on the impact of sequencing of such therapeutics and nanomedicines on the antitumor outcome. Here, we engineered a supramolecular cis-platinum nanoparticle, which induced apoptosis in breast cancer cells but also elicited prosurvival signaling via an EGF receptor/phosphoinositide 3-kinase (PI3K) pathway. A combination of mathematical modeling and in vitro and in vivo validation using a pharmacologic inhibitor of PI3K, PI828, demonstrate that administration of PI828 following treatment with the supramolecular cis-platinum nanoparticle results in enhanced antitumor efficacy in breast cancer as compared with when the sequence is reversed or when the two treatments are administered simultaneously. This study addresses, for the first time, the impact of drug sequencing in the case of a combination of a nanomedicine and a targeted therapeutic. Furthermore, our results indicate that a rational combination of cis-platinum nanoparticles and a PI3K-targeted therapeutic can emerge as a potential therapy for breast cancer.
AB - Nanomedicines that preferentially deploy cytotoxic agents to tumors and molecular targeted therapeutics that inhibit specific aberrant oncogenic drivers are emerging as the new paradigm for the management of cancer. While combination therapies are a mainstay of cancer chemotherapy, few studies have addressed the combination of nanomedicines and molecular targeted therapeutics. Furthermore, limited knowledge exists on the impact of sequencing of such therapeutics and nanomedicines on the antitumor outcome. Here, we engineered a supramolecular cis-platinum nanoparticle, which induced apoptosis in breast cancer cells but also elicited prosurvival signaling via an EGF receptor/phosphoinositide 3-kinase (PI3K) pathway. A combination of mathematical modeling and in vitro and in vivo validation using a pharmacologic inhibitor of PI3K, PI828, demonstrate that administration of PI828 following treatment with the supramolecular cis-platinum nanoparticle results in enhanced antitumor efficacy in breast cancer as compared with when the sequence is reversed or when the two treatments are administered simultaneously. This study addresses, for the first time, the impact of drug sequencing in the case of a combination of a nanomedicine and a targeted therapeutic. Furthermore, our results indicate that a rational combination of cis-platinum nanoparticles and a PI3K-targeted therapeutic can emerge as a potential therapy for breast cancer.
UR - http://www.scopus.com/inward/record.url?scp=84893838492&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84893838492&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-12-3783
DO - 10.1158/0008-5472.CAN-12-3783
M3 - Article
C2 - 24121494
AN - SCOPUS:84893838492
SN - 0008-5472
VL - 74
SP - 675
EP - 685
JO - Cancer research
JF - Cancer research
IS - 3
ER -