Improving Cancer Chemoradiotherapy Treatment by Dual Controlled Release of Wortmannin and Docetaxel in Polymeric Nanoparticles.
Combining molecularly targeted agents and chemotherapeutics is an emerging strategy in cancer treatment. We engineered sub-50 nm diameter diblock copolymer nanoparticles (NPs) that can sequentially release wortmannin (Wtmn, a cell signaling inhibitor) and docetaxel (Dtxl, genotoxic anticancer agent) to cancer cells. These NPs were studied in chemoradiotherapy, an important cancer treatment paradigm, in the preclinical setting. We demonstrated that Wtmn enhanced the therapeutic efficacy of Dtxl and increased the efficiency of radiotherapy (XRT) in H460 lung cancer and PC3 prostate cells in culture. Importantly, we showed that NPs containing both Wtmn and Dtxl release the drugs in a desirable sequential fashion to maximize therapeutic efficacy in comparison to administering each drug alone. An in vivo toxicity study in a murine model validated that NPs containing both Dtxl and Wtmn do not have a high toxicity profile. Lastly, we demonstrated that Dtxl/Wtmn-coencapsulated NPs are more efficient than each single-drug-loaded NPs or a combination of both single-drug-loaded NPs in chemoradiotherapy using xenograft models. Histopathological studies and correlative studies support that the improved therapeutic efficacy is through changes in signaling pathways and increased tumor cell apoptosis. Our findings suggest that our nanoparticle system led to a dynamic rewiring of cellular apoptotic pathways and thus improve the therapeutic efficiency.
Kin Man
KM
Au
Yuanzeng
Y
Min
Xi
X
Tian
Department of Radiation Oncology, Xuzhou Medical School , Xuzhou, China.
Longzhen
L
Zhang
Virginia
V
Perello
Joseph M
JM
Caster
Department of Radiation Oncology, Xuzhou Medical School , Xuzhou, China.
Andrew Z
AZ
Wang
D000730:Androstadienes / Q000008:administration & dosage / Q000737:chemistry; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations; D000077143:Docetaxel; D016503:Drug Delivery Systems; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D043823:Taxoids / Q000008:administration & dosage / Q000737:chemistry; D000077191:Wortmannin; D023041:Xenograft Model Antitumor Assays
D000730:Androstadienes; D003692:Delayed-Action Preparations; D043823:Taxoids; D000077143:Docetaxel; D000077191:Wortmannin
cancer; combination chemotherapy; concurrent chemoradiotherapy; diblock copolymer NPs; dual drug encapsulation; dynamic rewiring of cell apoptotic pathways