Improving Cancer Chemoradiotherapy Treatment by Dual Controlled Release of Wortmannin and Docetaxel in Polymeric Nanoparticles

Abstract

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.

Diverse Applications of Nanomedicine

“…459,460 The poor specificity of most drugs and the complexity of tumors ( e.g. , multiple targets) contribute greatly to the poor prognosis of chemotherapy.…”

Application of nanotechnology to cancer radiotherapy

“…The in vivo toxicity profile of the nanoparticles containing both docetaxel and wortmannin indicates the reduction of both hepatotoxicity and hematologic toxicity. Meanwhile, they achieved better chemoradiotherapeutic effect than each single-drug-loaded nanoparticle and combination of both single-drug-loaded nanoparticles using xenograft models (Au et al 2015a, b).

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Fig. 2Improving cancer chemoradiotherapy treatment by dual controlled release of wortmannin and docetaxel in polymeric nanoparticles (Au et al 2015a, b)

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“…The nanoparticles comprised a synthetic peptide targeting collagen IV fiber, which enables the nanoparticle to bind to the collagen IV-rich BM on the site of endothelium damage. Its ability to identify an early-stage blood vessel injury induced by high-dose radiotherapy was demonstrated in a Murine model (Au et al 2015a, b; Kamaly et al 2013). …”

Synthetic nanoparticles for delivery of radioisotopes and radiosensitizers in cancer therapy

“…Au et al (2015) prepared PEG–PLGA polymeric nanoparticles to encapsulate docetaxel and wortmannin. Docetaxel induces cell cycle arrest in G2/M phases, as well as increases ROS production (Rabi and Bishayee 2009).…”