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Tumor-Targeted Nanoparticles Deliver a Vitamin D-Based Drug Payload for Treatment of EGFR Tyrosine Kinase Inhibitor-Resistant Lung Cancer.

著者 Liu C , Shaurova T , Shoemaker S , Petkovich M , Hershberger PA , Wu Y
Mol Pharm.2018 Jun 14 ; ():.
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Mutation in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene drives the development of lung cancer. EGFR tyrosine kinase inhibitors (EGFR TKI) including erlotinib and afatinib are initially effective in treating EGFR mutant non-small cell lung cancer (NSCLC). However, drug resistance quickly develops due to several mechanisms, including induction of the epithelial-mesenchymal transition (EMT). No effective therapies are currently available for patients who develop EMT-associated EGFR TKI resistance. 1,25-dihydroxyvitamin D3 (1,25D3) promotes epithelial differentiation and inhibits growth of NSCLC cells. 1,25D3 thus represents a promising agent for treatment of EMT-associated EGFR TKI resistance. However, 1,25D3 induces the expression of 24-hydroxylase (24OHase), which decreases 1,25D3 activity. CTA091, a potent and selective 24OHase inhibitor, has been developed to attenuate this adverse effect. CTA091 also suppresses renal 24OHase activity and so may promote hypercalcemia. To exploit favorable effects of 1,25D3 plus CTA091 in tumor cells while avoiding problematic systemic effects of 24OHase inhibition, we developed EGFR-targeted, liposomal nanoparticles (EGFR-LP) to offer tumor-targeted co-delivery of 1,25D3 and CTA091. We then established an EMT-associated model of EGFR TKI resistance, and showed that such nanoparticles improved cellular uptake of 1,25D3 and CTA091, drove pro-epithelial signaling by upregulating E-cadherin (CDH1), and significantly inhibited the growth of EGFR TKI resistant cells. Our results demonstrated that the delivery of vitamin D based drug payloads via tumor-targeted EGFR-LP has promise as a new therapy for EFGR TKI resistant lung cancer. Future studies will focus on in vivo evaluation of biological activity, therapeutic benefits and systemic toxicity prior to clinical translation.
PMID: 29902012 [PubMed - as supplied by publisher]
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