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

Abstract

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 TKIs), including erlotinib and afatinib, are initially effective in treating EGFR mutant nonsmall 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 the 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.

Consensus statement from 2nd International Conference on Controversies in Vitamin D

“…Use of CYP24 inhibitors such as ketoconazole, liarazole and genistein among others have been shown to increase the anti-cancer activity of vitamin D in cell and animal models [116]. A recent study used a designed small molecule inhibitor of CYP24A1 known as CTA091 [117]. To avoid the systemic effects, a tumor targeted nanoparticle delivery system was developed to treat epidermal growth factor receptortyrosine kinase inhibitor (EGFR-TKI) lung cancer resistant to erlotinib.…”

Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer

“…Vitamin D receptor (VDR), a critical player in vitamin D signaling axis, is highly expressed in EGFR-mutant lung cancer cells, making them intrinsically sensitive to 1,25(OH)2D3. Moreover, 1,25(OH)2D3 restores expression of E-cadherin in models of EMT-associated resistance to EGFR TKIs, suggesting its capacity to promote sensitivity to this class of therapeutics (Liu et al, 2018). Studies to elucidate clinical relevance of 1,25(OH)2D3-based combination therapies in the context of acquired resistance to EGFR TKIs are currently under way in our laboratory.…”

<p>Targeted lipid nanoparticle delivery of calcitriol to human monocyte-derived macrophages in vitro and in vivo: investigation of the anti-inflammatory effects of calcitriol</p>

“…Recent attempts have been made to overcome this involving the encapsulation of calcitriol in nanoemulsions, liposomes, and PLGA nanoparticles. 2,3,31,45 Although such nanoparticles accumulate at the sites of inflammation or in tumor tissue due to the enhanced permeability and retention effect, 46,47 further improvement of the therapeutic index may be obtained by specific targeting of the inflammatory cells, in essence reducing the adverse effects of toxic therapeutic agents caused by systemic uptake. We used the Mϕ specific receptor CD163 as a target for antibodymodified LNPs.…”

“…30 Delivering encapsulated calcitriol to, for example, EGFR tyrosine kinase inhibitor-resistant lung cancer or to Mϕ involved in NASH has demonstrated effective cellular uptake and drug efficacy. 2,31 In the present study, we developed calcitriol lipid nanoparticles (LNP(Cal)) and PEGylated calcitriol lipid nanoparticles (PEG-LNP(Cal)) with a core of triolein-POPC (2-oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine), as reported by Zhigaltsev et al 32 PEG-LNPs have an improved half-life and circulation time in vivo compared to conventional LNPs 1 and are able to avoid rapid uptake by nontarget cells. Several studies have shown that the improved half-life of PEG-LNPs results in the increased accumulation of LNPs in tumor and inflamed areas, where increased presence of immune cells is observed in certain cancers and inflammatory diseases.…”