Calcitriol-Loaded Dual-pH-Sensitive Micelle Counteracts Pro-Metastasis Effect of Paclitaxel in Triple-Negative Breast Cancer Therapy

Abstract

The therapy of triple-negative breast cancer (TNBC) relies on chemotherapy basing on cytotoxic agents, including paclitaxel (PTX). Unfortunately, PTX will facilitate the invasion of cancer cells and the formation of metastases. To counteract pro-metastasis of PTX in TNBC therapy, in this work, calcitriol (CTL) is delivered along with PTX by a dual-pH-sensitive micelle. The PTX/CTL-co-loaded dual-pH-sensitive micelle (PCDM) can switch its surface charge from negative to positive at the tumor tissue and release PTX and CTL inside the lysosomes because of the structure change of the polymers composing PCDM under the acidic condition. This property makes PCDM able to escape from mononuclear-phagocyte system clearance and easy to enter tumor cells. PCDM efficiently suppresses the 4T1 primary tumor growth in mice and inhibits lung metastasis, due to downregulation of matrix metalloproteinase-9 and BCL-2 levels, upregulation of E-cadherin level, and counteracting the PTX-induced elevation of C-C motif chemokine ligand 2 (CCL2) and Ly6C⁺ monocytes levels by CTL. PCDM shows good biocompatibility without promoting the serum calcium level. Therefore, the combination of PTX and CTL based on this pH-sensitive micelle is promising for the TNBC treatment.

Keywords: breast cancer; calcitriol; metastasis; micelles; pH-sensitive micelles.