Rational Design of Tumor Microenvironment‐Activated Micelles for Programed Targeting of Breast Cancer Metastasis

Abstract

The poor drug delivery to primary and metastatic tumors of breast cancer remains a great challenge for effective antimetastasis therapy. Herein, a tumor microenvironment‐activated cabazitaxel micelles decorated with legumain‐specific melittin (TCM‐legM) are rationally designed for programed targeting of breast cancer metastasis. TCM‐legM is quiescent in blood circulation, but can be specifically activated by the highly expressed legumain in tumor microenvironments to improve their specific targeting and deep penetrating to primary or metastatic tumors. Thereafter, the activated TCM‐legM can be efficiently internalized by cancer cells and motivate the rapid pH‐responsive drug release for antimetastasis therapy. In metastatic 4T1 breast cancer cells, TCM‐legM presents significant inhibition on the proliferation, migration, and invasion activities. In vivo, TCM‐legM can be effectively delivered to both primary and metastatic tumors of breast cancer with deep tumor penetration and efficient cellular internalization, thereby resulting in a notable reduction of tumor growth and producing a 93.4% suppression of lung metastasis. Taken together, the rationally designed TCM‐legM can provide an intelligent drug delivery strategy to enhance the medical performance on treating breast cancer metastasis.

Rational Design of Nanoparticles with Deep Tumor Penetration for Effective Treatment of Tumor Metastasis

“…The overexpression of extracellular enzymes, especially MMPs and legumain, is another striking characteristic that can be used for programmed targeting of primary tumor or metastasis sites . Inspired by the highly expressed MMP in tumor regions, Wang and co‐workers designed an enzyme‐sensitive nanocapsule consisting of a nanovesicle core decorated with the penetrating CRGDK peptide and a MMP‐2‐degradable polymeric shell anchored on the core.…”

“…Upon their exposure to the tumor environment, the upregulated legumain activated the TAT peptide and recovered the penetrating ability for enhanced tumor therapy . Based on the high expression of legumain in primary tumors and metastases, we designed a legumain‐specific propeptide of melittin and linked it with phospholipid to synthesize a legumain‐activated conjugate, and then, we assembled it with a pH‐sensitive polymer to form tumor microenvironment‐activated cabazitaxel micelles ( Figure ) . The micelles were responsively activated to recover the functions of active melittin, leading to considerable enhancement of penetration in primary tumors and distant lung metastases.…”

“…C) Deep penetration of TCM‐legM in primary tumors measured by photoacoustic imaging. Reproduced with permission . Copyright 2017, Wiley‐VCH.…”

“…One option is rational regulation of the physicochemical properties of nanoparticles, and the other option is remodeling of the tumor microenvironment, including the tumor vasculature and stromal environment ( Scheme ) . Conceivably, the physicochemical properties of nanoparticles, including particle size, shape, and surface modifications, can be optimized to improve tumor‐penetrating ability, and these properties can be intelligently modulated to exhibit responsiveness to internal (e.g., pH or enzymes) or external (e.g., light, ultrasound or radiation) stimuli to offer a programmed strategy for improvement of tumor penetration . Meanwhile, the abnormal tumor vasculature, various stromal cells, and the dense physical barriers of extracellular matrix (ECM) in tumor tissues can be flexibly remodeled with nanoparticles loaded with various active cargos to augment nanoparticles permeations in tumor masses.…”

Recent Advances in Microfluidic Platforms Applied in Cancer Metastasis: Circulating Tumor Cells' (CTCs) Isolation and Tumor‐On‐A‐Chip

“…The tumor microenvironment dynamically includes blood vascular networks, ECM, stromal and tumor cells as well as biochemical and physical factors. Recent studies have focused on employing experimental models reproducing the tumor microenvironment for identification of cellular, biophysical, and molecular features for cancer metastasis . However, most tumor models are difficult to recapitulate the complex pathophysiological features, tumor cell–surrounding ECM, or tumor cell–stroma cell interactions of the metastatic microenvironment.…”