Premium
Multitargeted Nanoparticles Deliver Synergistic Drugs across the Blood–Brain Barrier to Brain Metastases of Triple Negative Breast Cancer Cells and Tumor‐Associated Macrophages
Author(s) -
Zhang Tian,
Lip Hoyin,
He Chunsheng,
Cai Ping,
Wang Zhigao,
Henderson Jeffrey T.,
Rauth Andrew M.,
Wu Xiao Yu
Publication year - 2019
Publication title -
advanced healthcare materials
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.288
H-Index - 90
eISSN - 2192-2659
pISSN - 2192-2640
DOI - 10.1002/adhm.201900543
Subject(s) - triple negative breast cancer , blood–brain barrier , cancer research , in vivo , doxorubicin , breast cancer , drug delivery , medicine , cancer , pharmacology , chemistry , chemotherapy , biology , central nervous system , microbiology and biotechnology , organic chemistry
Patients with brain metastases of triple negative breast cancer (TNBC) have a poor prognosis owing to the lack of targeted therapies, the aggressive nature of TNBC, and the presence of the blood–brain barrier (BBB) that blocks penetration of most drugs. Additionally, infiltration of tumor‐associated macrophages (TAMs) promotes tumor progression. Here, a terpolymer‐lipid hybrid nanoparticle (TPLN) system is designed with multiple targeting moieties to first undergo synchronized BBB crossing and then actively target TNBC cells and TAMs in microlesions of brain metastases. In vitro and in vivo studies demonstrate that covalently bound polysorbate 80 in the terpolymer enables the low‐density lipoprotein receptor‐mediated BBB crossing and TAM‐targetability of the TPLN. Conjugation of cyclic internalizing peptide (iRGD) enhances cellular uptake, cytotoxicity, and drug delivery to brain metastases of integrin‐overexpressing TNBC cells. iRGD‐TPLN with coloaded doxorubicin (DOX) and mitomycin C (MMC) (iRGD‐DMTPLN) exhibits higher efficacy in reducing metastatic burden and TAMs than nontargeted DMTPLN or a free DOX/MMC combination. iRGD‐DMTPLN treatment reduces metastatic burden by 6‐fold and 19‐fold and increases host median survival by 1.3‐fold and 1.6‐fold compared to DMTPLN or free DOX/MMC treatments, respectively. These findings suggest that iRGD‐DMTPLN is a promising multitargeted drug delivery system for the treatment of integrin‐overexpressing brain metastases of TNBC.