Multitargeted Nanoparticles Deliver Synergistic Drugs across the Blood–Brain Barrier to Brain Metastases of Triple Negative Breast Cancer Cells and Tumor‐Associated Macrophages

Abstract

Owing to the low expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), endocrine and anti-HER2 therapies are ineffective against TNBC. Thus currently, standard adjuvant and neoadjuvant treatments of TNBC are limited to conventional anthracycline-taxanebased chemotherapy. [1] Despite the initial response to chemotherapy, TNBC patients have a high risk of relapse and distal metastases, especially to the brain, leading to shortened survival times. [2] A number of targeted therapies have been investigated to treat TNBC including poly(ADPribose) polymerase (PARP) inhibitors, immune checkpoint inhibitors, antiandrogen agents, phosphoinositide 3-kinase inhibitors, mitogen-activated protein kinase inhibitors, antiangiogenic antibody, and integrin inhibitors. [1,3] Upregulation of cell surface αvβ3 and αvβ5 integrins in aggressive TNBC, especially in brain metastases and tumorassociated vasculature, has presented an opportunity for targeted therapy of TNBC using integrin-targeted peptides. [4] Of various peptide-based inhibitors of αv integrins, Cilengitide, an Arg-Gly-Asp (RGD) peptide mimetic, with high selectivity against integrins αvβ3 and αvβ5, reached phase 3 clinical trial; however, the results were negative. [5] This disappointing outcome may be caused by insufficient amounts of inhibitor reaching tumor cells to generate a direct cytotoxic effect against αvβ3 and αvβ5 positive cancer cells due to the short half-life of Cilengitide in vivo. [5] Nonetheless, RGD-conjugated nanoparticulate drug delivery systems have shown an ability to target chemotherapeutic drugs to integrin-overexpressing tumor vasculature and cancer cells. [6] Despite the promising results in preclinical models, it is challenging to find an optimal RGD particle coverage to balance tumor accumulation against liver uptake. For example, our previous studies on cyclic RGDfK (Arg-Gly-Asp-D-Phe-Lys; cRGD) peptide-conjugated solid-lipid nanoparticles (SLN) or polymer-lipid hybrid nanoparticles (PLN) revealed that a high density of cRGD on the surface led to increased liver uptake 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 integrinoverexpressing TNB...

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Understanding Patterns of Brain Metastasis in Triple-Negative Breast Cancer and Exploring Potential Therapeutic Targets

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