Cancer Cell Membrane Wrapped Nanoparticles for the Delivery of a Bcl-2 Inhibitor to Triple-Negative Breast Cancer

Abstract

Overexpression of the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) is correlated with poor survival outcomes in triple-negative breast cancer (TNBC), making Bcl-2 inhibition a promising strategy to treat this aggressive disease. Unfortunately, Bcl-2 inhibitors developed to date have limited clinical success against solid tumors, owing to poor bioavailability, insufficient tumor delivery, and off-target toxicity. To circumvent these problems, we loaded the Bcl-2 inhibitor ABT-737 in poly(lacticco-glycolic acid) (PLGA) nanoparticles (NPs) that were wrapped with phospholipid membranes derived from 4T1 murine mammary cancer cells, which mimic the growth and metastasis of human TNBC. We show that the biomimetic cancer cell membrane coating enabled the NPs to preferentially target 4T1 TNBC cells over noncancerous mammary epithelial cells in vitro and significantly increased NP accumulation in orthotopic 4T1 tumors in mice after intravenous injection by over 2-fold compared to poly(ethylene glycol)−poly(lactide-co-glycolic) (PEG−PLGA) copolymer NPs. Congruently, the ABT-737 loaded, cancer cell membrane-wrapped PLGA NPs (ABT CCNPs) induced higher levels of apoptosis in TNBC cells in vitro than ABT-737 delivered freely or in PEG−PLGA NPs. When tested in a syngeneic spontaneous metastasis model, the ABT CCNPs significantly increased apoptosis (evidenced by elevated active caspase-3 and decreased Bcl-2 staining) and decreased proliferation (denoted by reduced Ki67 staining) throughout tumors compared with saline or ABT-loaded PEG−PLGA NP controls. Moreover, the ABT CCNPs did not alter animal weight or blood composition, suggesting that the specificity afforded by the TNBC cell membrane coating mitigated the off-target adverse effects typically associated with ABT-737. Despite these promising results, the low dose of ABT CCNPs administered only modestly reduced primary tumor growth and metastatic nodule formation in the lungs relative to controls. We posit that increasing the dose of ABT CCNPs, altering the treatment schedule, or encapsulating a more potent Bcl-2 inhibitor may yield more robust effects on tumor growth and metastasis. With further development, drug-loaded biomimetic NPs may safely treat solid tumors such as TNBC that are characterized by Bcl-2 overexpression.

Functionalized siRNA-chitosan nanoformulations promote triple-negative breast cancer cell death via blocking the miRNA-21/AKT/ERK signaling axis: in-silico and in vitro studies

“…Many anticancer drugs increase the expression of caspase 3, Bax, and p53, which kills cancer cells (LeBlanc et al 2002). In this instance, we were able to trigger apoptosis in cancer cells by upregulating Bax and caspases and downregulating BCL2 expression (Scully et al 2023). The consistent changes in the expression of Bax and BCL2 revealed that the Bax/BCL2 signaling pathway might be a common mechanism to inhibit tumor growth, which is a viable direction for creating methods for treating various malignancies.…”

Cell Membrane-Coated Nanoparticles for Precision Medicine: A Comprehensive Review of Coating Techniques for Tissue-Specific Therapeutics

“…M any different cell types have been used for nanoparticle membrane coating (Table 1). Notably, a range of cancer lines has been used, including cervical and ovarian cancers [21][22][23][24], multiple myeloma [25], melanoma [12,[26][27][28][29][30][31][32], leukemia [23,[33][34][35][36][37][38][39][40][41][42][43][44], breast cancer [6,37,40,[45][46][47][48][49][50][51][52][53][54][55][56], neuroblastoma [79], colon carcinoma [23,57], head and neck squamous cell carcinoma [58][59][60][61], lung cancer…”

“…Most researchers employed hypotonic lysis in their studies [6,12,19,[21][22][23][24][25][26][27][29][30][31][32][33][34][35][36]38,39,[41][42][43][44][45][48][49][50][51][54][55][56][57][58][60][61][62][63][64][65][66][67][69][70][71][72][73][74][75][76][77]79,81,…”

“…This lysis method involves resuspending the utilized cells in a hypotonic solution containing low concentrations of salts and protease or phosphatase inhibitors. Several authors used a hypotonic lysis buffer with 20 mM Tris-HCl pH 7.5, 10 mM KCl, 2 mM MgCl 2 , and 1 EDTA-free mini protease inhibitor tablet per 10 mL of solution [12,23,25,34,44,45,51,54,56,58,67,72,95]. Parodi et al drew upon the use of the same salts as Qu et al, but adding 25 mM of sucrose and using PMSF and trypsin-chymotrypsin inhibitors [92].…”

“…More than half of the articles employing hypotonic lysis treatment incorporated homogenization to optimize the extraction of membrane fragments [12,[23][24][25][26][27]30,31,[33][34][35]38,[41][42][43]45,48,51,56,58,60,64,65,72,79,92,93,95,101,102]. In most of these studies [12,[23][24][25][26]33,34,38,[41][42][43]45,51,56,58,60,64,65,72,92,93,…”