Advances in siRNA Drug Delivery Strategies for Targeted TNBC Therapy

Abstract

Among breast cancers, triple-negative breast cancer (TNBC) has been recognized as the most aggressive type with a poor prognosis and low survival rate. Targeted therapy for TNBC is challenging because it lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Chemotherapy, radiation therapy, and surgery are the common therapies for TNBC. Although TNBC is prone to chemotherapy, drug resistance and recurrence are commonly associated with treatment failure. Combination therapy approaches using chemotherapy, mAbs, ADC, and antibody-siRNA conjugates may be effective in TNBC. Recent advances with siRNA-based therapy approaches are promising for TNBC therapy with better prognosis and reduced mortality. This review discusses advances in nanomaterial- and nanobiomaterial-based siRNA delivery platforms for TNBC therapy exploring targeted therapy approaches for major genes, proteins, and TFs upregulated in TNBC tumors, which engage in molecular pathways associated with low TNBC prognosis. Bioengineered siRNA drugs targeting one or several genes simultaneously can downregulate desired genes, significantly reducing disease progression.

Keywords: biomaterials; nanomaterials; siRNA; targeted therapy; triple-negative breast cancer.

Figure 1

Various methods of treatment in TNBC therapy. (Adapted from [4] in modified form).

Figure 2

Some therapeutic targets (VEGF, VEGFR, C-KIT, EGFR, PTEN, Chk1/2, WEE1, PARP, BRCA1/2, mTOR) and their inhibitors in TNBC therapy. (Adapted from [3]).

Figure 3

Mechanism of RNA interference in siRNA therapeutics for gene silencing. Adapted from [84].

Figure 4

Flow cytometry evaluation of apoptotic cell death with DLP/siRNA indicating cell populations in Q1, Q2, Q3, and Q4 phases (clockwise) (a) showed cellular uptake of DLP siRNA (after 2 h and 8 h) (b) and inhibition of tumor cells by DLP/siRNA in a mouse model (c) (Adapted from [95] with permission).

Figure 5

Identification of effective siRNA therapeutics for selective silencing of multiple genes (top) and relative cell viability of different breast cancer cell lines at different siRNA concentrations (bottom). (Adapted from [23] with permission).

Figure 6

Key genes, proteins, and TFs are intricate in molecular pathways allied with low TNBC prognosis. These factors are upregulated in TNBC tumors. Engineered siRNA-based anticancer drugs targeting single or multiple genes/proteins/TFs caused downregulation and suppression and significantly lowered disease progression. (Adapted from [85] in modified form).