Abstract
Treatment options for triple negative breast cancer (TNBC) are generally limited to cytotoxic chemotherapy. Recently, anti-epidermal growth factor receptor (EGFR) therapy has been introduced for TNBC patients. We engineered a novel nanobioconjugate based on a poly(β-L-malic acid) (PMLA) nanoplatform for TNBC treatment. The nanobioconjugate carries anti-tumor nucleosome-specific monoclonal antibody (mAb) 2C5 to target breast cancer cells, anti-mouse transferrin receptor (TfR) antibody for drug delivery through the host endothelial system, and Morpholino antisense oligonucleotide (AON) to inhibit EGFR synthesis. The nanobioconjugates variants were: (1) P (BioPolymer) with AON, 2C5 and anti-TfR for tumor endothelial and cancer cell targeting, and EGFR suppression (P/AON/2C5/TfR), and (2) P with AON and 2C5 (P/AON/2C5). Controls included (3) P with 2C5 but without AON (P/2C5), (4) PBS, and (5) P with PEG and leucine ester (LOEt) for endosomal escape (P/mPEG/LOEt). Drugs were injected intravenously to MDA-MB-468 TNBC bearing mice. Tissue accumulation of injected nanobioconjugates labeled with Alexa Fluor 680 was examined by Xenogen IVIS 200 (live imaging) and confocal microscopy of tissue sections. Levels of EGFR, phosphorylated and total Akt in tumor samples were detected by western blotting. In vitro western blot showed that the leading nanobioconjugate P/AON/2C5/TfR inhibited EGFR synthesis significantly better than naked AON. In vivo imaging revealed that 2C5 increased drug-tumor accumulation. Significant tumor growth inhibition was observed in mice treated with the lead nanobioconjugate (1) [P = 0.03 vs. controls; P<0.05 vs. nanobioconjugate variant (2)]. Lead nanobioconjugate (1) also showed stronger inhibition of EGFR expression and Akt phosphorylation than other treatments. Treatment of TNBC with the new nanobioconjugate results in tumor growth arrest by inhibiting EGFR and its downstream signaling intermediate, phosphorylated Akt. The nanobioconjugate represents a new generation of nanodrugs for treatment of TNBC.
Highlights
Triple negative breast cancer (TNBC) is an aggressive breast cancer phenotype characterized by lack of expression of estrogen receptor (ER) and progesterone receptor (PR), as well as the absence of overexpression of human epidermal growth factor receptor-2 (HER-2) [1].TNBC often presents as an advanced-stage disease and is treated mostly by systemic administration of conventional chemotherapy due to the lack of specific molecular markers expression [2]
Synthesis of Polymalic acid nanobioconjugates The nanobioconjugates were synthesized for TNBC treatment using the hierarchic organization as described previously, with modifications [13]
Of the two sequences of antisense oligonucleotide (AON) specific for EGFR, version 2 knocked down EGFR expression better than version 1
Summary
Triple negative breast cancer (TNBC) is an aggressive breast cancer phenotype characterized by lack of expression of estrogen receptor (ER) and progesterone receptor (PR), as well as the absence of overexpression of human epidermal growth factor receptor-2 (HER-2) [1].TNBC often presents as an advanced-stage disease and is treated mostly by systemic administration of conventional chemotherapy due to the lack of specific molecular markers expression [2]. Immunohistochemical analysis showed that TNBC is associated with a high expression of proliferation marker Ki-67 as well as several other markers favoring cancer cell growth, including mutated p53, cyclin E, epidermal growth factor receptor-1 (HER1, EGFR), vimentin, P-cadherin, and mutated BRCA1. Anti-EGFR therapy has been increasingly recognized as an important treatment for breast cancer patients [3]. High expression of EGFR induces erroneous development and unrestricted proliferation in a number of human malignancies, including breast cancer [4]. Tumors overexpressing EGFR represent clinically aggressive cases [6]. They tend to have more rapid cell cycle progression, greater chemoresistance, inhibition of apoptosis, increased angiogenesis, cell motility, and higher rates of metastasis [7]. EGFR is a potential therapeutic target for the successful treatment of TNBC
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