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Enhanced Anticancer Activity of Nanoformulation of Dasatinib against Triple-Negative Breast Cancer.

ABSTRACT: Triple negative breast cancer (TNBC) is the most aggressive breast cancer accounting for around 15% of identified breast cancer cases. TNBC lacks human epidermal growth factor receptor 2 (HER2) amplification, is hormone independent estrogen (ER) and progesterone receptors (PR) negative, and is not reactive to current targeted therapies. Existing treatment relies on chemotherapeutic treatment, but in spite of an initial response to chemotherapy, the inception of resistance and relapse is unfortunately common. Dasatinib is an approved second-generation inhibitor of multiple tyrosine kinases, and literature data strongly support its use in the management of TNBC. However, dasatinib binds to plasma proteins and undergoes extensive metabolism through oxidation and conjugation. To protect dasatinib from fast pharmacokinetic degradation and to prolong its activity, it was encapsulated on poly(styrene-co-maleic acid) (SMA) micelles. The obtained SMA-dasatinib nanoparticles (NPs) were evaluated for their physicochemical properties, in vitro antiproliferative activity in different TNBC cell lines, and in vivo anticancer activity in a syngeneic model of breast cancer. Obtained results showed that SMA-dasatinib is more potent against 4T1 TNBC tumor growth in vivo compared to free drug. This enhanced effect was ascribed to the encapsulation of the drug protecting it from a rapid metabolism. Our finding highlights the often-overlooked value of nanoformulations in protecting its cargo from degradation. Overall, results may provide an alternative therapeutic strategy for TNBC management.

SUBMITTER: Bahman F

PROVIDER: S-EPMC8234460 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Triple-negative breast cancer (TNBC) is one of the most malignant cancers associated with early metastasis, poor clinical prognosis, and high recurrence rate. TNBC is a distinct subtype of breast cancer that lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 receptors (HER2). Development of effective TNBC therapies has been limited partially due to the lack of specific molecular targets and chemotherapy involving different cytotoxic drugs suffers from significant side effects and drug-resistance development. Therefore, there is an unmet need for the development of novel and efficient therapeutic drugs with reduced side effects to treat TNBC. We have previously reported that certain analogues of haloperidol (a typical antipsychotic drug used for treating mental/mood disorders such as schizophrenia and bipolar disorder) suppress the viability of a variety of solid tumor cell lines, and we have identified 4-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-1-(4-fluoro-phenyl)butan-1-one (SYA013) with such antiproliferative properties. Interestingly, unlike haloperidol, SYA013 shows moderate selectivity toward σ2 receptors. In this study, we explored the potential of SYA013 in modulating the important biological events associated with cell survival and progression as well as the mechanistic aspects of apoptosis in a representative TNBC cell line (MDA-MB-231). Our results indicate that SYA013 inhibits the proliferation of MDA-MB-231 cells in a concentration-dependent manner and suppresses cell migration and invasion. Apoptotic studies were also conducted in MDA-MB-468 cells (cells derived from a 51-year old Black female with metastatic adenocarcinoma of the breast.). In addition, we have demonstrated that SYA013 induces MDA-MB-231 cell death through the intrinsic apoptotic pathway and may suppress tumor progression and metastasis. Taken together, our study presents a mechanistic pathway of the anticancer properties of SYA013 against TNBC cell lines and suggests a potential for exploring SYA013 as a lead agent for development against TNBC.

Project description:BackgroundRanpirnase (Rap) is an amphibian ribonuclease with reported antitumor activity, minimal toxicity, and negligible immunogenicity in clinical studies, but the unfavorable pharmacokinetics and suboptimal efficacy hampered its further clinical development. To improve the potential of Rap-based therapeutics, we have used the DOCK-AND-LOCK™ (DNL™) method to construct a class of novel IgG-Rap immunoRNases. In the present study, a pair of these constructs, (Rap)2-E1-(Rap)2 and (Rap)2-E1*-(Rap)2, comprising four copies of Rap linked to the CH3 and CK termini of hRS7 (humanized anti-Trop-2), respectively, were evaluated as potential therapeutics for triple-negative breast cancer (TNBC).MethodsThe DNL-based immunoRNases, (Rap)2-E1-(Rap)2 and (Rap)2-E1*-(Rap)2, were characterized and tested for biological activities in vitro on a panel of breast cancer cell lines and in vivo in a MDA-MB-468 xenograft model.Results(Rap)2-E1-(Rap)2 was highly purified (>95%), exhibited specific cell binding and rapid internalization in MDA-MB-468, a Trop-2-expressing TNBC line, and displayed potent in vitro cytotoxicity (EC50???1 nM) against diverse breast cancer cell lines with moderate to high expression of Trop-2, including MDA-MB-468, BT-20, HCC1806, SKBR-3, and MCF-7. In comparison, structural counterparts of (Rap)2-E1-(Rap)2, generated by substituting hRS7 with selective non-Trop-2-binding antibodies, such as epratuzumab (anti-CD22), were at least 50-fold less potent than (Rap)2-E1-(Rap)2 in MDA-MB-468 and BT-20 cells, both lacking the expression of the cognate antigen. Moreover, (Rap)2-E1-(Rap)2 was less effective (EC50 > 50 nM) in MDA-MB-231 (low Trop-2) or HCC1395 (no Trop-2), and did not show any toxicity to human peripheral blood mononuclear cells. In a mouse TNBC model, a significant survival benefit was achieved with (Rap)2-E1*-(Rap)2 when given the maximal tolerated dose.ConclusionsA new class of immunoRNases was generated with enhanced potency for targeted therapy of cancer. The promising results from (Rap)2-E1-(Rap)2 and (Rap)2-E1*-(Rap)2 support their further investigation as a potential treatment option for TNBC and other Trop-2-expressing cancers.

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Enhanced Anticancer Activity of Nanoformulation of Dasatinib against Triple-Negative Breast Cancer.

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