α_vβ₃ integrin-targeted micellar mertansine prodrug effectively inhibits triple-negative breast cancer in vivo

Abstract

Antibody-mertansine (DM1) conjugates (AMCs) are among the very few active targeting therapeutics that are approved or clinically investigated for treating various cancers including metastatic breast cancer. However, none of the AMCs are effective for the treatment of triple-negative breast cancers (TNBCs). Here, we show that cRGD-decorated, redox-activatable micellar mertansine prodrug (cRGD-MMP) can effectively target and deliver DM1 to α v β 3 integrin overexpressing MDA-MB-231 TNBC xenografts in nude mice, resulting in potent tumor growth inhibition. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays showed that cRGD-MMP had obvious targetability to MDA-MB-231 cells with a low half-maximal inhibitory concentration (IC 50 ) of 0.18 μM, which was close to that of free DM1 and 2.2-fold lower than that of micellar mertansine prodrug (MMP; nontargeting control). The confocal microscopy studies demonstrated that cRGD-MMP mediated a clearly more efficient cellular uptake and intracellular release of doxorubicin (used as a fluorescent anticancer drug model) in MDA-MB-231 cells. Notably, cRGD-MMP loaded with 1,1′-dioctadecyltetramethyl indotricarbocyanine iodide (DiR; a hydrophobic near-infrared dye) was shown to quickly accumulate in the MDA-MB-231 tumor with strong DiR fluorescence from 2 to 24 h post injection. MMP loaded with DiR could also accumulate in the tumor, although significantly less than cRGD-MMP. The biodistribution studies revealed a high DM1 accumulation of 8.1%ID/g in the tumor for cRGD-MMP at 12 h post injection. The therapeutic results demonstrated that cRGD-MMP effectively suppressed MDA-MB-231 tumor growth at 1.6 mg DM1 equiv./kg without causing noticeable side effects, as shown by little body weight loss and histological analysis. This MMP has appeared as a promising platform for potent treatment of TNBCs.

The Therapeutic Efficacy of Dendrimer and Micelle Formulations for Breast Cancer Treatment

“…Zhong and co-workers formulated cRGD-decorated, redox-activatable micellar mertansine prodrug to deliver mertansine to αvβ3 integrin overexpressed triple negative breast cancer. The cytotoxicity analysis showed that these micelles effectively suppressed MDA-MB-231 breast tumor growth without causing obvious side effects, as revealed by the body weight loss and histological analysis [ 224 ]. The formulation was effective in targeting and delivering of mertansine to α v β 3 integrin overexpressing triple negative breast cancer with a potent tumor growth inhibition.…”

Pyridyl Disulfide Functionalized Polymers as Nanotherapeutic Platforms

“…Recently, Zhong et al. utilized a PD functionalized polymer to deliver a fluorescent dye, 1,1′‐dioctadecyltetramethyl indotricarbocyanine iodide (DiR), into MDA‐MB‐231 tumor‐bearing mice for in vivo fluorescence imaging . DiR was encapsulated by the polymer to fabricate polymeric micelles, which were further modified with tumor targeting ligand RGD.…”

“…In vivo fluorescence imaging of MDA‐MB‐231 tumor‐bearing mice after intravenous injection with DiR‐loaded polymeric micelles A) with and B) without RGD decoration. Reproduced with permission . Copyright 2017, DOVE Medical Press.…”

Tumour targeted contrast enhanced ultrasound imaging dual-modal microbubbles for diagnosis and treatment of triple negative breast cancer

“…Effective internalization by TNBC cells is a prerequisite for chemotherapy drugs to kill the tumour cells. In this work, the RGD-MBs + UTMD were designed to promote drugs internalization and further improve the treatment effect to TNBC cells by delivering more RGD-MBs around tumour cells through peptide RGD, 17 and punching transient holes on the cells membrane surface by sonoporation effect inducing by UTMD. 11 The internalization and intracellular distribution of the RGD-MBs in TNBC cells (MDA-MB-231) were observed through uorescence inverted microscope.…”

“…16 In this work, we designed a drug carrier system, PTX-loaded RGD-lipid microbubbles (PTX@RGD-MBs) combining ultrasonic targeted microbubble destruction (UTMD), by the thin-lm hydration-sonication method (Fig. 1), where RGD peptide (three peptides, arginine-glycine-aspartic acid) as tumour active targeting peptide to precisely guide microbubbles to TNBC cells, [17][18][19] PTX in oil layer as chemotherapeutic agent to kill TNBC cells, sulfur hexauoride (SF 6 ) as internal gas of microbubbles to generate contrast enhanced ultrasound (CEUS) images through the nonlinear harmonics, 20 along with UTMD to promote PTX's internalization. 21 As shown in Fig.…”