EILDV-conjugated, etoposide-loaded biodegradable polymeric micelles directing to tumor metastatic cells overexpressing α4β1 integrin

Abstract

In the present study, poly(ethylene glycol)-b-poly(ε-caprolactone) micelles loaded with etoposide (ETO) were formulated and further conjugated with pentapeptide Glu-Ile-Leu-Asp-Val (EILDV) to target α4β1 integrin receptor overexpressed on metastatic tumor cell. Using a distinct ratio of carboxyl-terminated poly(ethylene glycol)-block-poly(ε-caprolactone) (HOOC–PEG-b-PCL) to methoxy-poly(ethylene glycol)-block-poly(ε-caprolactone (CH3O–PEG-b-PCL) polymers, we formulated a series of micellar formulations having different surface densities of EILDV and observed optimum cellular uptake of micelles with 10% EILDV surface density by B16F10 cells. The cytotoxicity of EILDV-conjugated micelles was observed close to 1.5-fold higher than plain ETO after 72 h of drug incubation, demonstrating controlled release of drug inside the cell after enhanced intracellular uptake with the ability to selectively target cancer cells. In addition, EILDV-conjugated micelles inhibited the migration of B16F10 cells effectively compared with plain ETO and non-conjugated micellar formulations when cells were treated with equivalent cytotoxic concentration of the drug, i.e., IC25. B16F10 cells treated with EILDV-conjugated micelles showed a significant reduction in the attachment of cells to the substrate-coated plate compared with non-conjugated micellar formulations, implying retention of the biological activity of EILDV after coupling to micelles. Furthermore, the in vivo experimental metastasis assay conducted on C57BL/6 mice demonstrated significant activity of EIDLV-conjugated micelles in the reduction of pulmonary metastatic nodule formation in both pretreatment and post-treatment methods. In conclusion, EIDLV-conjugated micelles showed higher efficacy in the treatment of metastasis and would be a promising approach in the treatment of metastasis.

Development and Characterization of the Shortest Anti-Adhesion Peptide Analogue of B49Mod1

“…Despite this drawback, the B18-mediated blockade of cancer cell adhesion is a property that may be harnessed in future drug development efforts. Indeed, a number of anti-adhesion peptides including arginine-glycine-aspartate (RGD), derived from the common conserved sequences of fibronectin, collagen, and fibrinogen [72]; YIGSR, derived from the basement membrane protein laminin [72], and EILDV, derived from the core sequence of fibronectin [73] have been described. Thus, the anti-adhesion property of B18 has significance for understanding cross-talking pathways of cell-cell or cell-ECM adhesion for the purpose of interrupting adhesion-dependent biological events that promote breast cancer.…”

Biomolecules Turn Self-Assembling Amphiphilic Block Co-polymer Platforms Into Biomimetic Interfaces

“…For instance, polymer-based micelles containing deprotected aldehyde groups were able to chemically bind RGD peptides (Duong et al, 2010). In this case the chemical conjugation of micelles with peptides not only does not affect negatively their self-assembly, but also enhances their biocompatibility and eases their uptake from mammalian cells (Ukawala et al, 2011; Han et al, 2017). Furthermore, this strategy applies also to the use of polymer micelles for siRNA delivery and micelle-protein conjugates (Amjad et al, 2017; Han et al, 2017).…”

Controlled micelle conjugation via charged peptide amphiphiles

“…Multimolecular micelles or liposomes, containing therapeutic agents or contrast reagents, have demonstrated their utility as delivery systems for both medicinal and diagnostic applications. This became possible once the outer surfaces of the above aggregates were modified with peptides (or antibodies) that produced site specificity for use in cancer therapy or diagnosis . Peptide self‐assembly was also shown to produce effective vaccines, thereby further emphasizing the utility of this class of compounds .…”

“…This became possible once the outer surfaces of the above aggregates were modified with peptides (or antibodies) that produced site specificity for use in cancer therapy or diagnosis. [1][2][3][4][5][6][7][8] Peptide self-assembly was also shown to produce effective vaccines, thereby further emphasizing the utility of this class of compounds. [9][10][11] The ready availability of synthetic peptides, combined with their broad range of physicochemical properties, has contributed to the design of polypeptide/polymer micelles classified as (a) unresponsive micelles, 12,13 (b) pH-responsive micelles, [14][15][16][17] and (c) redox-responsive micelles.…”