title: 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.
authors.affiliation: Centre for Post Graduate studies and Research, New Drug Delivery Systems Laboratory, Pharmacy Department, The M. S. University of Baroda, Vadodara, India.
authors.forename: Mukesh
authors.initials: M
authors.lastname: Ukawala
authors.affiliation: Centre for Post Graduate studies and Research, New Drug Delivery Systems Laboratory, Pharmacy Department, The M. S. University of Baroda, Vadodara, India.
authors.forename: Tushar
authors.initials: T
authors.lastname: Rajyaguru
authors.affiliation: Centre for Post Graduate studies and Research, New Drug Delivery Systems Laboratory, Pharmacy Department, The M. S. University of Baroda, Vadodara, India.
authors.forename: Kiran
authors.initials: K
authors.lastname: Chaudhari
authors.affiliation: Centre for Post Graduate studies and Research, New Drug Delivery Systems Laboratory, Pharmacy Department, The M. S. University of Baroda, Vadodara, India.
authors.forename: A S
authors.initials: AS
authors.lastname: Manjappa
authors.affiliation: Centre for Post Graduate studies and Research, New Drug Delivery Systems Laboratory, Pharmacy Department, The M. S. University of Baroda, Vadodara, India ; Center for Nanomedicine, ISF College of Pharmacy, Moga, Punjab India.
authors.forename: R S R
authors.initials: RS
authors.lastname: Murthy
authors.affiliation: Gude Lab, Tata Memorial Center, Advanced Center for Treatment Research and Education in Cancer (ACTREC), Cancer Research Institute, Navi Mumbai, India.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Gude
keywords: B16F10 cells; Cell adhesion; EILDV; Etoposide; Integrin; Metastasis