Folate-grafted glycyl-glycine-melphalan conjugate self-assembled amphilphilc nanomicelles augmented drug delivery, cytotoxicity and cellular uptake in human ovarian cancer cells

Abstract

Objectives: Folic acid was coupled to melphalan using glycyl-glycine (FA-Gly-Gly-Melphalan) to synthesize self-assembled nanomicelles for targeting ovarian cancer cells, SKOV3.Methods and Results: FA-Gly-Gly-Melphalan self-assembled nanomicelles were prepared with critical micellar concentration (CMC) of 12-μg/ml. The mean particle size of FA-Gly-Gly-Melphalan self-assembled nanomicelles was measured to be 95.9 ± 3.4-nm significantly (P < 0.05) higher than 73.8 ± 6.3-nm of Gly-Gly-Melphalan self-assembled nanomicelles. Subsequently, zeta-potential of FA-Gly-Gly-Melphalan self-assembled nanomicelles was estimated to be -28.0 ± 1.5-mV significantly (P < 0.05) lower than -36.6 ± 2.7-mV of Gly-Gly-Melphalan self-assembled nanomicelles. The IC50 of FA-Gly-Gly-Melphalan self-assembled nanomicelles was estimated to be 4.1-μg/ml significantly (P < 0.001) lower than 14.2-μg/ml of Gly-Gly-Melphalan self-assembled nanomicelles and >18-μg/ml of melphalan. FA-Gly-Gly-Melphalan self-assembled nanomicelles preferentially accumulated in cytoplasm of SKOV3 cells nearby nucleus via receptor mediated endocytosis pathway after 24-h of incubation period, whilst Gly-Gly-Melphalan self-assembled nanomicelles were not incorporated sufficiently.Conclusion: FA-Gly-Gly-Melphalan self-assembled nanomicelles warrant in depth in vivo study for their safety, efficacy, and potency in clinical settings.