Dual-functional c(RGDyK)-decorated Pluronic micelles designed for antiangiogenesis and the treatment of drug-resistant tumor

Abstract

Dual-functional drug delivery system was developed by decorating c(RGDyK) (cyclic RGD [arginine-glycine-aspartic acid] peptide) with Pluronic polymeric micelles (c[RGDyK]-FP-DP) to overcome the drawbacks of low transport of chemotherapeutics across the blood–tumor barrier and poor multidrug-resistant (MDR) tumor therapy. c(RGDyK) that can bind to the integrin protein richly expressed at the site of tumor vascular endothelial cells and tumor cells with high affinity and specificity was conjugated to the N-hydroxysuccinimide-activated PEO terminus of the Pluronic F127 block copolymer. In this study, decreased tumor angiogenic and increased apoptotic activity in MDR cancer cells were observed after the treatment with c(RGDyK)-FP-DP. c(RGDyK)-FP-DP was fully characterized in terms of morphology, particle size, zeta potential, and drug release. Importantly, in vitro antiangiogenesis results demonstrated that c(RGDyK)-FP-DP had a significant inhibition effect on the tubular formation of human umbilical vein endothelial cells and promoted cellular apoptotic activity in MDR KBv cells. In addition, the growth inhibition efficacy of KBv tumor spheroids after crossing the blood–tumor barrier was obviously increased by c(RGDyK)-FP-DP compared to other control groups. Results suggested that c(RGDyK)-decorated Pluronic polymeric micelles can take pharmacological action on both human umbilical vein endothelial cells and KBv MDR cancer cells, resulting in a dual-functional anticancer effect similar to that observed in our in vitro cellular studies.

Keywords:

• dual-functional
• micelles
• c(RGDyK)
• antiangiogenesis
• multidrug resistance

Supplementary materials

Figure S1 The synthetic route and characterization of P105-DOX.

Notes: Synthetic route of P105-DOX conjugate (a=36, b=56) (A); FT-IR spectra of Pluronic P105 and P105-COOH (B); ¹H-NMR spectra of P105 and P105-DOX in DMSO-d₆ (C).

Abbreviations: DOX, doxorubicin; FT-IR, Fourier transform infrared spectroscopy; DMSO, dimethyl sulfoxide; ¹H-NMR, ¹H-nuclear magnetic resonance spectroscopy; RT, room temperature; EDC, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide; NHS, N-hydroxysuccinimide.

Acknowledgments

This work was sponsored by National Natural Science Foundation of China (30901862), Postdoctoral Science Foundation of China (2014M550222), Shanghai Postdoctoral Sustentation Fund (14R21410500), National Basic Research Program of China (2013CB932500), and the Fundamental Research Funds for the Central Universities (22A201514055 ECUST). The authors also acknowledge the support from School of Pharmacy, Fudan University and the Open Project Program of Key Lab of Smart Drug Delivery (Fudan University), Ministry of Education (SDD2014-2), and State Key Laboratory of Molecular Engineering of Polymers (Fudan University) (K2015-15).

Disclosure

The authors report no conflicts of interest in this work. The abstract of this paper (ID: 86827 for IJN) was presented at the Conference on Nanomedicine and NanoBiotechnology in the People’s Republic of China from April 6 to 9, 2015 with the title “Dual-functional c(RGDyK)-decorated Pluronic micelles for antiangiogenesis and drug resistant tumor treatment in vitro” as a poster presentation with interim findings. The poster’s abstract was published in “Poster Abstracts” in the journal of Nanomedicine: Nanotechnology, Biology and Medicine with the title “Dual-functional c(RGDyK)-decorated Pluronic micelles for antiangiogenesis and drug resistant tumor treatment in vitro”. The actual paper, however, has never been published.