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

Chen Y, Zhang W, Huang Y, Gao F, Fang X - Int J Nanomedicine (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutics, School of Pharmacy, East China University of Science and Technology, Fudan University, Shanghai, People's Republic of China ; Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, School of Pharmacy, Fudan University, Shanghai, People's Republic of China.

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.

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Related in: MedlinePlus

Penetration of PF-DOX and c(RGDyK)-FP-DOX throughout the KBv tumor spheroids.Notes: The distribution of DOX was analyzed by confocal microscopy using Z-stack imaging with 30 μm intervals, merges of fluorescence, and DIC are shown. Scale bar represents 100 μm.Abbreviations: PF-DOX, Pluronic micelles loaded with DOX; c(RGDyK)-FP-DOX, c(RGDyK)-decorated Pluronic micelles loaded with DOX; DIC, differential interference contrast microscopy; c(RGDyK), cyclic RGD peptide; RGD, arginine-glycine-aspartic acid.
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f8-ijn-10-4863: Penetration of PF-DOX and c(RGDyK)-FP-DOX throughout the KBv tumor spheroids.Notes: The distribution of DOX was analyzed by confocal microscopy using Z-stack imaging with 30 μm intervals, merges of fluorescence, and DIC are shown. Scale bar represents 100 μm.Abbreviations: PF-DOX, Pluronic micelles loaded with DOX; c(RGDyK)-FP-DOX, c(RGDyK)-decorated Pluronic micelles loaded with DOX; DIC, differential interference contrast microscopy; c(RGDyK), cyclic RGD peptide; RGD, arginine-glycine-aspartic acid.

Mentions: There are hypoxic and avascular tumor regions in most of the solid tumors. For a cancer treatment to be curative, the drug delivery system must efficiently penetrate the tumor tissue to reach all of the viable cells. The ex vivo 3D tumor spheroids generated by liquid overlay technique are not only aggregates of cells in close contact but also contain an organized extracellular matrix consisting of fibronectin, laminin, collagen, and glycosaminoglycan, suggestive of the extracellular matrix of tumors in vivo.46–48 Thereby, 3D multicellular model represents the avascular regions similar to those found in many solid tumor tissues, and can serve as an invaluable tool to evaluate the effect of drug delivery system on solid tumor therapy.49 In this study, interstitial penetration and diffusion behavior of drug-loaded micelles was tested, and the growth inhibition effect of c(RGDyK)-decorated Pluronic micelles on avascular regions of the drug-resistant solid tumors was evaluated using the ex vivo KBv tumor spheroid model. Figure 8 shows confocal laser scanning microscopic images of KBv tumor spheroids after the treatment with DOX-labeled micelles. For the non-decorated micelles, red fluorescence of DOX was observed primarily on the periphery of tumor spheroids. However, after the application of micelles decorated with c(RGDyK) peptide, the red fluorescence was able to be observed throughout the whole tumor spheroid and the depth of fluorescence that could be observed in the spheroid can reach upto 90 μm, suggesting that micelles modified with c(RGDyK) exhibited a better capability of enhancing the spheroid penetration.


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

Chen Y, Zhang W, Huang Y, Gao F, Fang X - Int J Nanomedicine (2015)

Penetration of PF-DOX and c(RGDyK)-FP-DOX throughout the KBv tumor spheroids.Notes: The distribution of DOX was analyzed by confocal microscopy using Z-stack imaging with 30 μm intervals, merges of fluorescence, and DIC are shown. Scale bar represents 100 μm.Abbreviations: PF-DOX, Pluronic micelles loaded with DOX; c(RGDyK)-FP-DOX, c(RGDyK)-decorated Pluronic micelles loaded with DOX; DIC, differential interference contrast microscopy; c(RGDyK), cyclic RGD peptide; RGD, arginine-glycine-aspartic acid.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4525800&req=5

f8-ijn-10-4863: Penetration of PF-DOX and c(RGDyK)-FP-DOX throughout the KBv tumor spheroids.Notes: The distribution of DOX was analyzed by confocal microscopy using Z-stack imaging with 30 μm intervals, merges of fluorescence, and DIC are shown. Scale bar represents 100 μm.Abbreviations: PF-DOX, Pluronic micelles loaded with DOX; c(RGDyK)-FP-DOX, c(RGDyK)-decorated Pluronic micelles loaded with DOX; DIC, differential interference contrast microscopy; c(RGDyK), cyclic RGD peptide; RGD, arginine-glycine-aspartic acid.
Mentions: There are hypoxic and avascular tumor regions in most of the solid tumors. For a cancer treatment to be curative, the drug delivery system must efficiently penetrate the tumor tissue to reach all of the viable cells. The ex vivo 3D tumor spheroids generated by liquid overlay technique are not only aggregates of cells in close contact but also contain an organized extracellular matrix consisting of fibronectin, laminin, collagen, and glycosaminoglycan, suggestive of the extracellular matrix of tumors in vivo.46–48 Thereby, 3D multicellular model represents the avascular regions similar to those found in many solid tumor tissues, and can serve as an invaluable tool to evaluate the effect of drug delivery system on solid tumor therapy.49 In this study, interstitial penetration and diffusion behavior of drug-loaded micelles was tested, and the growth inhibition effect of c(RGDyK)-decorated Pluronic micelles on avascular regions of the drug-resistant solid tumors was evaluated using the ex vivo KBv tumor spheroid model. Figure 8 shows confocal laser scanning microscopic images of KBv tumor spheroids after the treatment with DOX-labeled micelles. For the non-decorated micelles, red fluorescence of DOX was observed primarily on the periphery of tumor spheroids. However, after the application of micelles decorated with c(RGDyK) peptide, the red fluorescence was able to be observed throughout the whole tumor spheroid and the depth of fluorescence that could be observed in the spheroid can reach upto 90 μm, suggesting that micelles modified with c(RGDyK) exhibited a better capability of enhancing the spheroid penetration.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutics, School of Pharmacy, East China University of Science and Technology, Fudan University, Shanghai, People's Republic of China ; Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, School of Pharmacy, Fudan University, Shanghai, People's Republic of China.

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.

No MeSH data available.


Related in: MedlinePlus