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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

The biocompatibility of blank PF and c(RGDyK)-FP to HUVEC cells and the in vitro antiangiogenesis of efficacy drug loaded micelles.Notes: (A) Cell viability of HUVEC as a function of varying concentrations of micelles at 72 hours. (B) The number of branches in the presence of varied carrier concentrations of PF-DP and c(RGDyK)-FP-DP (1 μg/mL, 10 μg/mL, 50 μg/mL, 100 μg/mL, 500 μg/mL and 1,000 μg/mL, w/v). Mean ± SD (n=3). *P<0.05, **P<0.01, and ***P<0.001 are compared with positive control group; #P<0.01 compared with PF-DP. Magnification is 40×.Abbreviations: HUVEC, human umbilical vein endothelial cells; PF-DP, Pluronic micelles loaded with DOX and PTX; c(RGDyK)-FP-DP, c(RGDyK)-decorated Pluronic micelles loaded with DOX and PTX; c(RGDyK), cyclic RGD peptide; RGD, arginine-glycine-aspartic acid; DOX, doxorubicin; PTX, paclitaxel; SD, standard deviation.
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f5-ijn-10-4863: The biocompatibility of blank PF and c(RGDyK)-FP to HUVEC cells and the in vitro antiangiogenesis of efficacy drug loaded micelles.Notes: (A) Cell viability of HUVEC as a function of varying concentrations of micelles at 72 hours. (B) The number of branches in the presence of varied carrier concentrations of PF-DP and c(RGDyK)-FP-DP (1 μg/mL, 10 μg/mL, 50 μg/mL, 100 μg/mL, 500 μg/mL and 1,000 μg/mL, w/v). Mean ± SD (n=3). *P<0.05, **P<0.01, and ***P<0.001 are compared with positive control group; #P<0.01 compared with PF-DP. Magnification is 40×.Abbreviations: HUVEC, human umbilical vein endothelial cells; PF-DP, Pluronic micelles loaded with DOX and PTX; c(RGDyK)-FP-DP, c(RGDyK)-decorated Pluronic micelles loaded with DOX and PTX; c(RGDyK), cyclic RGD peptide; RGD, arginine-glycine-aspartic acid; DOX, doxorubicin; PTX, paclitaxel; SD, standard deviation.

Mentions: The biocompatibility of blank PF and c(RGDyK)-FP to HUVEC cells was evaluated using MTT assay (Figure 5A). The results showed that when the concentration ranged from 10 μg/mL to 1000 μg/mL, the cytotoxicity of the two micelles was negligible in HUVEC cells. Micelles displayed increasing cellular growth inhibitory effects as the concentration increased from 1,000 μg/mL to 5,000 μg/mL, probably due to the cytostatic action of Pluronic micelles.38 This phenomenon can be partially attributed to the increasing amounts of Pluronic P105, since previous reports indicated that the increasing concentrations of Pluronic P105 increased cytotoxicity in KB, KBv, and HEK-293 cells.32,38 In addition, c(RGDyK)-FP was found to display higher cytotoxic effect than that of PF micelles when the concentration ranged from 10 μg/mL to to 1000 μg/mL, since c(RGDyK) peptide could facilitate c(RGDyK)-FP accumulation into the integrin protein-rich HUVEC cells and thus facilitate the intracellular uptake.


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)

The biocompatibility of blank PF and c(RGDyK)-FP to HUVEC cells and the in vitro antiangiogenesis of efficacy drug loaded micelles.Notes: (A) Cell viability of HUVEC as a function of varying concentrations of micelles at 72 hours. (B) The number of branches in the presence of varied carrier concentrations of PF-DP and c(RGDyK)-FP-DP (1 μg/mL, 10 μg/mL, 50 μg/mL, 100 μg/mL, 500 μg/mL and 1,000 μg/mL, w/v). Mean ± SD (n=3). *P<0.05, **P<0.01, and ***P<0.001 are compared with positive control group; #P<0.01 compared with PF-DP. Magnification is 40×.Abbreviations: HUVEC, human umbilical vein endothelial cells; PF-DP, Pluronic micelles loaded with DOX and PTX; c(RGDyK)-FP-DP, c(RGDyK)-decorated Pluronic micelles loaded with DOX and PTX; c(RGDyK), cyclic RGD peptide; RGD, arginine-glycine-aspartic acid; DOX, doxorubicin; PTX, paclitaxel; SD, standard deviation.
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Related In: Results  -  Collection

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f5-ijn-10-4863: The biocompatibility of blank PF and c(RGDyK)-FP to HUVEC cells and the in vitro antiangiogenesis of efficacy drug loaded micelles.Notes: (A) Cell viability of HUVEC as a function of varying concentrations of micelles at 72 hours. (B) The number of branches in the presence of varied carrier concentrations of PF-DP and c(RGDyK)-FP-DP (1 μg/mL, 10 μg/mL, 50 μg/mL, 100 μg/mL, 500 μg/mL and 1,000 μg/mL, w/v). Mean ± SD (n=3). *P<0.05, **P<0.01, and ***P<0.001 are compared with positive control group; #P<0.01 compared with PF-DP. Magnification is 40×.Abbreviations: HUVEC, human umbilical vein endothelial cells; PF-DP, Pluronic micelles loaded with DOX and PTX; c(RGDyK)-FP-DP, c(RGDyK)-decorated Pluronic micelles loaded with DOX and PTX; c(RGDyK), cyclic RGD peptide; RGD, arginine-glycine-aspartic acid; DOX, doxorubicin; PTX, paclitaxel; SD, standard deviation.
Mentions: The biocompatibility of blank PF and c(RGDyK)-FP to HUVEC cells was evaluated using MTT assay (Figure 5A). The results showed that when the concentration ranged from 10 μg/mL to 1000 μg/mL, the cytotoxicity of the two micelles was negligible in HUVEC cells. Micelles displayed increasing cellular growth inhibitory effects as the concentration increased from 1,000 μg/mL to 5,000 μg/mL, probably due to the cytostatic action of Pluronic micelles.38 This phenomenon can be partially attributed to the increasing amounts of Pluronic P105, since previous reports indicated that the increasing concentrations of Pluronic P105 increased cytotoxicity in KB, KBv, and HEK-293 cells.32,38 In addition, c(RGDyK)-FP was found to display higher cytotoxic effect than that of PF micelles when the concentration ranged from 10 μg/mL to to 1000 μg/mL, since c(RGDyK) peptide could facilitate c(RGDyK)-FP accumulation into the integrin protein-rich HUVEC cells and thus facilitate the intracellular uptake.

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