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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.

No MeSH data available.


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Cellular uptake of mixture of free DOX and PTX (DOX+PTX, DOX:PTX =2:3, w/w), PF-DP, and c(RGDyK)-FP-DP at equivalent total drug concentration (5 μg/mL) after incubation for 2 hours at 37°C in KBv cells with 5 μM CsA.Notes: Mean ± SD (n=3). **P<0.01 is compared with DOX+PTX treatment; #P<0.05 and ##P<0.01 are compared with PF-DP treatment.Abbreviations: DOX, doxorubicin; PTX, paclitaxel; PF-DP, Pluronic micelles loaded with DOX and PTX; c(RGDyK)-FP-DP, c(RGDyK)-decorated Pluronic micelles loaded with DOX and PTX; CsA, cyclosporin A; c(RGDyK), cyclic RGD peptide; RGD, arginine-glycine-aspartic acid; SD, standard deviation.
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f6-ijn-10-4863: Cellular uptake of mixture of free DOX and PTX (DOX+PTX, DOX:PTX =2:3, w/w), PF-DP, and c(RGDyK)-FP-DP at equivalent total drug concentration (5 μg/mL) after incubation for 2 hours at 37°C in KBv cells with 5 μM CsA.Notes: Mean ± SD (n=3). **P<0.01 is compared with DOX+PTX treatment; #P<0.05 and ##P<0.01 are compared with PF-DP treatment.Abbreviations: DOX, doxorubicin; PTX, paclitaxel; PF-DP, Pluronic micelles loaded with DOX and PTX; c(RGDyK)-FP-DP, c(RGDyK)-decorated Pluronic micelles loaded with DOX and PTX; CsA, cyclosporin A; c(RGDyK), cyclic RGD peptide; RGD, arginine-glycine-aspartic acid; SD, standard deviation.

Mentions: The intracellular accumulation of DOX and PTX was determined in KBv MDR tumor cells. As shown in Figure 6, the uptake amount of DOX and PTX of c(RGDyK)-FP-DP were found to be much higher than those of PF-DP in KBv cells (P<0.01). In addition, the drug cellular accumulation of Pluronic polymeric micelles was comparable to that of the P-gp inhibitor (cyclosporin A [CsA]) group (P<0.05), suggesting that Pluronic P105/F127 mixed micelles have the ability to enhance drug accumulation in MDR tumor cells possibly due to the presence of Pluronic unimers.41 Moreover, the results demonstrated that the enhanced cellular uptake of c(RGDyK)-FP-DP may be in part attributed to the c(RGDyK) active targeting since integrin receptor is overexpressed in solid tumor cells.42 However, further experiments need to be conducted to test the integrin receptor expression in KBv cells. The same trend was also found in HUVEC-based studies, as integrin is overexpressed on the surface of HUVEC cells.43


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)

Cellular uptake of mixture of free DOX and PTX (DOX+PTX, DOX:PTX =2:3, w/w), PF-DP, and c(RGDyK)-FP-DP at equivalent total drug concentration (5 μg/mL) after incubation for 2 hours at 37°C in KBv cells with 5 μM CsA.Notes: Mean ± SD (n=3). **P<0.01 is compared with DOX+PTX treatment; #P<0.05 and ##P<0.01 are compared with PF-DP treatment.Abbreviations: DOX, doxorubicin; PTX, paclitaxel; PF-DP, Pluronic micelles loaded with DOX and PTX; c(RGDyK)-FP-DP, c(RGDyK)-decorated Pluronic micelles loaded with DOX and PTX; CsA, cyclosporin A; c(RGDyK), cyclic RGD peptide; RGD, arginine-glycine-aspartic acid; SD, standard deviation.
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Related In: Results  -  Collection

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Show All Figures
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f6-ijn-10-4863: Cellular uptake of mixture of free DOX and PTX (DOX+PTX, DOX:PTX =2:3, w/w), PF-DP, and c(RGDyK)-FP-DP at equivalent total drug concentration (5 μg/mL) after incubation for 2 hours at 37°C in KBv cells with 5 μM CsA.Notes: Mean ± SD (n=3). **P<0.01 is compared with DOX+PTX treatment; #P<0.05 and ##P<0.01 are compared with PF-DP treatment.Abbreviations: DOX, doxorubicin; PTX, paclitaxel; PF-DP, Pluronic micelles loaded with DOX and PTX; c(RGDyK)-FP-DP, c(RGDyK)-decorated Pluronic micelles loaded with DOX and PTX; CsA, cyclosporin A; c(RGDyK), cyclic RGD peptide; RGD, arginine-glycine-aspartic acid; SD, standard deviation.
Mentions: The intracellular accumulation of DOX and PTX was determined in KBv MDR tumor cells. As shown in Figure 6, the uptake amount of DOX and PTX of c(RGDyK)-FP-DP were found to be much higher than those of PF-DP in KBv cells (P<0.01). In addition, the drug cellular accumulation of Pluronic polymeric micelles was comparable to that of the P-gp inhibitor (cyclosporin A [CsA]) group (P<0.05), suggesting that Pluronic P105/F127 mixed micelles have the ability to enhance drug accumulation in MDR tumor cells possibly due to the presence of Pluronic unimers.41 Moreover, the results demonstrated that the enhanced cellular uptake of c(RGDyK)-FP-DP may be in part attributed to the c(RGDyK) active targeting since integrin receptor is overexpressed in solid tumor cells.42 However, further experiments need to be conducted to test the integrin receptor expression in KBv cells. The same trend was also found in HUVEC-based studies, as integrin is overexpressed on the surface of HUVEC cells.43

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