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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

Cell apoptosis and cell cycle analysis in KBv cells of different formulations.Notes: (A) Induction of apoptosis images in KBv cells by mixture of free DOX and PTX (DOX+PTX, DOX:PTX =2:3, w/w), PF-DP, c(RGDyK)-FP-DP, and control using microscopy technique. Bright field and fluorescence micrographs of KBv cell nuclei were recorded following 24-hour incubation with PF-DP and c(RGDyK)-FP-DP at the equivalent total drug concentration (1 μg/mL). (B) Flow cytometric analysis of cell cycle distribution of KBv cells after the treatment with control, DOX+PTX, PF-DP, and c(RGDyK)-FP-DP for 24 hours at the equivalent total drug concentration (1 μg/mL). Magnification is 20×; the bar is 50 μm.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; c(RGDyK), cyclic RGD peptide; RGD, arginine-glycine-aspartic acid.
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f7-ijn-10-4863: Cell apoptosis and cell cycle analysis in KBv cells of different formulations.Notes: (A) Induction of apoptosis images in KBv cells by mixture of free DOX and PTX (DOX+PTX, DOX:PTX =2:3, w/w), PF-DP, c(RGDyK)-FP-DP, and control using microscopy technique. Bright field and fluorescence micrographs of KBv cell nuclei were recorded following 24-hour incubation with PF-DP and c(RGDyK)-FP-DP at the equivalent total drug concentration (1 μg/mL). (B) Flow cytometric analysis of cell cycle distribution of KBv cells after the treatment with control, DOX+PTX, PF-DP, and c(RGDyK)-FP-DP for 24 hours at the equivalent total drug concentration (1 μg/mL). Magnification is 20×; the bar is 50 μm.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; c(RGDyK), cyclic RGD peptide; RGD, arginine-glycine-aspartic acid.

Mentions: In order to verify the effect of c(RGDyK)-decorated Pluronic polymeric micelles on cell apoptosis, Hoechst 33342 staining method was used to qualitatively track the c(RGDyK)-FP-DP-induced apoptotic cell death. The nuclei of untreated KBv cells showed homogenous fluorescence with no evidence of segmentation and fragmentation after staining (Figure 7A). After treatment with the mixture of free DOX and PTX (DOX+PTX) with total drug concentration of 1 μg/mL, only slight apoptosis took place in KBv cells, which is consistent with the studies reporting that DOX and PTX are the substrates of P-gp, multidrug resistance-associated protein, and breast cancer-resistant protein.41,43–45 In contrast, after 24-hour treatment, the cell nuclei became severely fragmented and segmented into dense nuclear parts in the drug-loaded Pluronic polymeric micelles group. Compared with PF-DP, c(RGDyK)-FP-DP was found to induce more severe fragmentation of the cell nuclei as shown in Figure 7A. These results indicated that c(RGDyK)-FP-DP displayed higher apoptosis induction activity in KBv cells, probably due to the increased cellular uptake of DOX and PTX imparted by the active targeting and MDR modulation.


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)

Cell apoptosis and cell cycle analysis in KBv cells of different formulations.Notes: (A) Induction of apoptosis images in KBv cells by mixture of free DOX and PTX (DOX+PTX, DOX:PTX =2:3, w/w), PF-DP, c(RGDyK)-FP-DP, and control using microscopy technique. Bright field and fluorescence micrographs of KBv cell nuclei were recorded following 24-hour incubation with PF-DP and c(RGDyK)-FP-DP at the equivalent total drug concentration (1 μg/mL). (B) Flow cytometric analysis of cell cycle distribution of KBv cells after the treatment with control, DOX+PTX, PF-DP, and c(RGDyK)-FP-DP for 24 hours at the equivalent total drug concentration (1 μg/mL). Magnification is 20×; the bar is 50 μm.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; c(RGDyK), cyclic RGD peptide; RGD, arginine-glycine-aspartic acid.
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Related In: Results  -  Collection

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f7-ijn-10-4863: Cell apoptosis and cell cycle analysis in KBv cells of different formulations.Notes: (A) Induction of apoptosis images in KBv cells by mixture of free DOX and PTX (DOX+PTX, DOX:PTX =2:3, w/w), PF-DP, c(RGDyK)-FP-DP, and control using microscopy technique. Bright field and fluorescence micrographs of KBv cell nuclei were recorded following 24-hour incubation with PF-DP and c(RGDyK)-FP-DP at the equivalent total drug concentration (1 μg/mL). (B) Flow cytometric analysis of cell cycle distribution of KBv cells after the treatment with control, DOX+PTX, PF-DP, and c(RGDyK)-FP-DP for 24 hours at the equivalent total drug concentration (1 μg/mL). Magnification is 20×; the bar is 50 μm.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; c(RGDyK), cyclic RGD peptide; RGD, arginine-glycine-aspartic acid.
Mentions: In order to verify the effect of c(RGDyK)-decorated Pluronic polymeric micelles on cell apoptosis, Hoechst 33342 staining method was used to qualitatively track the c(RGDyK)-FP-DP-induced apoptotic cell death. The nuclei of untreated KBv cells showed homogenous fluorescence with no evidence of segmentation and fragmentation after staining (Figure 7A). After treatment with the mixture of free DOX and PTX (DOX+PTX) with total drug concentration of 1 μg/mL, only slight apoptosis took place in KBv cells, which is consistent with the studies reporting that DOX and PTX are the substrates of P-gp, multidrug resistance-associated protein, and breast cancer-resistant protein.41,43–45 In contrast, after 24-hour treatment, the cell nuclei became severely fragmented and segmented into dense nuclear parts in the drug-loaded Pluronic polymeric micelles group. Compared with PF-DP, c(RGDyK)-FP-DP was found to induce more severe fragmentation of the cell nuclei as shown in Figure 7A. These results indicated that c(RGDyK)-FP-DP displayed higher apoptosis induction activity in KBv cells, probably due to the increased cellular uptake of DOX and PTX imparted by the active targeting and MDR modulation.

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