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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.


Related in: MedlinePlus

For evaluating the dual-function effect of c(RGDyK)-modified micelles in vitro, the HUVEC cells–KBv tumor spheroids coculture model was established.Notes: (A) The elucidation of the HUVEC cells–KBv tumor spheroids coculture model in this study. (B) Representative confocal images of KBv tumor spheroids by the treatment with DOX+PTX, PF-DP, c(RGDyK)-FP-DP, and the control group on day 0, 1, 3, 5, and 7. (C) The ratio change in KBv spheroid volume (%) after the treatment with DOX+PTX, PF-DP, and c(RGDyK)-FP-DP. Mean ± SD (n=3); *P<0.05 and **P<0.01, compared with DOX+PTX group; #P<0.05, compared with PF-DP.Abbreviations: HUVEC, human umbilical vein endothelial cells; 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; c(RGDyK), cyclic RGD peptide; RGD, arginine-glycine-aspartic acid; SD, standard deviation.
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f9-ijn-10-4863: For evaluating the dual-function effect of c(RGDyK)-modified micelles in vitro, the HUVEC cells–KBv tumor spheroids coculture model was established.Notes: (A) The elucidation of the HUVEC cells–KBv tumor spheroids coculture model in this study. (B) Representative confocal images of KBv tumor spheroids by the treatment with DOX+PTX, PF-DP, c(RGDyK)-FP-DP, and the control group on day 0, 1, 3, 5, and 7. (C) The ratio change in KBv spheroid volume (%) after the treatment with DOX+PTX, PF-DP, and c(RGDyK)-FP-DP. Mean ± SD (n=3); *P<0.05 and **P<0.01, compared with DOX+PTX group; #P<0.05, compared with PF-DP.Abbreviations: HUVEC, human umbilical vein endothelial cells; 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; c(RGDyK), cyclic RGD peptide; RGD, arginine-glycine-aspartic acid; SD, standard deviation.

Mentions: In order to analyze the potential dual-functional effect of c(RGDyK)-FP-DP and to mimic the in vivo blood–tumor barrier, an in vitro HUVEC cells–KBv tumor spheroids coculture model was established and used for evaluation (Figure 9A).34 The growth inhibition of KBv tumor spheroids by drug-loaded micelles was tested in this study. As shown in Figure 9B, KBv tumor spheroids that did not receive treatment with free DOX and PTX mixture grew fast with clearly observable 3D structure. After applying PF-DP and c(RGDyK)-FP-DP, the tumor spheroids became more and more disintegrated and shrunk over time. As observed, the cells started dissociating from the main part of spheroids from day 1 after the micelle treatment, and the 3D structure also started to disappear over the treatment period. Figure 9C shows that the change ratios (of the control, %) of KBv tumor spheroid volumes after the treatment with free DOX, PTX mixture (DOX+PTX), PF-DP, and c(RGDyK)-FP-DP every other day, respectively. It was observed that KBv tumor spheroids continued to grow in volume in the absence of drug (127.4% of the control after 7 days). DOX+PTX treatment for 7 days did not lead to significant change in volume (109.6%). As for PF-DP, significant reduction in the volume of tumor spheroids was observed after treatment for 7 days (79.82%, P<0.05 compared to the control group), demonstrating the MDR modulation capacity of Pluronic-based micelles in tumors. For c(RGDyK)-FP-DP group, the spheroids became disintegrated and almost lost the 3D structure. The inhibition effect on spheroid volume was found to be superior in PF-DP group from 3 days of treatment (P<0.05), and the ultimate change ratio of KBv tumor spheroid volumes in c(RGDyK)-FP-DP group after 7 days of treatment was 54.3%, indicating that c(RGDyK)-FP-DP displayed higher transportation ability across the HUVEC cell monolayer model and stronger inhibitory effects on KBv tumor spheroids when compared with PF-DP, which was well consistent with the results of cellular uptake, tubular formation inhibition in HUVEC cells, and cell apoptosis studies.


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)

For evaluating the dual-function effect of c(RGDyK)-modified micelles in vitro, the HUVEC cells–KBv tumor spheroids coculture model was established.Notes: (A) The elucidation of the HUVEC cells–KBv tumor spheroids coculture model in this study. (B) Representative confocal images of KBv tumor spheroids by the treatment with DOX+PTX, PF-DP, c(RGDyK)-FP-DP, and the control group on day 0, 1, 3, 5, and 7. (C) The ratio change in KBv spheroid volume (%) after the treatment with DOX+PTX, PF-DP, and c(RGDyK)-FP-DP. Mean ± SD (n=3); *P<0.05 and **P<0.01, compared with DOX+PTX group; #P<0.05, compared with PF-DP.Abbreviations: HUVEC, human umbilical vein endothelial cells; 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; c(RGDyK), cyclic RGD peptide; RGD, arginine-glycine-aspartic acid; SD, standard deviation.
© Copyright Policy
Related In: Results  -  Collection

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

f9-ijn-10-4863: For evaluating the dual-function effect of c(RGDyK)-modified micelles in vitro, the HUVEC cells–KBv tumor spheroids coculture model was established.Notes: (A) The elucidation of the HUVEC cells–KBv tumor spheroids coculture model in this study. (B) Representative confocal images of KBv tumor spheroids by the treatment with DOX+PTX, PF-DP, c(RGDyK)-FP-DP, and the control group on day 0, 1, 3, 5, and 7. (C) The ratio change in KBv spheroid volume (%) after the treatment with DOX+PTX, PF-DP, and c(RGDyK)-FP-DP. Mean ± SD (n=3); *P<0.05 and **P<0.01, compared with DOX+PTX group; #P<0.05, compared with PF-DP.Abbreviations: HUVEC, human umbilical vein endothelial cells; 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; c(RGDyK), cyclic RGD peptide; RGD, arginine-glycine-aspartic acid; SD, standard deviation.
Mentions: In order to analyze the potential dual-functional effect of c(RGDyK)-FP-DP and to mimic the in vivo blood–tumor barrier, an in vitro HUVEC cells–KBv tumor spheroids coculture model was established and used for evaluation (Figure 9A).34 The growth inhibition of KBv tumor spheroids by drug-loaded micelles was tested in this study. As shown in Figure 9B, KBv tumor spheroids that did not receive treatment with free DOX and PTX mixture grew fast with clearly observable 3D structure. After applying PF-DP and c(RGDyK)-FP-DP, the tumor spheroids became more and more disintegrated and shrunk over time. As observed, the cells started dissociating from the main part of spheroids from day 1 after the micelle treatment, and the 3D structure also started to disappear over the treatment period. Figure 9C shows that the change ratios (of the control, %) of KBv tumor spheroid volumes after the treatment with free DOX, PTX mixture (DOX+PTX), PF-DP, and c(RGDyK)-FP-DP every other day, respectively. It was observed that KBv tumor spheroids continued to grow in volume in the absence of drug (127.4% of the control after 7 days). DOX+PTX treatment for 7 days did not lead to significant change in volume (109.6%). As for PF-DP, significant reduction in the volume of tumor spheroids was observed after treatment for 7 days (79.82%, P<0.05 compared to the control group), demonstrating the MDR modulation capacity of Pluronic-based micelles in tumors. For c(RGDyK)-FP-DP group, the spheroids became disintegrated and almost lost the 3D structure. The inhibition effect on spheroid volume was found to be superior in PF-DP group from 3 days of treatment (P<0.05), and the ultimate change ratio of KBv tumor spheroid volumes in c(RGDyK)-FP-DP group after 7 days of treatment was 54.3%, indicating that c(RGDyK)-FP-DP displayed higher transportation ability across the HUVEC cell monolayer model and stronger inhibitory effects on KBv tumor spheroids when compared with PF-DP, which was well consistent with the results of cellular uptake, tubular formation inhibition in HUVEC cells, and cell apoptosis studies.

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