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A Light-Driven Therapy of Pancreatic Adenocarcinoma Using Gold Nanorods-Based Nanocarriers for Co-Delivery of Doxorubicin and siRNA.

Yin F, Yang C, Wang Q, Zeng S, Hu R, Lin G, Tian J, Hu S, Lan RF, Yoon HS, Lu F, Wang K, Yong KT - Theranostics (2015)

Bottom Line: The antitumor effect is contributed from the inactivation of K-Ras gene and thereby causing a profound synthesis (S) phase arrest in treated Panc-1 cells.Our study shows that the percentage of Panc-1 cells treated by nanoplex formulation with S phase is determined to be 35% and it is 17% much higher than that of Panc-1 cells without any treatments.The developed nanotherapy formulation here, that combines chemotherapy, RNA silencing and NIR window light-mediated therapy, will be seen to be the next natural step to be taken in the clinical research for improving the therapeutic outcomes of the pancreatic adenocarcinoma treatment.

View Article: PubMed Central - PubMed

Affiliation: 1. School of Electrical and Electronic Engineering, Nanyang Technological University, Singapore 639798, Singapore.

ABSTRACT
In this work, we report the engineering of polyelectrolyte polymers coated Gold nanorods (AuNRs)-based nanocarriers that are capable of co-delivering small interfering RNA (siRNA) and an anticancer drug doxorubicin (DOX) to Panc-1 cancer cells for combination of both chemo- and siRNA-mediated mutant K-Ras gene silencing therapy. Superior anticancer efficacy was observed through synergistic combination of promoted siRNA and DOX release upon irradiating the nanoplex formulation with 665 nm light. Our antitumor study shows that the synergistic effect of AuNRs nanoplex formulation with 665 nm light treatment is able to inhibit the in vivo tumor volume growth rate by 90%. The antitumor effect is contributed from the inactivation of K-Ras gene and thereby causing a profound synthesis (S) phase arrest in treated Panc-1 cells. Our study shows that the percentage of Panc-1 cells treated by nanoplex formulation with S phase is determined to be 35% and it is 17% much higher than that of Panc-1 cells without any treatments. The developed nanotherapy formulation here, that combines chemotherapy, RNA silencing and NIR window light-mediated therapy, will be seen to be the next natural step to be taken in the clinical research for improving the therapeutic outcomes of the pancreatic adenocarcinoma treatment.

No MeSH data available.


Related in: MedlinePlus

Cell cycle analysis of Panc-1 cells treated with different nanoparticle formulations of blank, AuNRs, DOX, siRNA, Lipo2000, AuNRs/scramble siRNA, Lipo-scramble siRNA, AuNRs/DOX/siRNA, AuNRs/DOX, AuNRs/siRNA and Lipo-siRNA. (A) Representative images of flow cytometry analysis carried out 48 hours after treatment. (B) The statistic results of flow cytometry. Cell cycles of Panc-1 cells were significantly arrested in the S phase in the groups treated with AuNRs/DOX/siRNA, AuNRs/DOX, AuNRs/siRNA, Lipo-siRNA and DOX compared with the others.
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Figure 6: Cell cycle analysis of Panc-1 cells treated with different nanoparticle formulations of blank, AuNRs, DOX, siRNA, Lipo2000, AuNRs/scramble siRNA, Lipo-scramble siRNA, AuNRs/DOX/siRNA, AuNRs/DOX, AuNRs/siRNA and Lipo-siRNA. (A) Representative images of flow cytometry analysis carried out 48 hours after treatment. (B) The statistic results of flow cytometry. Cell cycles of Panc-1 cells were significantly arrested in the S phase in the groups treated with AuNRs/DOX/siRNA, AuNRs/DOX, AuNRs/siRNA, Lipo-siRNA and DOX compared with the others.

Mentions: Among all the malignant carcinomas, pancreatic adenocarcinoma has the highest mutation rate of K-Ras gene and the rate is estimated to be over 70%. The mutant K-Ras gene plays a significant role in promoting cell proliferation, transformation and anti-apoptotic through multiple cell signaling pathways and eventually causes cell malignant transformation. According to the gene knockdown results, both DOX and AuNRs/DOX/K-Ras siRNA nanoplex formulations can down-regulate the expression of K-Ras in both the protein and mRNA levels. Such discovery has led us to examine the cell cycle of Panc-1 cells after K-Ras inactivation and the study is carried out using fluorescence activated cell sorting (FACS) analysis. We have found that the inactivation of K-Ras causes a profound S phase arrest in Panc-1 cells (Fig. 6 and Supplementary Fig. S2). The percentage of Panc-1 cells treated by DOX or AuNRs/K-Ras siRNA nanoplex with S phase is determined to be 30.86% and 28.47%, respectively, which is 12% and 10% higher than that of Panc-1 cells without receiving any treatments. On the other hand, the percentage of Panc-1 cells treated by AuNRs/DOX/K-Ras siRNA nanoplex with S phase is calculated to be 35.46% and it is 17% much higher than the untreated ones. Moreover, the comparison between co-delivery and single delivery has significant differences (Supplementary Fig. S2B). This shows that the co-delivery of DOX and K-Ras siRNA by the AuNRs nanocarriers have a more pronounce efficiency in inactivating the K-Ras gene and in blocking the proliferation of Panc-1 cells by S cell cycle arrest.


A Light-Driven Therapy of Pancreatic Adenocarcinoma Using Gold Nanorods-Based Nanocarriers for Co-Delivery of Doxorubicin and siRNA.

Yin F, Yang C, Wang Q, Zeng S, Hu R, Lin G, Tian J, Hu S, Lan RF, Yoon HS, Lu F, Wang K, Yong KT - Theranostics (2015)

Cell cycle analysis of Panc-1 cells treated with different nanoparticle formulations of blank, AuNRs, DOX, siRNA, Lipo2000, AuNRs/scramble siRNA, Lipo-scramble siRNA, AuNRs/DOX/siRNA, AuNRs/DOX, AuNRs/siRNA and Lipo-siRNA. (A) Representative images of flow cytometry analysis carried out 48 hours after treatment. (B) The statistic results of flow cytometry. Cell cycles of Panc-1 cells were significantly arrested in the S phase in the groups treated with AuNRs/DOX/siRNA, AuNRs/DOX, AuNRs/siRNA, Lipo-siRNA and DOX compared with the others.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4440440&req=5

Figure 6: Cell cycle analysis of Panc-1 cells treated with different nanoparticle formulations of blank, AuNRs, DOX, siRNA, Lipo2000, AuNRs/scramble siRNA, Lipo-scramble siRNA, AuNRs/DOX/siRNA, AuNRs/DOX, AuNRs/siRNA and Lipo-siRNA. (A) Representative images of flow cytometry analysis carried out 48 hours after treatment. (B) The statistic results of flow cytometry. Cell cycles of Panc-1 cells were significantly arrested in the S phase in the groups treated with AuNRs/DOX/siRNA, AuNRs/DOX, AuNRs/siRNA, Lipo-siRNA and DOX compared with the others.
Mentions: Among all the malignant carcinomas, pancreatic adenocarcinoma has the highest mutation rate of K-Ras gene and the rate is estimated to be over 70%. The mutant K-Ras gene plays a significant role in promoting cell proliferation, transformation and anti-apoptotic through multiple cell signaling pathways and eventually causes cell malignant transformation. According to the gene knockdown results, both DOX and AuNRs/DOX/K-Ras siRNA nanoplex formulations can down-regulate the expression of K-Ras in both the protein and mRNA levels. Such discovery has led us to examine the cell cycle of Panc-1 cells after K-Ras inactivation and the study is carried out using fluorescence activated cell sorting (FACS) analysis. We have found that the inactivation of K-Ras causes a profound S phase arrest in Panc-1 cells (Fig. 6 and Supplementary Fig. S2). The percentage of Panc-1 cells treated by DOX or AuNRs/K-Ras siRNA nanoplex with S phase is determined to be 30.86% and 28.47%, respectively, which is 12% and 10% higher than that of Panc-1 cells without receiving any treatments. On the other hand, the percentage of Panc-1 cells treated by AuNRs/DOX/K-Ras siRNA nanoplex with S phase is calculated to be 35.46% and it is 17% much higher than the untreated ones. Moreover, the comparison between co-delivery and single delivery has significant differences (Supplementary Fig. S2B). This shows that the co-delivery of DOX and K-Ras siRNA by the AuNRs nanocarriers have a more pronounce efficiency in inactivating the K-Ras gene and in blocking the proliferation of Panc-1 cells by S cell cycle arrest.

Bottom Line: The antitumor effect is contributed from the inactivation of K-Ras gene and thereby causing a profound synthesis (S) phase arrest in treated Panc-1 cells.Our study shows that the percentage of Panc-1 cells treated by nanoplex formulation with S phase is determined to be 35% and it is 17% much higher than that of Panc-1 cells without any treatments.The developed nanotherapy formulation here, that combines chemotherapy, RNA silencing and NIR window light-mediated therapy, will be seen to be the next natural step to be taken in the clinical research for improving the therapeutic outcomes of the pancreatic adenocarcinoma treatment.

View Article: PubMed Central - PubMed

Affiliation: 1. School of Electrical and Electronic Engineering, Nanyang Technological University, Singapore 639798, Singapore.

ABSTRACT
In this work, we report the engineering of polyelectrolyte polymers coated Gold nanorods (AuNRs)-based nanocarriers that are capable of co-delivering small interfering RNA (siRNA) and an anticancer drug doxorubicin (DOX) to Panc-1 cancer cells for combination of both chemo- and siRNA-mediated mutant K-Ras gene silencing therapy. Superior anticancer efficacy was observed through synergistic combination of promoted siRNA and DOX release upon irradiating the nanoplex formulation with 665 nm light. Our antitumor study shows that the synergistic effect of AuNRs nanoplex formulation with 665 nm light treatment is able to inhibit the in vivo tumor volume growth rate by 90%. The antitumor effect is contributed from the inactivation of K-Ras gene and thereby causing a profound synthesis (S) phase arrest in treated Panc-1 cells. Our study shows that the percentage of Panc-1 cells treated by nanoplex formulation with S phase is determined to be 35% and it is 17% much higher than that of Panc-1 cells without any treatments. The developed nanotherapy formulation here, that combines chemotherapy, RNA silencing and NIR window light-mediated therapy, will be seen to be the next natural step to be taken in the clinical research for improving the therapeutic outcomes of the pancreatic adenocarcinoma treatment.

No MeSH data available.


Related in: MedlinePlus