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Site-Specific Drug-Releasing Polypeptide Nanocarriers Based on Dual-pH Response for Enhanced Therapeutic Efficacy against Drug-Resistant Tumors.

Dong Y, Yang J, Liu H, Wang T, Tang S, Zhang J, Zhang X - Theranostics (2015)

Bottom Line: To enhance effective drug accumulation in drug-resistant tumors, a site-specific drug-releasing polypeptide system (PEG-Phis/Pasp-DOX/CA4) was exploited in response to tumor extracellular and intracellular pH.This system could firstly release the embedded tumor vascular inhibitor (CA4) to transiently 'normalize' vasculature and facilitate drug internalization to tumors efficiently, and then initiate the secondary pH-response to set the conjugated active anticancer drug (DOX) free in tumor cells.The encapsulated system (PEG-Phis/DOX/CA4), both CA4 and DOX embedding in the nanoparticles, was used as a control.

View Article: PubMed Central - PubMed

Affiliation: 1. National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, China ; 2. College of Chemistry & Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding, 071002, China.

ABSTRACT
To enhance effective drug accumulation in drug-resistant tumors, a site-specific drug-releasing polypeptide system (PEG-Phis/Pasp-DOX/CA4) was exploited in response to tumor extracellular and intracellular pH. This system could firstly release the embedded tumor vascular inhibitor (CA4) to transiently 'normalize' vasculature and facilitate drug internalization to tumors efficiently, and then initiate the secondary pH-response to set the conjugated active anticancer drug (DOX) free in tumor cells. The encapsulated system (PEG-Phis/DOX/CA4), both CA4 and DOX embedding in the nanoparticles, was used as a control. Comparing with PEG-Phis/DOX/CA4, PEG-Phis/Pasp-DOX/CA4 exhibited enhanced cytotoxicity against DOX-sensitive and DOX-resistant cells (MCF-7 and MCF-7/ADR). Moreover, PEG-Phis/Pasp-DOX/CA4 resulted in enhanced therapeutic efficacy in drug-resistant tumors with reduced toxicity. These results suggested that this site-specific drug-releasing system could be exploited as a promising treatment for cancers with repeated administration.

No MeSH data available.


Related in: MedlinePlus

(A) Immunostaining with anti-CD31 tumor tissues was used to detect tumor vasculature (arrows represented) after treatment with different formulations. (B) Quantification of tumor vessel density after treatments. Five randomly selected microscopic fields after treatments were counted. Results are shown as mean±S.D. (n=5). Statistical significance: *P<0.05, **P<0.005 and ***P<0.0005 versus control.
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Figure 10: (A) Immunostaining with anti-CD31 tumor tissues was used to detect tumor vasculature (arrows represented) after treatment with different formulations. (B) Quantification of tumor vessel density after treatments. Five randomly selected microscopic fields after treatments were counted. Results are shown as mean±S.D. (n=5). Statistical significance: *P<0.05, **P<0.005 and ***P<0.0005 versus control.

Mentions: By temporarily normalizing the tumor microenvironment, our system exhibited enhanced drug accumulation in the tumor tissues. Herein, the relevant assays were exploited to examine the modification of the tumor microenvironment. Collagen, a major extracellular matrix component, was secreted by TAFs (tumor-associated fibroblasts) 35. The collagen was stained using Masson Trichrome assay. As shown in Figure 9, PEG-Phis60/Pasp-DOX/CA4 significantly reduced the amount of collagen (blue color) compared to PBS control, suggesting the regulation of tumor microenvironment 35. To further confirm the effect of the tumor vascular inhibitor to normalize the tumor microenvironment, blood vessels were stained by using an anti-CD31 antibody (Figure 10). Comparing with the control, PEG-Phis60/Pasp-DOX/CA4 significantly reduced the tumor angiogenesis, revealing that this system could regulate the balance between the pro-angiogenic and anti-angiogenic factors. It was in accordance with the Masson Trichrome assay results. These results revealed that PEG-Phis60/Pasp-DOX/CA4 could produce a superior anticancer efficacy against drug-resistant tumors, since they could release CA4 in tumor vessels to modify tumor microenvironment and induce more therapeutic drug accumulation in tumors.


Site-Specific Drug-Releasing Polypeptide Nanocarriers Based on Dual-pH Response for Enhanced Therapeutic Efficacy against Drug-Resistant Tumors.

Dong Y, Yang J, Liu H, Wang T, Tang S, Zhang J, Zhang X - Theranostics (2015)

(A) Immunostaining with anti-CD31 tumor tissues was used to detect tumor vasculature (arrows represented) after treatment with different formulations. (B) Quantification of tumor vessel density after treatments. Five randomly selected microscopic fields after treatments were counted. Results are shown as mean±S.D. (n=5). Statistical significance: *P<0.05, **P<0.005 and ***P<0.0005 versus control.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4440445&req=5

Figure 10: (A) Immunostaining with anti-CD31 tumor tissues was used to detect tumor vasculature (arrows represented) after treatment with different formulations. (B) Quantification of tumor vessel density after treatments. Five randomly selected microscopic fields after treatments were counted. Results are shown as mean±S.D. (n=5). Statistical significance: *P<0.05, **P<0.005 and ***P<0.0005 versus control.
Mentions: By temporarily normalizing the tumor microenvironment, our system exhibited enhanced drug accumulation in the tumor tissues. Herein, the relevant assays were exploited to examine the modification of the tumor microenvironment. Collagen, a major extracellular matrix component, was secreted by TAFs (tumor-associated fibroblasts) 35. The collagen was stained using Masson Trichrome assay. As shown in Figure 9, PEG-Phis60/Pasp-DOX/CA4 significantly reduced the amount of collagen (blue color) compared to PBS control, suggesting the regulation of tumor microenvironment 35. To further confirm the effect of the tumor vascular inhibitor to normalize the tumor microenvironment, blood vessels were stained by using an anti-CD31 antibody (Figure 10). Comparing with the control, PEG-Phis60/Pasp-DOX/CA4 significantly reduced the tumor angiogenesis, revealing that this system could regulate the balance between the pro-angiogenic and anti-angiogenic factors. It was in accordance with the Masson Trichrome assay results. These results revealed that PEG-Phis60/Pasp-DOX/CA4 could produce a superior anticancer efficacy against drug-resistant tumors, since they could release CA4 in tumor vessels to modify tumor microenvironment and induce more therapeutic drug accumulation in tumors.

Bottom Line: To enhance effective drug accumulation in drug-resistant tumors, a site-specific drug-releasing polypeptide system (PEG-Phis/Pasp-DOX/CA4) was exploited in response to tumor extracellular and intracellular pH.This system could firstly release the embedded tumor vascular inhibitor (CA4) to transiently 'normalize' vasculature and facilitate drug internalization to tumors efficiently, and then initiate the secondary pH-response to set the conjugated active anticancer drug (DOX) free in tumor cells.The encapsulated system (PEG-Phis/DOX/CA4), both CA4 and DOX embedding in the nanoparticles, was used as a control.

View Article: PubMed Central - PubMed

Affiliation: 1. National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, China ; 2. College of Chemistry & Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding, 071002, China.

ABSTRACT
To enhance effective drug accumulation in drug-resistant tumors, a site-specific drug-releasing polypeptide system (PEG-Phis/Pasp-DOX/CA4) was exploited in response to tumor extracellular and intracellular pH. This system could firstly release the embedded tumor vascular inhibitor (CA4) to transiently 'normalize' vasculature and facilitate drug internalization to tumors efficiently, and then initiate the secondary pH-response to set the conjugated active anticancer drug (DOX) free in tumor cells. The encapsulated system (PEG-Phis/DOX/CA4), both CA4 and DOX embedding in the nanoparticles, was used as a control. Comparing with PEG-Phis/DOX/CA4, PEG-Phis/Pasp-DOX/CA4 exhibited enhanced cytotoxicity against DOX-sensitive and DOX-resistant cells (MCF-7 and MCF-7/ADR). Moreover, PEG-Phis/Pasp-DOX/CA4 resulted in enhanced therapeutic efficacy in drug-resistant tumors with reduced toxicity. These results suggested that this site-specific drug-releasing system could be exploited as a promising treatment for cancers with repeated administration.

No MeSH data available.


Related in: MedlinePlus