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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

The accumulation of DOX in MCF-7 cells (A) and MCF-7/ADR cells (B) after incubation with PEG-Phis60/Pasp-DOX/CA4 at pH 7.4 for 1, 2 and 4 h. Data are shown as the mean±S.D. of three independent experiments. Statistical significance: *P<0.05, **P<0.005 and ***P<0.0005.
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Figure 6: The accumulation of DOX in MCF-7 cells (A) and MCF-7/ADR cells (B) after incubation with PEG-Phis60/Pasp-DOX/CA4 at pH 7.4 for 1, 2 and 4 h. Data are shown as the mean±S.D. of three independent experiments. Statistical significance: *P<0.05, **P<0.005 and ***P<0.0005.

Mentions: The accumulation of DOX in tumor cells was analyzed by the fluorescent intensity on a BD Calibur (Figure 6). DOX and DOX+CA4 exhibited higher accumulation than other formulations in DOX-sensitivecells (MCF-7) when the time extended to 4 h. This suggested that free drugs could quickly entered the cells by diffusion. However, in DOX-resistant cells, free DOX and DOX+CA4 were accumulated extremely low even when incubation for 4 h. This was probably due to the high expression of P-gp in MCF-7/ADR cells, which resulted in the exclusion of the DOX 29. The accumulations significantly increased when treated with PEG-Phis60/Pasp-DOX/CA4 and PEG-Phis60/DOX/CA4, confirming that drug delivery by nanoparticles through endocytosis could significantly enhance cellular uptake in drug-resistant tumor cells. The cellular uptake of these formulations was also evaluated at pH 6.6, which was close to the acidic microenvironment of tumors (Supplementary Material: Figure S13). The trend of the DOX accumulation in MCF-7 and MCF-7/ADR cells was similar with the condition at pH 7.4, which suggested that the cellular uptake was not affected by the size change of the nanoparticles.


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)

The accumulation of DOX in MCF-7 cells (A) and MCF-7/ADR cells (B) after incubation with PEG-Phis60/Pasp-DOX/CA4 at pH 7.4 for 1, 2 and 4 h. Data are shown as the mean±S.D. of three independent experiments. Statistical significance: *P<0.05, **P<0.005 and ***P<0.0005.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4440445&req=5

Figure 6: The accumulation of DOX in MCF-7 cells (A) and MCF-7/ADR cells (B) after incubation with PEG-Phis60/Pasp-DOX/CA4 at pH 7.4 for 1, 2 and 4 h. Data are shown as the mean±S.D. of three independent experiments. Statistical significance: *P<0.05, **P<0.005 and ***P<0.0005.
Mentions: The accumulation of DOX in tumor cells was analyzed by the fluorescent intensity on a BD Calibur (Figure 6). DOX and DOX+CA4 exhibited higher accumulation than other formulations in DOX-sensitivecells (MCF-7) when the time extended to 4 h. This suggested that free drugs could quickly entered the cells by diffusion. However, in DOX-resistant cells, free DOX and DOX+CA4 were accumulated extremely low even when incubation for 4 h. This was probably due to the high expression of P-gp in MCF-7/ADR cells, which resulted in the exclusion of the DOX 29. The accumulations significantly increased when treated with PEG-Phis60/Pasp-DOX/CA4 and PEG-Phis60/DOX/CA4, confirming that drug delivery by nanoparticles through endocytosis could significantly enhance cellular uptake in drug-resistant tumor cells. The cellular uptake of these formulations was also evaluated at pH 6.6, which was close to the acidic microenvironment of tumors (Supplementary Material: Figure S13). The trend of the DOX accumulation in MCF-7 and MCF-7/ADR cells was similar with the condition at pH 7.4, which suggested that the cellular uptake was not affected by the size change of the nanoparticles.

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