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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 pH-dependent cumulative CA4 (A) and DOX (B) were released from the PEG-phis60/Pasp-DOX/CA4 nanoparticles at pH 7.4, 6.6, 5.8 and 5.0 with gentle shaking. The incubation temparature was 37 oC. Data are shown as the mean±S.D. of three independent experiments.
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Figure 3: The pH-dependent cumulative CA4 (A) and DOX (B) were released from the PEG-phis60/Pasp-DOX/CA4 nanoparticles at pH 7.4, 6.6, 5.8 and 5.0 with gentle shaking. The incubation temparature was 37 oC. Data are shown as the mean±S.D. of three independent experiments.

Mentions: The drug release amount of PEG-Phis60/Pasp-DOX/CA4 nanoparticles at different pH buffers was tested by HPLC. As shown in Figure 3A, the release of CA4 was very slow at pH 7.4, whereas exhibited a rapid process when the pH changed to 6.6, with 8.7% vs. 64.1% for 12 h. This suggested that the nanoparticles was stable in physiological condition, but could quickly respond to the tumor extracellular pH to set the CA4 free. This was consistent with the pH buffering range of PEG-Phis60 and the size change of the nanoparticles, demonstrating that the system could initiate the primary pH response in tumor microenvironment. Seen from Figure 3B, the conjugated DOX had an obviously fast and continuous release when the pH changed from 7.4 to 5.8, 8.1% vs. 57.1% for two weeks, respectively. This demonstrated that the hydrazone bonds facilitated to break when the pH less than 5.8, which was in line with the endosomal pH.


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 pH-dependent cumulative CA4 (A) and DOX (B) were released from the PEG-phis60/Pasp-DOX/CA4 nanoparticles at pH 7.4, 6.6, 5.8 and 5.0 with gentle shaking. The incubation temparature was 37 oC. Data are shown as the mean±S.D. of three independent experiments.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: The pH-dependent cumulative CA4 (A) and DOX (B) were released from the PEG-phis60/Pasp-DOX/CA4 nanoparticles at pH 7.4, 6.6, 5.8 and 5.0 with gentle shaking. The incubation temparature was 37 oC. Data are shown as the mean±S.D. of three independent experiments.
Mentions: The drug release amount of PEG-Phis60/Pasp-DOX/CA4 nanoparticles at different pH buffers was tested by HPLC. As shown in Figure 3A, the release of CA4 was very slow at pH 7.4, whereas exhibited a rapid process when the pH changed to 6.6, with 8.7% vs. 64.1% for 12 h. This suggested that the nanoparticles was stable in physiological condition, but could quickly respond to the tumor extracellular pH to set the CA4 free. This was consistent with the pH buffering range of PEG-Phis60 and the size change of the nanoparticles, demonstrating that the system could initiate the primary pH response in tumor microenvironment. Seen from Figure 3B, the conjugated DOX had an obviously fast and continuous release when the pH changed from 7.4 to 5.8, 8.1% vs. 57.1% for two weeks, respectively. This demonstrated that the hydrazone bonds facilitated to break when the pH less than 5.8, which was in line with the endosomal pH.

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