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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) The pH-profile of PEG-Phis20, PEG-Phis40, PEG-Phis60, PEG-Phis80 copolymers and NaCl by acid-base titration. (B) TEM image of the PEG-Phis60/Pasp-DOX/CA4 nanoparticles prepared from the diluted solution (0.1 mg/mL) at pH 7.4. The scale bar represents 100 nm.
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Figure 2: (A) The pH-profile of PEG-Phis20, PEG-Phis40, PEG-Phis60, PEG-Phis80 copolymers and NaCl by acid-base titration. (B) TEM image of the PEG-Phis60/Pasp-DOX/CA4 nanoparticles prepared from the diluted solution (0.1 mg/mL) at pH 7.4. The scale bar represents 100 nm.

Mentions: The PEG-Phis block polymers were prepared by ring-opening polymerization (Supplementary Material: Figure S1 and S2). To precisely tuning the pH-responsive range of the block polymer, a series of PEG-Phis (PEG-Phis20, PEG-Phis40, PEG-Phis60 and PEG-Phis80) was synthesized, and the degree of polymerization (DP) of the polyhistidine block was calculated by NMR (Supplementary Material: Table S1). The protonation of PEG-Phis was determined by using acid-base titration. Comparing with PEG-Phis20 and PEG-Phis80, PEG-Phis40 and PEG-Phis60 showed significant buffering capacity, in the pH range of 5.6-7.1 (Figure 2A), and responded to the tumor extracellular pH (pH 6-7) 26, 27. The pH-responsive macromolecular prodrug Pasp-DOX was prepared by conjugating the ketone group of DOX with the hydrazine group of polyaspartate to form a hydrazone linker (Supplementary Material: Figure S3). The structure was confirmed by NMR spectra (Supplementary Material: Figure S4), and the DOX concentration was 65.9%, which was calculated by ultraviolet and visible spectrophotometer (UV) analysis.


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) The pH-profile of PEG-Phis20, PEG-Phis40, PEG-Phis60, PEG-Phis80 copolymers and NaCl by acid-base titration. (B) TEM image of the PEG-Phis60/Pasp-DOX/CA4 nanoparticles prepared from the diluted solution (0.1 mg/mL) at pH 7.4. The scale bar represents 100 nm.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: (A) The pH-profile of PEG-Phis20, PEG-Phis40, PEG-Phis60, PEG-Phis80 copolymers and NaCl by acid-base titration. (B) TEM image of the PEG-Phis60/Pasp-DOX/CA4 nanoparticles prepared from the diluted solution (0.1 mg/mL) at pH 7.4. The scale bar represents 100 nm.
Mentions: The PEG-Phis block polymers were prepared by ring-opening polymerization (Supplementary Material: Figure S1 and S2). To precisely tuning the pH-responsive range of the block polymer, a series of PEG-Phis (PEG-Phis20, PEG-Phis40, PEG-Phis60 and PEG-Phis80) was synthesized, and the degree of polymerization (DP) of the polyhistidine block was calculated by NMR (Supplementary Material: Table S1). The protonation of PEG-Phis was determined by using acid-base titration. Comparing with PEG-Phis20 and PEG-Phis80, PEG-Phis40 and PEG-Phis60 showed significant buffering capacity, in the pH range of 5.6-7.1 (Figure 2A), and responded to the tumor extracellular pH (pH 6-7) 26, 27. The pH-responsive macromolecular prodrug Pasp-DOX was prepared by conjugating the ketone group of DOX with the hydrazine group of polyaspartate to form a hydrazone linker (Supplementary Material: Figure S3). The structure was confirmed by NMR spectra (Supplementary Material: Figure S4), and the DOX concentration was 65.9%, which was calculated by ultraviolet and visible spectrophotometer (UV) analysis.

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