cRGD mediated redox and pH dual responsive poly(amidoamine) dendrimer-poly(ethylene glycol) conjugates for efficiently intracellular antitumor drug delivery.

Abstract

To improve antitumor efficiency of chemotherapy and reduce side effect, according to the physiological characteristics of tumor tissues and tumor intracellular microenvironment, a multifunctional drug delivery system with properties of long circulation, active targeting, redox and pH triggered drug release was established based on the Generation 4 polyamidoamine dendrimer (PAMAM). First, the redox cleavable disulfide bonds (SS) were introduced for linking polyethylene glycol (PEG) with PAMAM to form PAMAM-S-S-PEG (PSSP). Then cRGD peptide was applied to the PEG end of PSSP to construct RGD-PSSP conjugates. Finally, encapsulating the antitumor chemotherapy drug doxorubicin (DOX) into the hydrophobic cavity of RGD-PSSP conjugates constructed the RGD-PSSP/DOX drug delivery system. The in vitro experiments displayed that RGD-PSSP/DOX NPs showed obviously redox and pH dual sensitive drug release profile. MTT and cell uptake observation elucidated cRGD modification could increase the cytotoxicity, and promote the uptake of B16 cells and HUVEC cells both overexpressing integrin ανβ3on cell membrane. Cell uptake mechanism investigation further revealed that RGD-PSSP/DOX interacted with plasma membrane via specific recognition of cRGD peptide with integrin ανβ3, and was subsequently internalized mainly through clathrin- and caveolin-mediated endocytosis. Remarkably, RGD-PSSP/DOX presented superior anticancer activity and lower heart and kidney toxicity in vivo, which could be regarded as a potential candidate for efficient antitumor chemotherapy drug delivery.

• Authors: Yifei Wang, Wen Hu, Bomei Ding, Dawei Chen, Lifang Cheng
• Journal: Colloids and surfaces. B, Biointerfaces (Colloids Surf B Biointerfaces) Vol. 194 Pg. 111195 (Oct 2020) ISSN: 1873-4367 [Electronic] Netherlands
• PMID: 32619785 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Dendrimers
• Drug Carriers
• Poly(amidoamine)
• Polyamines
• Polyethylene Glycols
• Doxorubicin

Topics

• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Dendrimers
• Doxorubicin (pharmacology)
• Drug Carriers
• Drug Delivery Systems
• Hydrogen-Ion Concentration
• Oxidation-Reduction
• Polyamines
• Polyethylene Glycols