Benzylguanidine and Galactose Double-Conjugated Chitosan Nanoparticles with Reduction Responsiveness for Targeted Delivery of Doxorubicin to CXCR 4 Positive Tumors.

Abstract

Benzylguanidine, a small cationic and amphiphilic molecule, exhibits a high affinity to C-X-C chemokine receptor type 4 (CXCR 4) and a membrane penetration ability. It has not been used as a functional moiety of nanocarriers for the systemic delivery of chemotherapeutic drugs in tumor therapy. In this study, we investigated the membrane penetration of benzylguanidine-conjugated nanocarriers and their efficiency and safety for targeted delivery of doxorubicin (DOX) in CXCR 4 positive tumors. We conjugated the benzylguanidine bearing guanidinobenzoic acid onto the cystamine bismethacrylamide cross-linked chitosan-poly(methyl methacrylate) nanoparticles, which were then decorated with lactobionic acid (abbreviated as LGCC NPs). A small proportion of LGCC NPs were able to directly penetrate the plasma membrane to enter cells, thereby circumventing endocytic vesicles. The DOX-loaded LGCC NPs (LGCC NPs/DOX) displayed good stability under extracellular physiological conditions and reduction-triggered drug release under high glutathione (GSH) concentration. Moreover, LGCC NPs/DOX showed an increase in tumor-targeted cellular uptake through receptor-mediated endocytosis, enhanced endo/lysosomal escape, and a high nuclear distribution. More importantly, LGCC NPs/DOX significantly suppressed the in vitro and in vivo proliferation of CXCR 4 positive hepatocarcinoma and breast cancer. The findings provide a guideline for the combined application of benzylguanidine and other functional groups in antitumor nanomedicines.

• Authors: Fei Kong, Cui Tang, Chunhua Yin
• Journal: Bioconjugate chemistry (Bioconjug Chem) Vol. 31 Issue 10 Pg. 2446-2455 (10 21 2020) ISSN: 1520-4812 [Electronic] United States
• PMID: 32991164 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• CXCR4 protein, human
• Drug Carriers
• Guanidines
• Receptors, CXCR4
• benzylguanidine
• Doxorubicin
• Chitosan
• Galactose

Topics

• Animals
• Antibiotics, Antineoplastic (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Cell Line, Tumor
• Chitosan (analogs & derivatives, metabolism)
• Doxorubicin (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Drug Carriers (chemistry, metabolism)
• Drug Delivery Systems
• Galactose (analogs & derivatives, metabolism)
• Guanidines (chemistry, metabolism)
• Humans
• Mice
• Nanoparticles (chemistry, metabolism)
• Neoplasms (drug therapy, metabolism)
• Receptors, CXCR4 (metabolism)