CXCR4-Receptor-Targeted Liposomes for the Treatment of Peritoneal Fibrosis.

Abstract

Peritoneal fibrosis (PF) is a common complication of long-term peritoneal dialysis (PD). It is considered as the main reason for dialysis inadequacy and PD withdrawal. Transforming growth factor beta (TGF-β) regulates the expression of stromal cell-derived factor 1 (SDF-1α) and its receptor C-X-C chemokine receptor type 4 (CXCR4) on human peritoneal mesothelial cells (HPMCs), resulting in an increased migratory potential of HPMCs and extracellular matrix (ECM) deposition in the scar tissue and eventually fibrosis. Because SDF-1α/CXCR4 activation has a vital role in the pathogenesis of PF, codelivery of a CXCR4-receptor targeting agent with an antifibrotic agent in a single nanocarrier can be a promising strategy for treating PF. Here, for the first time, AMD3100 (AMD), a CXCR4-receptor antagonist, was coformulated with sulfotanshinone IIA sodium (STS IIA) into a liposome (STS-AMD-Lips) to develop a CXCR4 receptor targeting form of combination therapy for PF. CXCR4 targeting increased the ability of liposomes to target fibrotic peritoneal mesothelial cells overexpressing CXCR4 and facilitated the ability of STS IIA treatment at the fibrotic site. The liposome had an average diameter of 103 nm with encapsulated efficiencies of above 50%. The in vivo studies confirmed the reversal of PD solution-induced epithelial-to-mesenchymal transition by STS-AMD-Lips in HPMCs. The in vivo studies also revealed the precise biodistribution of the liposomes to peritoneum. Significant reduction of the morphological lesions and decreased level of ECM proteins were observed in rats treated with STS-AMD-Lips, proving that the liposomal nanocarrier has excellent ability to reverse PF. It has been concluded that the STS-AMD-Lips exhibit specific peritoneal targeting ability and could be used to improve STS-AMD combination delivery for the treatment of PF.

• Authors: Khan Asifullah, Zhanwei Zhou, Weiming He, Kun Gao, Muhammad Waseem Khan, Raza Faisal, Hasnat Muhammad, Minjie Sun
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 16 Issue 6 Pg. 2728-2741 (06 03 2019) ISSN: 1543-8392 [Electronic] United States
• PMID: 31070930 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokine CXCL12
• Liposomes
• Receptors, CXCR4

Topics

• Animals
• Blotting, Western
• Cell Survival (physiology)
• Chemokine CXCL12 (metabolism)
• Female
• Flow Cytometry
• Humans
• Immunochemistry
• Liposomes (therapeutic use)
• Mice, Inbred BALB C
• Peritoneal Fibrosis (drug therapy, metabolism)
• Receptors, CXCR4 (metabolism)