Pro-inflammatory macrophage polarization enhances the anti-cancer efficacy of self-assembled galactomannan nanoparticles entrapped with hydrazinocurcumin.

Abstract

Galactomannan (GM), a natural polymer, is recognized to specifically target macrophage mannose receptors (CD206). Interestingly, some reports indicate that GM has an ability to induce pro-inflammatory (M1-like, tumericidal) polarization in macrophages, suggesting its potential use as an anti-cancer agent. Hydrazinocurcumin (HC), a pyrazole derivative of curcumin, is reported to possess increased anti-cancer efficacy over curcumin. Moreover, HC-encapsulated nanoparticles (NPs) have been reported to re-polarize tumor-associated macrophages (TAMs) from anti-inflammatory (M2-like, tumor-promoting) to pro-inflammatory phenotype. To club the therapeutic properties of both GM and HC, we synthesized self-assembled amphiphilic PEGylated GM NPs loaded with HC (PSGM-HCNPs) and evaluated their potential to re-polarize TAMs towards M1-like phenotype. PSGM-HCNPs re-polarized IL-4 polarized RAW 264.7 cells via a phenotypic switch from M2- to M1-like by elevating ROS level, decreasing CD206 and arginase-1 expressions and increasing pro-inflammatory cytokines' secretion. Conditioned medium (CM) taken from re-polarized RAW 264.7 cells containing residual PSGM-HCNPs elevated ROS, arrested cell cycle, and induced apoptosis in 4T1, breast cancer cells, and Ehrlich's ascites carcinoma (EAC) cells. Decreased levels of MMP-2, MMP-9, and Bcl-2 with increased levels of Bax in both 4T1 and EAC cells indicated anti-metastatic and apoptosis-inducing potential of the CM. Treatment of PSGM-HCNPs in EAC-bearing mice reduced tumor burden, increased their survival time, decreased CD206+F4/80+ cells, and increased TNF-α+F4/80+ cells signifying decrease in M2- and increase in M1-like skewness among ascitic TAMs.

• Authors: Manisha Kumari, Mahaveer P Purohit, Richa Pahuja, Satyakam Patnaik, Yogeshwer Shukla, Pradeep Kumar, Kailash C Gupta
• Journal: Drug delivery and translational research (Drug Deliv Transl Res) Vol. 9 Issue 6 Pg. 1159-1188 (12 2019) ISSN: 2190-3948 [Electronic] United States
• PMID: 31440985 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cytokines
• Hydrazines
• Mannans
• hydrazinocurcumin
• galactomannan
• Polyethylene Glycols
• Curcumin
• Galactose

Topics

• Animals
• Antineoplastic Agents (administration & dosage)
• Apoptosis (drug effects)
• Carcinoma, Ehrlich Tumor (drug therapy, immunology, pathology)
• Cell Cycle (drug effects)
• Cell Line
• Curcumin (administration & dosage, analogs & derivatives)
• Cytokines (immunology)
• Drug Synergism
• Female
• Galactose (analogs & derivatives)
• Hydrazines (administration & dosage)
• Macrophages (drug effects, immunology)
• Mannans (administration & dosage)
• Mice
• Nanoparticles (administration & dosage)
• Polyethylene Glycols (administration & dosage)