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

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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.

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Acknowledgments

KCG thanks the Indian Council of Medical Research (ICMR), New Delhi, for the award of Dr. A.S. Paintal Distinguished Scientist Chair at CSIR-IGIB, Delhi. MK thanks CSIR for providing Senior Research Fellowship. Dr. B. Jagadeesh and Dr. M.K.R. Mudiam from CSIR-IICT, Hyderabad, are acknowledged for NMR and LC-MS studies, respectively. Ms. N. Arjaria, CSIR-IITR and Mr. Jaishankar of CSIR-IITR Lucknow are acknowledged for their help in TEM studies. Dr. P.N. Saxena of CSIR-IITR Lucknow is acknowledged for the help in SEM studies. The authors are thankful to Mr. S.H.N. Naqvi of CSIR-IITR Lucknow for helping in animal experiments.

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Authors and Affiliations

  1. CSIR-Institute of Genomics and Integrative Biology, Delhi University Campus, Mall Road, Delhi, 110007, India

    Manisha Kumari, Richa Pahuja, Pradeep Kumar & Kailash C. Gupta

  2. Academy of Scientific and Innovative Research (AcSIR), New Delhi, India

    Manisha Kumari, Mahaveer P. Purohit & Richa Pahuja

  3. CSIR-Indian Institute of Toxicology Research, M.G. Marg, Lucknow, Uttar Pradesh, 226 001, India

    Mahaveer P. Purohit, Satyakam Patnaik & Yogeshwer Shukla

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  1. Manisha Kumari
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Kumari, M., Purohit, M.P., Pahuja, R. et al. Pro-inflammatory macrophage polarization enhances the anti-cancer efficacy of self-assembled galactomannan nanoparticles entrapped with hydrazinocurcumin. Drug Deliv. and Transl. Res. 9, 1159–1188 (2019). https://doi.org/10.1007/s13346-019-00661-y

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