Liposomal TriCurin, A Synergistic Combination of Curcumin, Epicatechin Gallate and Resveratrol, Repolarizes Tumor-Associated Microglia/Macrophages, and Eliminates Glioblastoma (GBM) and GBM Stem Cells.

Sumit Mukherjee,Lovena David,Leah Cohen,Samay Sampat,Andrew Mancuso,Shuiqin Zhou,Juliet Baidoo,Probal Banerjee

doi:10.3390/molecules23010201

Abstract

Glioblastoma (GBM) is a deadly brain tumor with a current mean survival of 12–15 months. Despite being a potent anti-cancer agent, the turmeric ingredient curcumin (C) has limited anti-tumor efficacy in vivo due to its low bioavailability. We have reported earlier a strategy involving the use two other polyphenols, epicatechin gallate (E) from green tea and resveratrol (R) from red grapes at a unique, synergistic molar ratio with C (C:E:R: 4:1:12.5, termed TriCurin) to achieve superior potency against HPV+ tumors than C alone at C:E:R (μM): 32:8:100 (termed 32 μM+ TriCurin). We have now prepared liposomal TriCurin (TrLp) and demonstrated that TrLp boosts activated p53 in cultured GL261 mouse GBM cells to trigger apoptosis of GBM and GBM stem cells in vitro. TrLp administration into mice yielded a stable plasma concentration of 210 nM C for 60 min, which, though sub-lethal for cultured GL261 cells, was able to cause repolarization of M2-like tumor (GBM)-associated microglia/macrophages to the tumoricidal M1-like phenotype and intra-GBM recruitment of activated natural killer cells. The intratumor presence of such tumoricidal immune cells was associated with concomitant suppression of tumor-load, and apoptosis of GBM and GBM stem cells. Thus, TrLp is a potential onco-immunotherapeutic agent against GBM tumors.

Highlights

Glioblastoma Multiforme (GBM) is a pernicious form of primary brain tumor, which arises from malignancy of astrocytes and constitutes approximately 15% of adult primary brain tumor cases [1,2,3]
Dynamic light scattering (DLS) analysis revealed a median hydrodynamic diameter of ~260 nm for Curcumin Liposome (CLp) and ~200 nm for TriCurin Lipososme (TrLp) (Figure 1B,E). Liposomes in these diameter ranges are reportedly useful for medical applications such as drug delivery [39]
We investigated the possibility of TrLp- and CLp-triggered, recruitment of activated Natural Killer (NK)

Summary

Introduction

Glioblastoma Multiforme (GBM) is a pernicious form of primary brain tumor, which arises from malignancy of astrocytes and constitutes approximately 15% of adult primary brain tumor cases [1,2,3]. Th average survival of patients with established GBM is about 12–15 months from diagnosis despite the current standard of care, which includes surgical removal of the tumor bulk followed by radiation and chemotherapy to eliminate residual tumor cells. The patient undergoes a 5-day chemotherapy regimen with a high-dose of temozolomide (TMZ). Molecules 2018, 23, 201 radiotherapy and chemotherapy can increase extracellular concentrations of glutamine, which nourishes the GBM cells and triggers tumor proliferation [8]. Radiation can cause tumor recurrence by triggering proliferation of brain tumor stem cells [9].

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