Abstract
Glioblastoma multiforme (GBM) is the most common and lethal primary intracranial tumor in humans. Monotherapeutic interventions have not been successful. The objective of the current studies was to establish the effective combination therapy consisting of pifitrin as a sensitizer, and curcumin as therapeutic incorporated into miktoarm micelles. A2B type miktoarm stars were prepared using a combination of click chemistry with ring opening polymerization on a core with orthogonal functionalities. These self-assemble into spherical micelles with hydrophobic core and hydrophilic corona structure. Micellar delivery systems for curcumin based on these miktoarm star polymers were prepared, characterized and tested on cultures sensitized with pifitrin. The results show that: (1) pifitrin and temozolamide in combination with curcumin cause significant cell death compared with the individual therapeutics (incorporated or not in micelles), and (2) repeated exposure to the same treatments is necessary to fully prevent a re-growth of glioblastoma cells both in 2D and 3D cultures. Although the incorporation of curcumin into A2B star polymer micelles did not increase the extent of cell death compared with curcumin alone, the advantage of micelles is that they significantly increase the aqueous solubility of curcumin and sustain its release; this will likely reduce the frequency of its administration required to be effective in vivo. A2B miktoarm polymers could be a new viable delivery system for curcumin and other anticancer drugs with similar limitations.
Highlights
Glioblastoma multiforme (GBM) is the most common and lethal intracranial tumor in humans due to its uncontrolled cellular proliferation, diffuse infiltration, propensity for necrosis, robust angiogenesis, intense resistance to apoptosis, rampant genomic instability, significant intra-tumoral heterogeneity, and a putative cancer stem cell component [1,2].The major causes of primary glioblastomas are not well known, but often involve gene multiplications, deletions and mutations affecting growth factor receptor signaling
The synthesis of A2B miktoarm star polymers was achieved by an adaptation of our previously published procedure, using a core with orthogonal functionalities (1), and Cu(I) catalyzed alkyne azide click reaction in sequence with ring opening polymerization (ROP), (Figure 1A) [22]
Combination therapy using nanocarriers that could enhance the efficacy of hydrophobic drugs which are poorly soluble in an aqueous medium constitute a topical area of research
Summary
Glioblastoma multiforme (GBM) is the most common and lethal intracranial tumor in humans due to its uncontrolled cellular proliferation, diffuse infiltration, propensity for necrosis, robust angiogenesis, intense resistance to apoptosis, rampant genomic instability, significant intra-tumoral heterogeneity (cytopathology, transcriptional, genomic), and a putative cancer stem cell component [1,2].The major causes of primary glioblastomas are not well known, but often involve gene multiplications, deletions and mutations affecting growth factor receptor signaling. Temozolomide and bevacizumab (anti-angiogenic, humanized monoclonal antibody vs VEGF-A) are often used in combination with other treatments such as IFNα, irinotecan (topoisomerase-I inhibitor), doxorubicin, and alkylating agents such as carmustine and lomustine (nitrosoureas). A micellar system based on amphiphilic peptides and incorporating bis-chloroethylnitrosourea (BCNU) and vascular endothelial growth factor (VEGF) small interfering RNA (VEGF-siRNA), was prepared and tested in C6 glioblastoma cells [6]. The micelles showed better delivery of BCNU into the cells and remarkably reduced expression of VEGF. In another recent study, polymeric micelles coated with cyclic Arg-Gly-Asp (cRGD) ligand molecules showed highly efficient anticancer drug delivery to U87MG tumors [7]
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