Miktoarm Star Micelles Containing Curcumin Reduce Cell Viability of Sensitized Glioblastoma

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. A 2 B 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 A 2 B 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. A 2 B miktoarm polymers could be a new viable delivery system for curcumin and other anticancer drugs with similar limitations.

Pharmacological inhibition of lipid droplet formation enhances the effectiveness of curcumin in glioblastoma

“…Polymeric carriers have the potential to improve the stability and solubility of curcumin [60][61][62]. Our research group has previously reported the incorporation of curcumin into A2B star polymer micelles and effectiveness of this preparation in glioblastoma [63,64]. A retention of curcumin's biological activity in nanocarriers, an enhanced permeability and retention (EPR) effect and diffusion of curcumin into the neighboring glioblastoma cells could provide an improved therapeutic intervention in vivo [65] Pyrrolidine-2 is an inhibitor of cPLA2a, a key rate limiting enzyme in the synthesis of eicosanoids and a necessary player in the formation of lipid droplets [66,67].…”

Miktoarm Star Polymers: Branched Architectures in Drug Delivery

“…Owing to their tailorable architecture, superior CMCs, improved drug loading, and sustained drug release, there has been much recent interest in miktoarm star polymer-based assemblies for drug delivery [ 21 , 25 , 26 ]. Drug incorporation into micelles has been shown to have varied effects on the size of miktoarm micelles, where it can lower, increase, or have a negligible effect upon drug encapsulation [ 24 , 42 , 47 , 48 , 49 ]. Though generally, a decrease in size has been attributed to good polymer-drug compatibility [ 47 , 49 , 57 ].…”

“…Drug incorporation into micelles has been shown to have varied effects on the size of miktoarm micelles, where it can lower, increase, or have a negligible effect upon drug encapsulation [ 24 , 42 , 47 , 48 , 49 ]. Though generally, a decrease in size has been attributed to good polymer-drug compatibility [ 47 , 49 , 57 ]. One of the beneficial effects of including multiple branching arms as in miktoarm stars, is in increasing drug loading content into their self-assemblies.…”

Designing Dendrimer and Miktoarm Polymer Based Multi-Tasking Nanocarriers for Efficient Medical Therapy

“…As discussed earlier, multi-tasking is one of the key tenets of nanomedicine, and it requires nanocarriers to simultaneously perform multiple functions including drug loading and delivery, avoiding premature drug release, monitoring the fate of the drug as well as the carrier, and targeting the nanocarriers to intended site of action. In this regard, amphiphilic miktoarm star polymers are of specific interest to design synthetically articulated and tailor made micelles, and are currently being investigated extensively for the development of multifunctional nanocarriers for biological applications [117,118,119,120,121]. Miktoarm polymers have star shaped well-defined molecular architecture where different polymeric arms originate from a common central core.…”

“…Recently, we have used similar polymers for the encapsulation of curcumin to treat glioblastoma multiform tumor using combination therapy. Curcumin has poor aqueous solubility and low bioavailability [121]. Micellar encapsulation significantly improved the solubility of curcumin, and the combination of curcumin loaded micelles with pifitrin and temozolamide were quite effective in killing glioblastoma cells.…”