Controlling the release rate of topotecan from PLGA spheres and increasing its cytotoxicity towards glioblastoma cells by co-loading with calcium chloride.

Citation:

Racheli Sharon Gabbay ו Abraham Rubinstein. 2021. “Controlling the release rate of topotecan from PLGA spheres and increasing its cytotoxicity towards glioblastoma cells by co-loading with calcium chloride.” International journal of pharmaceutics, 602, Pp. 120616.

תקציר:

It has been suggested that local administration of topotecan (TT) could increase its efficacy in the treatment of glioblastoma. In this context, a PLGA implant model in the form of spheres with a porous core and stiff surface, loaded with TT and CaCl(2) was developed. An array of formulations differing from each other by the type of PLGA used, the integrity of the surface, the concentrations of TT and CaCl(2) added during the preparation, and the volume of water in the PLGA mix, was prepared, screened and explored by computerized multifactorial analysis. This analysis enabled the simultaneous identification of the most influential experimental factors on the experimental responses, which were pre-determined as the efficiency of TT loading and the TT % cumulative release at 14 days. The multifactorial analysis also revealed how the interactions among the experimental factors affect the performance of the various formulations. Thus, TT concentration and its factorial interaction with the concentration of CaCl(2) added during the spheres' preparation were identified as most prominent on the loading efficiency, while the surface integrity (intact or punctured) and CaCl(2) amount in the spheres were identified as most prominent on the TT % cumulative release from the spheres. TT was found to be cytotoxic towards glioblastoma U87 MG cells, an activity which was enhanced, synergistically, in the presence of CaCl(2) (the relative viability was reduced from 36 to 28% with combination indices of 1.0, 0.37, 0.13 and 0.06 for EC(50), EC(75), EC(90) and EC(95), respectively). Interestingly, dividing the TT dose into 3 equal portions, replenished daily to the incubation medium, increased TT cytotoxicity. The relative viability was then reduced from 35 to 7% and in the presence of CaCl(2) - from 28 to 1.9%, suggesting that a local, slow input of TT could be effective in the treatment of glioblastoma by an adjacent TT implant. The increased effect of CaCl(2) on cytotoxicity was also observed when it was co-loaded into the TT spheres. In that case, the cells' viability was reduced from 72 to 27%. It is suggested that the PLGA spheres could be used for tunable local delivery of TT in post-resection adjuvant therapy of glioblastoma.