Thermal dose as a universal tool to evaluate nanoparticle-induced photothermal therapy.

Thermal isoeffect dose (TID) is a widely applied concept to evaluate the safety of medical devices that can expose patients to heat. However, it has rarely been used in photothermal therapy (PTT), where nanoparticles are used as light absorbers. Utilizing TID in an appropriate way would make it feasible to compare the results obtained with different light absorbers as well as clarifying their cellular effects. Herein, we apply TID as a definitive parameter to evaluate the outcomes of a nanoparticle-induced PTT in vitro. We show that cell death measured with an ATP-based viability assay and flow cytometry can be correlated with TID if time-temperature data is available. As an experimental model, black porous silicon nanoparticles were studied as photothermal agents to kill HeLa cancer cells. The results indicate that as the critical TID of 70 min is reached, the cells start to undergo apoptosis independently of the way in which the TID was attained: by long heating at low temperatures or by short heating at high temperatures. Overall, TID is proposed as a valid parameter which could be determined in the PTT studies to allow a straightforward comparison of the published results and the elucidation of the cell death mechanisms.

A conceptually new treatment approach for relapsed glioblastoma: coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care.

To improve prognosis in recurrent glioblastoma we developed a treatment protocol based on a combination of drugs not traditionally thought of as cytotoxic chemotherapy agents but that have a robust history of being well-tolerated and are already marketed and used for other non-cancer indications. Focus was on adding drugs which met these criteria: a) were pharmacologically well characterized, b) had low likelihood of adding to patient side effect burden, c) had evidence for interfering with a recognized, well-characterized growth promoting element of glioblastoma, and d) were coordinated, as an ensemble had reasonable likelihood of concerted activity against key biological features of glioblastoma growth. We found nine drugs meeting these criteria and propose adding them to continuous low dose temozolomide, a currently accepted treatment for relapsed glioblastoma, in patients with recurrent disease after primary treatment with the Stupp Protocol. The nine adjuvant drug regimen, Coordinated Undermining of Survival Paths, CUSP9, then are aprepitant, artesunate, auranofin, captopril, copper gluconate, disulfiram, ketoconazole, nelfinavir, sertraline, to be added to continuous low dose temozolomide. We discuss each drug in turn and the specific rationale for use- how each drug is expected to retard glioblastoma growth and undermine glioblastoma's compensatory mechanisms engaged during temozolomide treatment. The risks of pharmacological interactions and why we believe this drug mix will increase both quality of life and overall survival are reviewed.