Targeted and Synergic Glioblastoma Treatment: Multifunctional Nanoparticles Delivering Verteporfin as Adjuvant Therapy for Temozolomide Chemotherapy

Abstract

Despite advances in cancer therapies, glioblastoma multiforme treatment remains inefficient due to the brain− blood barrier (BBB) inhibitory activity and to the low temozolomide (TMZ) chemotherapeutic selectivity. To improve therapeutic outcomes, in this work we propose two strategies, (i) photodynamic therapy (PDT) as adjuvant treatment and (ii) engineering of multifunctional theranostic/targeted nanoparticles (m-NPs) that integrate biotin as a targeting moiety with rhodamine-B as a theranostic agent in pluronic P85/F127 copolymers. These smart m-NPs can surmount the BBB and coencapsulate multiple cargoes under optimized conditions. Overall, the present study conducts a rational m-NP design, characterization, and optimizes the formulation conditions. Confocal microscopy studies on T98-G, U87-MG, and U343 glioblastoma cells and on NIH-3T3 normal fibroblast cells show that the m-NPs and the encapsulated drugs are selectively taken up by tumor cells presenting a broad intracellular distribution. The formulations display no toxicity in the absence of light and are not toxic to healthy cells, but they exert a robust synergic action in cancer cells in the case of concomitant PDT/TMZ treatment, especially at low TMZ concentrations and higher light doses, as demonstrated by nonlinear dose−effect curves based on the Chou−Talalay method. The results evidenced different mechanisms of action related to the disjoint cell cycle phases at the optimal PDT/TMZ ratio. This effect favors synergism between the PDT and the chemotherapy with TMZ, enhances the antiproliferative effect, and overcomes cross-resistance mechanisms. These results point out that m-NP-based PDT adjuvant therapy is a promising strategy to improve TMZ-based glioblastoma multiforme treatments.

Characterization of Perturbing Actions by Verteporfin, a Benzoporphyrin Photosensitizer, on Membrane Ionic Currents

“…VP has been recently reported to inhibit the proliferation of glioma cells (Al-Moujahed et al, 2017; Eales et al, 2018; Pellosi et al, 2019). In a final series of experiments, we therefore intended to investigate whether the presence of VP is also able to modulate ionic currents in another types of neoplastic cells (e.g., malignant glioma cells).…”

“…Upon cell exposure to VP particularly along with long-term light exposure, the reactive oxygen species would be excessively produced, and resultant byproducts of oxidative metabolism can then interact with membrane phospholipids and proteins that constitute ion transport pathways such as BK Ca channels. Lastly, It will be worthy of being investigated regarding to what extent VP-mediated modifications on membrane ion channels reported herein is closely linked to the inhibition of VAP-TEAD complex followed by changes in proliferation or differentiation of different types of neoplastic or stem cells, given that the fact that such photosensitizers as sensitized photochemical modification in an array of tumors, including pituitary tumors and gliomas, have been widely utilized (Marks et al, 2000; Brown et al, 2004; Solban et al, 2006; Triesscheijn et al, 2006; Cole et al, 2008; Brodowska et al, 2014; Valero et al, 2015; Morishita et al, 2016; Nemes et al, 2016; Chen and Hu, 2017; Baskaran et al, 2018; Liao et al, 2018; Mulder et al, 2018; Chen et al, 2019; Li et al, 2019; Pellosi et al, 2019; Qin et al, 2019; Zhang et al, 2019). Alternatively, the efficacy of VP in inhibiting YAP/TEAD interaction was currently noted to remain debated (Lui et al, 2019).…”

“…Yes-associated protein (YAP) has been reported to be a main mediator of the Hippo pathway, which is thought to promote cancer development (Feng et al, 2016; Gibault et al, 2016; Kandoussi et al, 2017; Abe et al, 2018; Chen et al, 2019). A number of recent reports has demonstrated that VP can suppress the aberrant growth in a variety of tumor cell lines, including breast cancer, glioma, ovarian cancer, hepatocellular carcinoma, and retinoblastoma, through an intriguing mechanism linked to specific suppression of YAP-TEAD complex (Valero et al, 2015; Feng et al, 2016; Al-Moujahed et al, 2017; Gibault et al, 2017; Abe et al, 2018; Mulder et al, 2018; Li et al, 2019; Pellosi et al, 2019; Qin et al, 2019; Zhang et al, 2019). This compound has been indeed long supposed to be an inhibitor of YAP-TEAD complex and hence to play the roles in growth inhibition in different types of neoplastic cells including pituitary tumors and gliomas (Feng et al, 2016; Gibault et al, 2016, 2017; Al-Moujahed et al, 2017; Deng et al, 2018; Eales et al, 2018; Liao et al, 2018; Pellosi et al, 2019; Zhang et al, 2019).…”

The Role of Photoactivated and Non-Photoactivated Verteporfin on Tumor

“…Multifunctional VP nanoparticles can also be used as an adjuvant to augment the efficacy of chemotherapy drugs and reduce the side effects of chemotherapy drugs. For example, temozolomide used in conjunction with VP nanoparticles markedly decreased the growth of the glioblastoma multiforme U87-MG, T98-G, and U343 cells (VP nano 5.0 μg/ml, TMZ 700, 500, 300 μg/ml, 0.3, 0.7, 1.0 J/cm 2 at 690 nm) ( Pellosi et al, 2019 ). Kaneko et al used Hsp90 as a PS target in tumor targeted PDT, and combined Hsp90 small molecule inhibitor with VP to enhance the therapeutic effect of VP in human breast cancer xenografts VP or Hsp90-targeted VP i.p., 25 nmol/mouse, 120 J/cm 2 at 690 nm).…”

Devices based on light emitting fabrics dedicated to PDT preclinical studies

“…In vivo preclinical studies laser sources are widely used as they provide high intensity with narrow spectral distribution. LASER sources can easily be associated to frontal end optical fibers or cylindrical diffuser end optical fibers previously introduced into tumor sites to perform intralesional illumination [13][14][15]. As visible light depth penetration within biological tissues is limited to few millimeters [16], external illumination are mostly dedicated to superficial lesions or in vitro studies.…”