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.

Nanomedical approaches are the major transforming factor in cancer therapies. Based on important previous works in the field of drug delivery nanomaterials, recent years have brought a broad array of new and improved intelligent nanoscale platforms that are suited to deliver drugs. In this context, the purpose of this study was to investigate the action of different nanoemulsions designed to encapsulate chloroaluminum phthalocyanine, a hydrophobic photosensitizer used in photodynamic therapy, and doxorubicin, a well-known chemotherapeutic agent used to treat aggressive breast cancer cells. The mean nanostructured system size ranged from 170.8 to 181.0 nm, and the nanoemulsions presented spherical morphology. All formulations exhibited negative zeta potential values (-68.7 to -75.0 mV) and suitable polydispersity values (0.20 to 0.28), explaining their colloidal stability up to three months. Murine breast cancer cells (4T1) were incubated with nanoemulsions for three hours at various concentrations and were subjected to cell viability tests to find the concentration dependence profile. Thereafter, the in vitro phototoxic effect was evaluated in the presence of the visible laser light irradiation. Less than 10% of 4T1 viable cells were observed when photodynamic therapy and chemotherapy were combined at a 1.0 J · cm-2 laser light dose with 1.0 μM phthalocyanine and 0.5 μM doxorubicin. The cell death assay and cell cycle arrest analysis confirmed the therapy efficiency demonstrating an increase in the apoptosis rate and in the cell cycle arrest on G2. Additionally, 15 genes related to apoptosis and 25 target genes of anti-cancer drugs were overexpressed. Four genes related to apoptosis and four target genes of anti-cancer drugs were downregulated in 4T1 cells after treatment with nanoemulsion with phthalocyanine and doxorubicin associated with photodynamic therapy. Thus, the nanoemulsions loaded with phthalocyanine and doxorubicin presented appropriate physical stability, improved photophysical properties, and remarkable activity in vitro to be considered as promising formulations for photodynamic therapy and chemotherapeutic use in breast cancer treatment.

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The PDT induced apoptosis in high APE1 expressive HeLa cells, and the blockage of BER by MX increased its effects.