Metronomic Photodynamic Therapy with Conjugated Polymer Nanoparticles in Glioblastoma Tumor Microenvironment

Abstract

Alternative therapies such as photodynamic therapy (PDT) that combine light, oxygen and photosensitizers (PSs) have been proposed for glioblastoma (GBM) management to overcome conventional treatment issues. An important disadvantage of PDT using a high light irradiance (fluence rate) (cPDT) is the abrupt oxygen consumption that leads to resistance to the treatment. PDT metronomic regimens (mPDT) involving administering light at a low irradiation intensity over a relatively long period of time could be an alternative to circumvent the limitations of conventional PDT protocols. The main objective of the present work was to compare the effectiveness of PDT with an advanced PS based on conjugated polymer nanoparticles (CPN) developed by our group in two irradiation modalities: cPDT and mPDT. The in vitro evaluation was carried out based on cell viability, the impact on the macrophage population of the tumor microenvironment in co-culture conditions and the modulation of HIF-1α as an indirect indicator of oxygen consumption. mPDT regimens with CPNs resulted in more effective cell death, a lower activation of molecular pathways of therapeutic resistance and macrophage polarization towards an antitumoral phenotype. Additionally, mPDT was tested in a GBM heterotopic mouse model, confirming its good performance with promising tumor growth inhibition and apoptotic cell death induction.

Glioblastoma Therapy: Past, Present and Future

“…Recent advances in PDT-GB research are as follows: (1) coupled NIR and photo immunotherapy (NIR-PIT), where a photosensitizer is conjugated to a highly specific monoclonal antibody [ 1043 , 1044 , 1045 ]; (2) NP-based PDT to augment systemic therapies and avoid skin photosensitization [ 1046 , 1047 ]; (3) NP-based PDT linked to miRNA or other chemotherapeutic agents [ 1048 ]; (4) strategies to increase PDT efficacy in hypoxic TME conditions [ 1049 , 1050 , 1051 , 1052 ]. Although some studies have demonstrated the enhanced penetration of light by simultaneous application of ultrasounds [ 1053 ], combined effects of PDT and SDT did not show any benefit in glioma rat models [ 1054 ].…”

Optimizing cancer therapy: a review of the multifaceted effects of metronomic chemotherapy

“…Other than brain tumors, the potential of mPDT has been demonstrated in various other types of cancers, such as colorectal cancer and cervical cancer ( Shi et al, 2019 ; Dai et al, 2023 ) In a study by Caverzán et al, standard and metronomic regimens of conjugated polymer nanoparticles-based PDT was assessed on glioblastoma cell lines and xenograft mouse models. They reported that mPDT regimes induced increased cancer cell death, and lowered therapeutic resistance furthermore resulted in the polarization of one of the most important cancer-related immune cell subtypes, macrophages, towards an anti-tumoral phenotype ( Caverzán et al, 2023 ).…”

Photosensitizers for Photodynamic Therapy of Brain Cancers—A Review

“…The last literature report cited in the field of PDT supported by conjugated polymer nanoparticles for the treatment of glioblastoma cells is the article by Caverzán et al [ 125 ] from 2023. In this experiment, the authors, starting in 2020, used three glioblastoma cell lines and PDT coupled with polymer nanoparticles.…”

“…This experiment provides information on the development of advanced PDT concepts in conjunction with the application of lower irradiance. The polymer nanoparticles used contribute to the inhibition of tumor growth and initiate subsequent cell death pathways [ 125 ].…”