Overview of studies combining photodynamic therapy (PDT) with additional therapeutic strategies to overcome PDT resistance mechanisms
| Photosensitizer (PS) | Alternative therapy/therapeutic agent | Cell line or in vivo model | Fundamentals | Reference |
|---|---|---|---|---|
| Aminolevulinic acid (ALA) | Photobiomodulation (PBM) | U87MG/glioma tumors grafted on the chorioallantoic membrane (CAM) of chicken embryos | Due to PBM’s enhancement of cellular metabolism, as demonstrated by increased mitochondrial ATP production, elevated oxygen (O2) consumption, and improved mitochondrial membrane polarization (even in hypoxic conditions), it has stimulated the investigation of PBM’s capacity to augment protoporphyrin IX (PpIX) production and improve PpIX-PDT. | [175] |
| 5-ALA | Hypericin/PBM | U87MG | Observing that PBM induces autophagy, its application prior to hypericin was investigated, resulting in the production of plasma membrane-associated vesicles that enhanced the intracellular transport and dissolution of hypericin. This enhanced the accessibility of its physiologically active/fluorescent state for PDT, augmenting lactate dehydrogenase synthesis and improving PDT efficacy. | [39] |
| 5-ALA | ABT-263 | U251 | Navitoclax (ABT-263) is an inhibitor of Bcl-2 and Bcl-xL, which are anti-apoptotic proteins, and it reinstates a pro-apoptotic phenotype. This alteration results from compromised sequestration of Bcl-2-associated X protein (BAX) and/or Bcl-2-antagonist/killer 1 (BAK) and the displacement of pro-apoptotic molecules (e.g., Noxa or BAD) from anti-apoptotic proteins within this family (e.g., Mcl-1 or Bcl-2). PDT has demonstrated a synergistic enhancement of the pro-apoptotic activity of the Bcl-2 and Bcl-xL inhibitor, ABT-263. | [176] |
| 5-ALA | PDT combined with Acriflavine (ACF, PA) | U-251 and GL261 | ACF was employed due to its selective inhibition of hypoxia-inducible factor-1 (HIF-1) activation, which is linked to oxidative stress, the mechanism of cell death induced by PDT, and the activation of several survival signaling pathways. The amalgamation of ACF with PDT diminished the expression of HIF-1a, GLUT-1, GLUT-3, and HK2, while augmenting tumor suppression, underscoring the significant function of ACF as an innovative adjuvant for PDT. | [177] |
| 5-ALA | Biocompatible periodic mesoporous organosilica-coated Prussian blue nanoparticle (PB@PMO) | U87MG/mice | PB, a clinically utilized antidote for radioactive heavy metal toxicity, possesses the catalytic capacity to convert hydrogen peroxide (H2O2) into O2, hence enhancing the efficacy of PDT. | [80] |
| Dicysteamine-modified hypocrellin derivative (DCHB) | Multifunctional phototheranostic agent based on octadecane-modified temozolomide (TMZ-C18) for chemotherapy (CTX) | U87MG subcutaneous tumor in mice | A multifunctional phototheranostic agent is formulated using TMZ-C18 for CTX, DCHB as a natural-origin PS with a singlet O2 production (ΦΔ) of 0.51, and a cyclic peptide (cRGD) as a targeting unit for glioblastoma (GBM). | [178] |
| Hematoporphyrin monomethyl ether (HMME) | TMZ | Rat C6 glioma model using male Wistar rats | PDT markedly reduced the expression of P-glycoprotein in endothelial cells forming the blood-tumor barrier and in glioma tissues. The integration of TMZ with PDT markedly elevated TMZ levels in glioma tissues, enhanced glioma cell apoptosis, and extended the median lifespan of glioma-bearing mice. | [179] |
| Chlorin e6 | β-Mannose | U-251 | The primary justification for use of glucose in treatment is that tumor cells metabolize glucose at a higher rate than normal cells. The second objective is to enhance PS specificity by targeting tumor-associated macrophages (TAMs), which display elevated levels of the mannose receptor and promote tumorigenesis, therefore undermining therapeutic efficacy. The development of a chlorin derivative conjugated with mannose showed notable anticancer effects and enhanced PS accumulation in M2 macrophages. | [180] |
| 5,10,15,20-tetrakis(3-hydroxyphenyl)chlorin (mTHPC) | IR-780, a photothermal agent | Murine astrocytoma (ALTS1C1) | Near-infrared radiation (NIR)-triggered PDT and photothermal therapy (PTT). | [181] |
| Chlorin e6 | Gold nanoparticles (AuNPs) | Orthotopic GBM mice | Light-triggered PDT and PTT. | [182] |
