Nanolipid Formulations of Benzoporphyrin Derivative: Exploring the Dependence of Nanoconstruct Photophysics and Photochemistry on Their Therapeutic Index in Ovarian Cancer Cells

Abstract

With the rapidly emerging designs and applications of light-activated, photodynamic therapy (PDT)-based nanoconstructs, photonanomedicines (PNMs), an unmet need exists to establish whether conventional methods of photochemical and photophysical characterization of photosensitizers are relevant for evaluating new PNMs in order to intelligently guide their design. As a model system, we build on the clinical formulation of benzoporphyrin derivative (BPD), Visudyne , by developing a panel of nanolipid formulations entrapping new lipidated chemical variants of BPD with differing chemical, photochemical and photophysical properties. These are 16:0 and 20:0 lysophosphocholine-BPD (16:0/20:0 BPD-PC), DSPE-PEG-BPD and BPD-cholesterol. We show that Visudyne was the most phototoxic formulation to OVCAR-5 cells, and the least effective was liposomal DSPE-PEG-BPD. However, these differences did not match their optical, photophysical and photochemical properties, as the static BPD quenching was highest in Visudyne, which also exhibited the lowest generation of singlet oxygen. Furthermore, we establish that OVCAR-5 cell phototoxicity also does not correlate with rates of photosensitizer photobleaching and fluorescence quantum yields in any nanolipid formulations. These findings warrant critical future studies into subcellular targets and molecular mechanisms of phototoxicity of photodynamic nanoconstructs, as more reliable prognostic surrogates for predicting efficacy to appropriately and intelligently guide their design.

A Combination of Visudyne and a Lipid‐anchored Liposomal Formulation of Benzoporphyrin Derivative Enhances Photodynamic Therapy Efficacy in a 3D Model for Ovarian Cancer

“…The PS, being conjugated to a nonswitchable phospholipid, remains anchored to the liposome during this process and eventually ends up trapped in lysosomes, thereby modulating (and expanding) the subcellular localization of BPD. Our prior work has demonstrated that this BPD anchoring behavior is unique from BPD formulated in the clinical preparation Visudyne, whereby the PS rapidly leaches out of the formulation in the presence of serum‐containing media . The rapid dissociation of BPD from Visudyne is therefore responsible for the mitochondria/ER subcellular localization, as is typical of native BPD.…”

Photodynamic Therapy and the Biophysics of the Tumor Microenvironment

“…Depending on the type of photodamage and the underlying biology of the target cells, PDT can also cause lethal levels of autophagy , or as has been reported more recently, can trigger paraptosis, a response, in part, to misfolded endoplasmic reticulum (ER) proteins . Combining PS or PS formulations to enhance PDT efficacy by targeting complementary tumor compartments or subcellular sites has also shown promise . Importantly, because the timing, location and intensity of light activation can be carefully controlled, PDT is inherently a targeted therapeutic modality.…”

The role of ABCG2 in modulating responses to anti-cancer photodynamic therapy

“…The photosensitiser Benzoporphyrin Derivative (BpD) has been the subject of many previous PDT investigations, gaining FDA approval in 2000 for clinical applications [79]. Huang et al found a liposomal formulation of BpD to be an efficient mediator of PDT in MIA PaCa-2 pancreatic cancer cells [80].…”