Photodynamic Priming Mitigates Chemotherapeutic Selection Pressures and Improves Drug Delivery

Self Cite

Longitudinal monitoring of tumor size in vivo can provide important biological information about disease progression and treatment efficacy that is not captured by other modes of quantification. Ultrasound enables high-throughput evaluation of orthotopic mouse models via fast acquisition of three-dimensional tumor images and calculation of volume with a reasonable degree of accuracy. Herein, we compare orthotopic pancreatic tumor volume measurements determined by ultrasound with volume measured by calipers and tumor weight, and found strong correlations between the three modalities over a large range of tumor sizes, suggesting ultrasound can accurately quantify tumor volumes in this model. Furthermore, we demonstrate the unique ability of longitudinal treatment monitoring to reveal a tumor size-dependent response to Benzoporphyrin Derivative photodynamic therapy (BPD-PDT) and irinotecan. Small tumors (5-35 mm ) were found to respond well to a single round of PDT, while large tumors (35-65 mm ) showed no response to the same treatment. These results highlight the role that tumor size can play in preclinical interpretation of treatment response and more generally suggest that careful evaluation of subtle biological features such as this must be carefully considered in order to grant a more comprehensive understanding of disease biology in vivo.

Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 95%

Size‐dependent Tumor Response to Photodynamic Therapy and Irinotecan Monotherapies Revealed by Longitudinal Ultrasound Monitoring in an Orthotopic Pancreatic Cancer Model

Pigula

Huang

Mallidi

et al. 2018

Self Cite

“…Visudyne is the first and only approved photonanomedicine (PNM) formulation, which gained FDA approval for photodynamic therapy (PDT) in 2000 using the photosensitizer (PS) benzoporphyrin derivative (BPD) and is formulated with egg phosphatidylglycerol, dimyristoyl phosphatidylcholine, ascorbyl palmitate and butylated hydroxytoluene . Since its approval, Visudyne has set the scene for almost two decades of preclinical and clinical advancements of light activatable nanotechnologies . Although initially approved for PDT of Wet Age‐Related Macular Degeneration , the clinical use of Visudyne in oncology is on the rise, with the successful clinical demonstration of pancreatic ductal adenocarcinoma tumor necrosis , and recent clinical trials in pancreatic cancer (NCT03033225), prostate cancer (NCT03067051), primary (NCT02872064) and metastatic breast cancer (NCT02939274), and in lung cancer for the PDT‐dependent enhancement of liposomal cisplatin delivery (NCT02702700).…”

Section: Introductionmentioning

confidence: 99%

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

Obaid

Jin

Bano

et al. 2018

Self Cite

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.

“…Nal‐BPD and Nal‐PpIX were reproducibly synthesized via the freeze‐thaw extrusion method . A lipid composition of dipalmitoylphosphatidylcholine (DPPC), cholesterol and distearoylphosphatidylethanolamine‐methoxy polyethylene glycol (DSPE‐PEG) at a 20:10:1 molar ratio was used based on the clinically approved PEGylated nanoliposomal formulations .…”

Section: Resultsmentioning

confidence: 99%

“…Nanoliposomes containing BPD or PpIX within the bilayer (Nal‐BPD or Nal‐PpIX) were synthesized via freeze‐thaw extrusion as described previously . Briefly, dipalmitoylphosphatidylcholine (DPPC), cholesterol, distearoylphosphatidylethanolamine‐methoxy polyethylene glycol (DSPE‐PEG) and 1,2‐dioleoyl‐3‐trimethylammonium‐propane (DOTAP) (Avanti Polar Lipids, Alabaster, AL, USA) were codissolved with BPD (50 nmoles, U.S. Pharmacopeia, Rockville, MD, USA) at 0.15 mol% BPD‐to‐lipid ratio or PpIX (60 nmoles, Santa Cruz Biotechnology, Dallas, TX, USA) at 0.18 mol% PpIX‐to‐lipid ratio.…”

Section: Methodsmentioning

confidence: 99%

Predictors and Limitations of the Penetration Depth of Photodynamic Effects in the Rodent Brain

Inglut

Gaitan

Najafali

et al. 2019

Fluorescence‐guided surgery (FGS) is routinely utilized in clinical centers around the world, whereas the combination of FGS and photodynamic therapy (PDT) has yet to reach clinical implementation and remains an active area of translational investigations. Two significant challenges to the clinical translation of PDT for brain cancer are as follows: (1) Limited light penetration depth in brain tissues and (2) Poor selectivity and delivery of the appropriate photosensitizers. To address these shortcomings, we developed nanoliposomal protoporphyrin IX (Nal‐PpIX) and nanoliposomal benzoporphyrin derivative (Nal‐BPD) and then evaluated their photodynamic effects as a function of depth in tissue and light fluence using rat brains. Although red light penetration depth (defined as the depth at which the incident optical energy drops to 1/e, ~37%) is typically a few millimeters in tissues, we demonstrated that the remaining optical energy could induce PDT effects up to 2 cm within brain tissues. Photobleaching and singlet oxygen yield studies between Nal‐BPD and Nal‐PpIX suggest that deep‐tissue PDT (>1 cm) is more effective when using Nal‐BPD. These findings indicate that Nal‐BPD‐PDT is more likely to generate cytotoxic effects deep within the brain and allow for the treatment of brain invading tumor cells centimeters away from the main, resectable tumor mass.