Photodynamic therapy (PDT) is intrinsically restricted by the low penetration depth of light in tissue and is therefore mostly used to treat superficial or optical-fiber accessible lesions. An elegant non-invasive approach to overcome this limitation is to conjugate the photosensitizers to radioluminescent nanomaterials, also called nanoscintillators, and to activate these with radiation therapy. Upon X-ray irradiation, nanoscintillators are “switched on” and emit light that can subsequently excite the photosensitizer and induce PDT. As X-rays penetrate deeply in tissues, radioluminescence can activate PDT non-invasively at depth and without being restricted by large tumor volumes and optical shielding by blood vessels. The feasibility of exciting photosensitizers using nanoscintillators has been demonstrated, but the effects of this complex concept may stem from several therapeutic contributions that remain under-investigated. In this presentation, we report on the investigation of two confirmed contributions: 1) a potential synergy between low dose PDT and radiation therapy, and 2) a radiation dose enhancement effect stemming from increased radiation absorption by nanoscintillators composed of high-Z elements. The combination between low dose PDT and radiation therapy was assessed on heterocellular spheroid models of pancreatic cancer. The ability of nanoscintillators to induce radiation dose enhancement was experimentally assessed on 3D models of glioma, using synchrotron radiation to deliver radiation therapy. For this research, synchrotron radiation offers the unique opportunity to monochromatize the beam and tune its energy to an optimal value.
Drug resistance to conventional therapies remains a major cause of treatment failure, tumor recurrence and dismal survival rates for patients with advanced stage cancers. Photodynamic therapy (PDT) provides an opportunity to exploit photochemically-triggered death mechanisms via targeting of sub-cellular, cellular and stromal compartments to overcome treatment resistance in unresponsive populations of stubborn disease. The informed design of mechanism-based combinations is emerging as increasingly important to targeting resistance and improving the efficacy of conventional treatments, while minimizing toxicity. PDT has been shown to synergize with conventional agents and to overcome the evasion pathways that cause resistance. Increasing evidence shows that PDT-based combinations cooperate mechanistically with, and improve the therapeutic index of, traditional chemotherapies. These and other findings emphasize the importance of including PDT as part of comprehensive treatment plans for cancer, particularly in complex disease sites. Identifying effective combinations requires a multi-faceted approach that includes the development of bioengineered cancer models and corresponding image analysis tools. The presentation will focus on the molecular and phenotypic basis of verteporfin PDT-based enhancement of chemotherapeutic efficacy and predictability in complex 3D models and in vivo models, with a particular emphasis on ovarian and pancreatic cancer.
Targeting the molecular and cellular cues that influence treatment resistance in tumors is critical to effectively treating unresponsive populations of stubborn disease. The informed design of mechanism-based combinations is emerging as increasingly important to targeting resistance and improving the efficacy of conventional treatments, while minimizing toxicity. Photodynamic therapy (PDT) has been shown to synergize with conventional agents and to overcome the evasion pathways that cause resistance. Increasing evidence shows that PDT-based combinations cooperate mechanistically with, and improve the therapeutic index of, traditional chemotherapies. These and other findings emphasize the importance of including PDT as part of comprehensive treatment plans for cancer, particularly in complex disease sites. Identifying effective combinations requires a multi-faceted approach that includes the development of bioengineered cancer models and corresponding image analysis tools. The molecular and phenotypic basis of verteporfin-mediated PDT-based enhancement of chemotherapeutic efficacy and predictability in complex 3D models for ovarian cancer will be presented.
Nanocarriers, such as liposomes, have the ability to potentiate photodynamic therapy (PDT) treatment regimens by the encapsulation of high payloads of photosensitizers and enhance their passive delivery to tumors through the enhanced permeability and retention effect. By conjugating targeting moieties to the surface of the liposomal nanoconstructs, cellular selectivity is imparted on them and PDT-based therapies can be performed with significantly higher dose tolerances, as off-target toxicity is simultaneously reduced.1 However, the maximal benefits of conventional targeted nanocarriers, including liposomes, are hindered by practical limitations including chemical instability, non-selective conjugation chemistry, poor control over ligand orientation, and loss of ligand functionality following conjugation, amongst others.2
We have developed a robust, physically and chemically stable liposomal nanoplatform containing benzoporphyrin derivative photosensitizer molecules within the phospholipid bilayer and an optimized surface density of strained cyclooctyne moieties for ‘click’ conjugation to azido-functionalized antibodies.3 The clinical chimeric anti-EGFR antibody Cetuximab is site-specifically photocrosslinked to a recombinant bioengineered that recognizes the antibody’s Fc region, containing a terminal azide.4 The copper-free click conjugation of the bioengineered Cetuximab derivative to the optimized photosensitizing liposome provides exceptional control over the antibody’s optimal orientation for cellular antigen binding. Importantly, the reaction occurs rapidly under physiological conditions, bioorthogonally (selectively in the presence of other biomolecules) and without the need for toxic copper catalysis.3 Such state-of-the-art conjugation strategies push the boundaries of targeted photodynamic therapy beyond the limitations of traditional chemical coupling techniques to produce more robust and effective targeted therapeutics with applications beyond conventional treatments.
A major barrier to treating advanced-stage cancers is heterogeneity in the responsiveness of metastatic disease to conventional therapies leading to resistance and treatment failure. Photodynamic therapy (PDT) has been shown to synergize with conventional agents and to overcome the evasion pathways that cause resistance. Developing PDT-based combinations that target resistant tumor populations and cooperate mechanistically with conventional agents is an increasingly promising approach to improve therapeutic efficacy while minimizing toxicity, particularly in complex disease sites. Identifying the molecular, cellular, and microenvironmental cues that lead to heterogeneity and treatment resistance is critical to developing strategies to target unresponsive regions of stubborn disease. Cell-based research platforms that integrate key microenvironmental cues are emerging as increasingly important tools to improve the translational efficiency of new agents, and to design combination regimens. Among the challenges associated with developing and scaling complex cell-based screening platforms is the need to integrate, and balance, biological relevance with appropriate, high-content imaging routines that provide meaningful quantitative readouts of therapeutic response. The benefits and challenges associated with deriving meaningful insights from complex cell-based models will be presented, with a particular emphasis on overcoming chemoresistance mediated by physical stress and communication with stromal partners (e.g. tumor endothelial cells, which are emerging as dynamic regulators of treatment resistance) using PDT-based combinations.
Conference Committee Involvement (1)
17th International Photodynamic Association World Congress
28 June 2019 | Cambridge, Massachusetts, United States
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