Abstract
Light is known to excite photosensitizers (PS) to produce cytotoxic reactive oxygen species (ROS) in the presence of oxygen. This modality is attractive for designing control measures against animal diseases and pests. Many PS have a proven safety record. Also, the ROS cytotoxicity selects no resistant mutants, unlike other drugs and pesticides. Photodynamic therapy (PDT) refers to the use of PS as light activable tumoricides, microbicides and pesticides in medicine and agriculture.Here we describe “photodynamic vaccination” (PDV) that uses PDT-inactivation of parasites, i.e. Leishmania as whole-cell vaccines against leishmaniasis, and as a universal carrier to deliver transgenic add-on vaccines against other infectious and malignant diseases. The efficacy of Leishmania for vaccine delivery makes use of their inherent attributes to parasitize antigen (vaccine)-presenting cells. Inactivation of Leishmania by PDT provides safety for their use. This is accomplished in two different ways: (i) chemical engineering of PS to enhance their uptake, e.g. Si-phthalocyanines; and (ii) transgenic approach to render Leishmania inducible for porphyrinogenesis. Three different schemes of Leishmania-based PDV are presented diagrammatically to depict the cellular events resulting in cell-mediated immunity, as seen experimentally against leishmaniasis and Leishmania-delivered antigen in vitro and in vivo. Safety versus efficacy evaluations are under way for PDT-inactivated Leishmania, including those further processed to facilitate their storage and transport. Leishmania transfected to express cancer and viral vaccine candidates are being prepared accordingly for experimental trials.We have begun to examine PS-mediated photodynamic insecticides (PDI). Mosquito cells take up rose bengal/cyanosine, rendering them light-sensitive to undergo disintegration in vitro, thereby providing a cellular basis for the larvicidal activity seen by the same treatments. Ineffectiveness of phthalocyanines and porphyrins for PDI underscores its requirement for different PS. Differential uptake of PS by insect versus other cells to account for this difference is under study.The ongoing work is patterned after the one-world approach by enlisting the participation of experts in medicinal chemistry, cell/molecular biology, immunology, parasitology, entomology, cancer research, tropical medicine and veterinary medicine. The availability of multidisciplinary expertise is indispensable for implementation of the necessary studies to move the project toward product development.
Highlights
Photosensitizers (PS) These are ring compounds whose soluble form is lightexcitable to produce cytotoxic reactive oxygen species (ROS) [1]
Scheme 2 is similar to Scheme 1, except that the uroporphyrinogenic Leishmania are doubly pre-PS-sensitized for the 1st Photodynamic therapy (PDT) step with ALA for uroporphyrin I (URO) accumulation in the cytosol and Si-PC for uptake into endosomes [11, 12]
Proliferation of CFSE-labeled lymphocytes was assayed flow cytometrically, providing the results briefly described in the text; [3D in vivo]: Female BLAB/c mice (~30 g) were immunized exactly as described for [2D in vivo], except that doubly PS-sensitized Leishmania were used
Summary
Photosensitizers (PS) These are ring compounds whose soluble form is lightexcitable to produce cytotoxic reactive oxygen species (ROS) [1]. The evolution of Leishmania for intra-antigen-presenting cells (APC) parasitism and their sensitivity to PDT via PS accumulation are exploited for developing strategies to optimize the efficacy and safety of PDV. We exploit PDT as a new modality of Leishmania inactivation for assessing the safety and efficacy of their use for vaccination.
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