Photo-induced release of liposome-encapsulated molecules
Randles, Edward Graham
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Many therapeutic molecules have severe side effects, poor bioavailability or have a narrow temporal window in which they are most effective. Liposomes offer a method to encapsulate high concentrations of a drug, protecting it upon in vivo administration. With an appropriate mechanism to manipulate lipid bilayer permeability, liposomes can deliver encapsulated drugs in a spatially and temporally controlled manner. Tissue penetrating wavelengths of light could trigger the release of liposome-encapsulated molecules. However, the photonic energy at these wavelengths is insufficient to power many photochemical reactions. The aim of this research was to develop a photochemical mechanism that uses such wavelengths to initiate the release of liposome-encapsulated molecules. It was proposed that aluminum phthalocyanine disulfonic acids (AIPcS2) adsorbs to lipid bilayers, and produces singlet oxygen 1O2) via photodynamic action (PDA) in response to red light. The 1O2 then reacts with unsaturated acyl chains of phospholipids, leading to increased lipid bilayer permeability. The release of liposome-encapsulated molecules was experimentally modeled using detergents. By measuring the thermodynamics of detergent binding and liposome size increase, a model of lipid bilayer permeabilization was established. A mathematical model of release using principles from random walk diffusion theory was developed from the experimental data. The adsorption of AIPcS2 to liposomes was measured and followed a Frumkin isotherm due to a repulsive force between photosensitizer molecules. Using reaction field theory, the location of the photosensitizer in the lipid bilayer was also predicted. Anisotropy data suggest that AIPcS2 interacts with the phospholipid to increase lipid bilayer stability. The presence of AIPcS2 also lowered background liposome leakage due to an electrostatic repulsion of the encapsulated material. This results in a more stable liposome system that contained a higher dose of the encapsulated material for longer. Irradiation of the AIPcS2-liposome system with tissue penetrating red light increased lipid bilayer permeability ten-fold over the baseline carboxyfluorescein flux. The release was a singlet oxygen mediated process, due to the type II PDA of AIPcS2. This activity provides a novel photochemical mechanism for liposome mediated drug delivery and increases temporal control of release.
Thesis (Ph.D.)--Boston University