“Dosimetric optimization of interstitial gene therapy delivery systems”

摘要

We are developing a novel method for localized gene therapy based on small implantable capsules (GeneSeeds) containing a biological payload. This payload can create a strong local transfection of nearby cells and avoid the problems involved with systemic administration of gene therapy. Numerous different payloads are possible, including direct cytotoxic agents, compounds which inhibit cellular repair mechanisms, or drugs which enhance injury recovery. In order to better understand the dosimetry of the GeneSeed, we are pursuing theoretical, computational, and experimental imaging studies. The basic GeneSeed structure is a titanium cylinder similar in size and shape to a brachytherapy seed, with openings at both ends to allow the payload to diffuse out into the surrounding tissue. By creating holes along the wall of the cylinder, the diffusion of the vector proceeds more quickly and can be made more isotropic. However, the addition of holes to the cylinder also has the negative effect of making the cylinder structurally weaker. Thus, the proper GeneSeed design needs to balance these opposing properties. For simulation of diffusion, we have investigated both a Monte Carlo particle diffusion model and a simple computational fluid dynamics (CFD) model. For the Monte Carlo model, the gene vector payload is treated as an ensemble of particles, each of which moves along a random walk per unit time. Variance reduction methods are used to screen out impossible paths, such as those which pass through the impervious metal of the cylinder. In the CFD model, the GeneSeed and the surrounding tissues are divided into small volume elements and the transport of the payload is calculated according to Fick's law. For simplicity, the initial studies have been two-dimensional since this enables us to determine the general behavior of the GeneSeed with less computation time. Where possible, in vivo studies measuring transfection rates have been used to scale our results and provide an ex-nperimental check on our simulation methodology. To determine structural strength for the GeneSeed, we have employed basic mechanical engineering methods as well as limited finite element analysis. Although the addition of small holes in the cylinder does weaken the overall structure, the expected loads from insertion of the GeneSeed into soft tissue are relatively small. Thus, we have concluded from our study that the dosimetry of the GeneSeed can be significantly enhanced by changes to the cylindrical capsule without having an adverse effect on usability or patient safety. These results will help us to design and manufacture the best possible GeneSeed for use in early stage clinical trials.