We are interested in two research topics. One is the interstitial transport of macromolecules in solid tumors; another is morphogenesis of microvascular networks in biological tissues.

Drug and gene delivery in solid tumors has become an important concern with the advances in molecular medicine. One of the major problems in both systemic and local delivery of large therapeutic agents is the interstitial transport. The problem is attributed to several unique features in tumor tissues. First, convective transport is low due to uniformly elevated interstitial fluid pressure (IFP) and the lack of functional lymphatics. Second, there exists an outward IFP gradient in the periphery of tumors, causing a convective transport of extravasated therapeutic agents from tumor interior to surrounding host tissues. Third, the diffusion distance can be large in some regions of tumors, due to heterogeneous blood supply and heterogeneous extravasation of drugs and genes. Fourth, therapeutic agents may specifically or nonspecifically bind to plasma membrane of cells and extracellular matrix. Fifth, therapeutic agents may be inactivated in the interstitial space before reaching their targets. The features listed here may significantly hinder interstitial penetration of drugs and genes, limit the accessibility of these therapeutic agents to intracellular targets, and thus reduce the efficacy of molecular medicines in cancer treatment.

Drug and gene delivery in the interstitial space is governed by driving forces and transport parameters such as the diffusion coefficient, the hydraulic conductivity, the retardation coefficient, and the available volume fraction. These parameters depend on physicochemical properties of drugs and genes (e.g., size, charge, and configuration) as well as structures of tumor tissues.

We are interested in quantitative analysis of interstitial transport of macromolecules in normal and tumor tissues as well as physical and chemical interventions of the interstitial transport for improving drug and gene delivery. Current projects in our lab are as follows.

Drug and gene delivery in tumor tissues is likely to be governed by the same principles as those for transport in porous media. We are interested in general mechanisms of transport for macromolecules in porous materials. One of our research focuses is to investigate how structures of available pores affect interstitial transport of drugs and genes in solid tumors. The volume fraction of available pores (K_AV) depends on physicochemical properties of therapeutic agents, volume fraction of cells, as well as structure and composition of extracellular matrix. We are interested in quantifying these dependences in different tumor tissues and understanding mechanisms of these dependences at molecular and cellular levels. We are also interested in improving drug and gene delivery in solid tumors through increasing K_AV, based on both physical and chemical interventions.

Interstitial transport of large therapeutic agents is one of the major obstacles for drug and gene delivery in solid tumors. These agents accumulate only in perivascular regions during systemic delivery or in the vicinity of implanted devices during local delivery. To enhance the interstitial penetration, we are investigating mechanisms of direct infusion of therapeutic agents into solid tumors. Intratumoral infusion may improve interstitial transport of macromolecules and nanoparticles through two distinct mechanisms: (a) establishing a driving force for convective transport and (b) increasing the size and the connectedness of pores in the interstitial space. Intratumoral infusion has shown promising results in the treatment of nonresectable tumors in the brain and the pancreas. The goal of our study is to identify optimal infusion conditions for improving drug and gene delivery. These conditions are likely to be tumor-dependent. Therefore, we are interested in quantitative analysis of the hydraulic conductivity (K) and the distribution volume of macromolecules (V_d) in tumor tissues. In addition, we are interested in the dependences of K and V_d on tissue compositions and structures as well as infusion-induced tissue deformation.

Gene delivery is one of the major obstacles for gene-based treatment of diseases. Delivery of genes depends on design and construction of specific carriers, transport of genes and carriers in both extracellular and intracellular spaces, and transport of genes into the nucleus of cells. Carriers for gene delivery can, in general, be divided into three categories: viral vectors, synthetic systems, and genetically engineered cells. Our research is focused on delivery of plasmid DNA using electrical methods. The advantage of electric field-mediated gene transfer is several-fold. First, it is less dependent on cell types. Second, it facilitates both interstitial and intracellular transport of genes. Third, it allows nucleic acids to bypass the endocytosis pathways and thus avoids the entrapment problem in receptor-mediated internalization of DNA. We are interested in understanding mechanisms of DNA transport in both extracellular and intracellular spaces and effects of electric fields on DNA transport. Results from these study will be used to optimize electric field-mediated gene delivery.

Liposome has been used as a carrier for drug and gene delivery. Liposome can significantly change whole body distribution of drugs and genes, preferentially deliver therapeutic agents to solid tumors, facilitate gene transfer into cells, and allow controlled release of encapsulated drugs in specific tissues. We are interested in quantitative analysis of drug and liposome transport in tumor tissues, mechanisms of drug release from temperature sensitive liposomes, and effects of drugs on both tumor and stroma cells in vivo. Results from these studies will be used to optimize liposomal drug delivery.

Angiogenesis is the formation of new blood vessels from preexisting ones. It plays an important role in embryonic development, wound healing, tumor growth, and various vascular diseases. Angiogenesis needs to be either inhibited or stimulated in a controlled manner, depending on the requirements in disease treatment. Angiogenesis is a complicated process. It involves angiogenic factors, inhibitors, and regulators released by different cells (e.g., tumor cells and macrophages). These molecules interact with endothelial and mesenchymal cells as well as extracellular matrix in tissues. Multiple interactions may happen simultaneously and nonlinearly; and all interactions must be coordinated in a specific manner in order to form a vascular network. We are interested in molecular mechanisms of morphogenesis of vascular networks during angiogenesis. Our study is based on both experimental studies and numerical simulations. In addition, we are interested in how different angiogenic factors, inhibitors, and regulators affect the structures of vascular networks.