Ocular Drug Delivery and ADME Group
Ocular drug delivery is a limiting factor in the development of new medications to the treat diseases of the posterior eye segment. Research on delivery systems, test models and computational models opens avenues for improved ocular drug treatments. Our group has more than 20 years of experience in ocular drug delivery including: cell model development, drug discovery, drug formulation, kinetic modeling, and basic cell research of the eye. The research group is multidisciplinary including expertise in pharmaceutical sciences, molecular and cell biology, materials science, bio-organic chemistry, physical chemistry, and molecular modeling.
Retinal pigment epithelium (RPE) is the main component of the blood-retina barrier that regulates the access of drugs from blood circulation into the eye and vice versa. Currently, there is no established cell model for this important PK barrier. We established an immortalized human cell model cell model of RPE (1). This model shows fairly close values of epithelial permeability for a range of drugs and macromolecular probes. However, this model is also an immortalized cell line that may deviate from the normal RPE cells in human eye. For example, normal cells contain melanin granules and are highly pigmented. Therefore, we extended our research to human embryonic stem cells. In this model, cells are cultured and differentiated on porous polyimide membranes that are coated with extracellular matrices. We discovered ECM coatings and culture conditions that supported differentiation into a stem cell-derived RPE mimic (2). These cells are highly pigmented, they express many RPE-specific markers, they display proper barrier properties, and they phagocytose rod outer segments (the normal function of the RPE). This is a promising result that paves the way to realistic blood-retina barrier cell models and to RPE transplantations on biomaterial supports. The latter is a potential treatment in age-related macular degeneration.
We characterized an immortalized human corneal epithelium cell model (HCE) for ocular absorption studies. The physical barrier properties and the relevance of this cell model were established earlier. However, the efflux transporters and monocarboxylic acid transporters in the model showed different expression profiles compared to human corneal epithelium (3, 4). Universal expression analysis with DNA arrays (aaproximately 11,000 genes) was performed on HCE cell model and human corneal epithelium (5). The expression profiles were strikingly different demonstrating the power of systems biology approaches in the evaluation of ADME cell models and the limitations of the HCE model.
We have generated a series of baculovirus-infected insect cells for selective over-expression of efflux proteins MRP-2, MRP-4, MDR-1, and BCRP. The systems are used to investigate the efflux protein interactions of chemical libraries. The goal is to make QSPR models of these interactions. We performed experiments with MRP-2 overexpressing cells, and the modeling is under way. We have also demonstrated that various assays yield different conclusions on drug interactions with MRP-2 (6). Furthermore, we showed that the corneal epithelium and RPE (anterior and posterior ocular barriers) express MRP-1, MRP-4 and MRP-5 (3, 7). This profile is different from many other barriers. The PK importance of these transporters in the eye remains to be discovered.
Ocular ADME modeling is an important tool in understanding the relationships between molecular structure and PK properties in the eye. Along these lines, we have carried out modeling of all existing and curated data on corneal drug permeability (describes ocular absorption) and half-life in vitreous (describes elimination and distribution in the posterior eye segment). In both cases, we were able to generate a reliable model with only two chemical descriptors (8, 9). These models are useful tools in estimating the PK behavior of ocular compounds early in drug discovery.
Sub-conjunctival administration is an interesting alternative to more invasive intravitreal ocular injections, but yet this route is poorly understood. We built the first PK simulation model that includes all relevant parameters (elimination from subconjunctival site to blood and lymphatic flow, scleral permeability, choroidal elimination to blood flow, RPE permeability and vitreal elimination). The simulations show that, eventually, high molecular weight is beneficial for drug delivery. Large molecules are lost to blood flow slower than small compounds, and this factor is more important than the permeability advantage of small molecules (10). The model also provides insights on strategies for posterior segment drug delivery.
Selected Publications:
9. Kidron H, Del Amo E, Vellonen K.S., Urtti A: Prediction of the vitreal half-life of drug-like compounds. Pharm Res, in press
Arto Urtti, Ph.D, Professor
Professor Urtti has led the Centre for Drug Research (CDR) at the University of Helsinki since 2005. Professor Urtti’s has authored more than 220 peer-reviewed articles and 20 patents and patent applications.
Login to post comments
