Delivery of antiangiogenic and antioxidant drugs of ophthalmic interest through a nanoporous inorganic filter.
OBJECTIVE
We propose a novel method of administration of antiangiogenic and antioxidant drugs, with potential clinical application in the treatment of proliferative diabetic retinopathy (PDR) and age-related macular degeneration (AMD). We suggest the encapsulation of drugs in implantable sustained release devices, limited by membranes with pores in the tens of nanometers diameter range, which display a slower, quasi-linear release kinetics, and a better selectivity than other membranes. In this paper we explored the feasibility of this approach by testing in vitro several key elements of the nanofilter system: diffusion of drugs of interest, efficacy in producing desirable effects on cells, and biocompatibility of used material with some of the cells encountered in the ocular cavity.


METHODS
We used an aluminum oxide filter (Anopore) with pores of 20 nm as a limiting medium for the administration of drugs. First, we induced an oxidative stress in human retinal endothelial cells (HREC) by treating them with hydrogen peroxide diffused across the filter, in the absence or in the presence of catalase. HREC attached to the culture plate, or emerging as angiogenic sprouts from aggregates embedded in collagen gels, were also exposed to vitamin C or to endostatin delivered across the nanoporous filter. Direct exposure of the cells to the agents served as positive controls. Growth of cells on the filter was considered an indication for biocompatibility.


RESULTS
Catalase diffused across the nanoporous membrane counteracted the cytotoxic effect of hydrogen peroxide on HREC. We also found that vitamin C, acting directly or after diffusion across the filter, up to concentrations physiologically present in the eye, was a concentration dependent modulator of HREC's ability to survive and sprout. Additionally, we confirmed the ability of endostatin to block the growth of HREC either attached or sprouting from cell aggregates, after diffusion across the Anopore nanofilter.


CONCLUSIONS
The drug delivery method based on the administration of angiostatic and antioxidant agents across the inorganic aluminum oxide nanoporous filter passed the key in vitro tests for diffusibility and biocompatibility, opening the way for medical applications.
Orosz
Kathleen E
KE
Division of Ophthalmology, Ohio State University, Columbus, OH 43210, USA.
Gupta
Somil
S
Hassink
Marla
M
Abdel-Rahman
Mohamed
M
Moldovan
Leni
L
Davidorf
Frederick H
FH
Moldovan
Nicanor I
NI
D000537:Aluminum Oxide; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000975:Antioxidants / Q000008:administration & dosage*; D001205:Ascorbic Acid / Q000008:administration & dosage*; D001672:Biocompatible Materials; D002374:Catalase / Q000008:administration & dosage; D002460:Cell Line; D002470:Cell Survival; D016503:Drug Delivery Systems; D043169:Endostatins / Q000008:administration & dosage*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D008851:Micropore Filters; D036103:Nanotechnology; D018384:Oxidative Stress / Q000187:drug effects; D016062:Porosity; D012171:Retinal Vessels / Q000166:cytology / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D000975:Antioxidants; D001672:Biocompatible Materials; D043169:Endostatins; D006861:Hydrogen Peroxide; D002374:Catalase; D000537:Aluminum Oxide; D001205:Ascorbic Acid