Periocular injection of microspheres containing PKC412 inhibits choroidal neovascularization in a porcine model.
OBJECTIVE
Oral administration of PKC412, a kinase inhibitor that blocks several isoforms of protein kinase C (PKC) and receptors for vascular endothelial growth factor (VEGF), platelet-derived growth factor, and stem cell factor, inhibits ocular neovascularization in a murine model. The purpose of this study was to determine whether sustained local delivery of PKC412 in a human-sized eye inhibits choroidal neovascularization (CNV).


METHODS
Laser photocoagulation was used to rupture Bruch's membrane in young domestic pigs, and then a periocular injection of control microspheres or microspheres containing 25% or 50% PKC412 was given. After 10 days the integrated area of CNV at Bruch's membrane rupture sites was measured by image analysis. The levels of PKC412 in choroid, retina, and vitreous were measured either 10 or 20 days after periocular injection of 50% PKC microspheres or at 20 days after injection of 25% PKC412 microspheres.


RESULTS
The areas of CNV at Bruch's membrane rupture sites were significantly smaller in eyes that received a periocular injection of microspheres containing 25% (P=0.0042) or 50% (P=0.0012) PKC412 than those in eyes injected with control microspheres. Ten days after periocular injection of 50% PKC412 microspheres, PKC412 was detected in the choroid, but not in the retina or vitreous. Twenty days after periocular injection of 50% PKC412, high levels of PKC412 were measured in the choroid, vitreous, and retina. Levels were lower but still substantial in all three compartments 20 days after periocular injection of 25% microspheres.


CONCLUSIONS
Sustained local delivery of PKC412 provides a promising approach for treatment of CNV.
Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA.
Yoshitsugu
Y
Saishin
Raquel Lima
RL
Silva
Yumiko
Y
Saishin
Kevin
K
Callahan
Christian
C
Schoch
Markus
M
Ahlheim
Hong
H
Lai
Frances
F
Kane
R K
RK
Brazzell
David
D
Bodmer
Peter A
PA
Campochiaro
D000818:Animals; D001672:Biocompatible Materials; D001682:Biological Availability; D016570:Bruch Membrane / Q000601:surgery; D002829:Choroid / Q000378:metabolism; D020256:Choroidal Neovascularization / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004337:Drug Carriers; D005260:Female; D007267:Injections / Q000379:methods; D019344:Lactic Acid; D017075:Laser Coagulation; D008863:Microspheres; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D012160:Retina / Q000378:metabolism; D019311:Staurosporine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D013552:Swine; D014822:Vitreous Body / Q000378:metabolism
D001672:Biocompatible Materials; D004337:Drug Carriers; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011493:Protein Kinase C; D019311:Staurosporine; C059539:midostaurin