Topotecan Periocular Delivery for Retinoblastoma Chemotherapy

Abstract

 

Purpose:

 

To study topotecan (TPT) access to the vitreous when administeredby periocular injection (p.o.i.) as compared to intravenous(i.v.) infusion. To design biodegradable implants suitable fortransscleral delivery of TPT for retinoblastoma chemotherapy.

 

Methods:

 

21 rabbits received 1 mg TPT by p.o.i. and 14 rabbits by i.v.infusion. TPT-loaded polycaprolactone implants (0.25 mg TPTin 120 mg total weight), coated in the side not facing the sclera,were obtained by a melt-molding method.

 

Results:

 

The figure displays vitreous levels of total (triangles) andactive lactone (circles) TPT in treated (A) and contralateral(B) eyes after p.o.i. administration and after i.v. infusion(C). Similar vitreous lactone exposures were found, as indicatedby the area under the curve (AUC_{treated p.o.} = 34.0 ±3.9; AUC_{control p.o.} = 35.3 ± 4.0; AUC_i.v. = 36.4 ±4.1 ng×h/mL).Thesystemic absorption from the periocular depot led to high TPTplasma exposures (AUC_p.o. = 339 ± 10; AUC_i.v. = 338 ±10 ng×h/mL).Implants (D) released near 100 % TPT in vitro in7 days (E). Most interestingly, the rapid hydrolysis of TPTto inactive carboxylate at pH 7.4 was avoided and the activelactone form was preferentially released throughout the study. 

 

Conclusions:

 

Our results show that after periocular injection of TPT systemicabsorption accounts for most of its vitreous delivery. The needfor a preferentially transscleral delivery was evidenced anda candidate system was designed. 

 

Keywords: retinoblastoma • vitreous