The Role of Cryotherapy in Vitreous Concentrations of Topotecan Delivered by Episcleral Hydrogel Implant

Abstract

Transscleral diffusion delivery of chemotherapy is a promising way to reach the vitreal seeds of retinoblastoma, the most common intraocular malignancy in childhood. In this in vivo study, the delivery of topotecan via lens-shaped, bi-layered hydrogel implants was combined with transconjunctival cryotherapy to assess whether cryotherapy leads to higher concentrations of topotecan in the vitreous. The study included 18 New Zealand albino rabbits; nine rabbits received a topotecan-loaded implant episclerally and another nine rabbits received transconjunctival cryotherapy superotemporally 2 weeks before implant administration. Median vitreous total topotecan exposures (area under the curve, AUC) were 455 ng·h/mL for the cryotherapy group and 281 ng·h/mL for the non-cryotherapy group, and were significantly higher in the cryotherapy group, similar to maximum levels. Median plasma AUC were 50 ng·h/mL and 34 ng·h/mL for the cryotherapy and non-cryotherapy groups, respectively, with no statistically significant differences between them. In both groups, AUC values in the vitreous were significantly higher than in plasma, with plasma exposure at only approximately 11–12% of the level of vitreous exposure. The results confirmed the important role of the choroidal vessels in the pharmacokinetics of topotecan during transscleral administration and showed a positive effect of cryotherapy on intravitreal penetration, resulting in a significantly higher total exposure in the vitreous.

Multilayered Polyurethane/Poly(vinyl alcohol) Nanofibrous Mats for Local Topotecan Delivery as a Potential Retinoblastoma Treatment

“…In vitro biological experiments on cell lines proved prolonged biological activity and confirmed the premise of using PUR-PVA-PUR constructs as a TPT delivery system. Compared with the hydrogel system for periocular delivery presented in our previous work [ 46 , 50 , 57 ], this system has several advantages: (i) TPT is preserved in its active lactone form; (ii) TPT release can be controlled by inactive PUR covering layers; (iii) TPT is incorporated into the DDS during the implant production, allowing for easier implant preparation prior to in vivo application. Compared with another DDS system in the form of compressed polycaprolactone tablets [ 45 ], nanofibrous mats provide a convenient and versatile design feasible for periocular implantation with a tight fit to the eyeball.…”

Multidisciplinary Approaches in the Treatment of Retinal Degenerative Diseases: A Review

“…[12,13] In addition, intravitreal injections are considered quite invasive, and frequent injections owing to the short retention time have shown to be associated with endophthalmitis, vitreous hemorrhage, retinal detachment, and poor patient tolerance. [14][15][16] Consequently, it is essential to make efforts to ameliorate intraocular delivery systems using multidisciplinary strategies to improve bioavailability and reduce complications.…”

“…Previous studies have proposed periocular implants as a less-invasive way to deliver drugs for better treatment compliance. [14,29] Implants can be placed outside the eyeball (e.g., subconjunctival, subtendon, or peribulbar) without requiring complicated procedures. However, as traditional periocular implant devices must be replaced once they run out, self-sustainable approaches have been reported in recent studies.…”

Therapy for Vitreous Seeding Caused by Retinoblastoma. A Review

“…Oproti systémovému podání karboplatiny bylo u pacientů s Rb periokulárním podáním dosaženo 10krát vyšších koncentrací v oku při zanedbatelných hladinách cytostatika v krvi [50,51]. Mnoho vědeckých skupin se snažilo o lokální podání CHT (karboplatina, topotekan) periokulárně v různých formách, a to podáním CHT v depotním gelu [52], solidním polymeru [53][54][55], systémem iontoforézy [56] či miniaturním katétrem umístěným na skléru [51]. Ke kompletní regresi seedingu však došlo zřídka, a přestože bylo dosaženo minimální systémové toxicity, často byly zaznamenány lokální nežádoucí účinky včetně orbitální pseudocelulitidy až v 50 % případů, atrofii optiku a jizvení v periorbitální oblasti [57].…”

“…Ke kompletní regresi seedingu však došlo zřídka, a přestože bylo dosaženo minimální systémové toxicity, často byly zaznamenány lokální nežádoucí účinky včetně orbitální pseudocelulitidy až v 50 % případů, atrofii optiku a jizvení v periorbitální oblasti [57]. V našich in vivo experimentech podání topotekanu králičímu modelu episklerálně pomocí dvouvrstvého hydrogelového nosiče tyto lokální vedlejší účinky nebyly zaznamenány [54,55]. V současné době probíhá v Kanadě I. fáze klinické studie nového episklerálního nosiče s topotekanem nazvaným "Chemoplaque" [58].…”