Episcleral Implants for Topotecan Delivery to the Posterior Segment of the Eye

Abstract

Purpose. Intravenous or periocular topotecan has been proposed as new treatment modality for patients with advanced intraocular retinoblastoma, but systemic topotecan lactone exposure induced by both approaches may cause toxicity. The purpose of this study was to develop a topotecan-loaded ocular delivery system to minimize systemic exposure and achieve selective transscleral penetration. Methods. Biocompatible polymer implants containing low (0.3 mg) or high (2.3 mg) topotecan load were manufactured and characterized in vitro. Adrenaline (500 mug) was coloaded to induce local vasoconstriction in vivo in 2 of 4 animal groups. Implants were inserted into the episclera of rabbits, and topotecan (lactone and total) concentrations in ocular tissues and plasma were determined over a period of 48 hours. Results. In vitro, implants released 30% to 50% of the loaded drug within 48 hours and 45% to 70% by day 10. In vivo, topotecan lactone was highly accumulated in locally exposed ocular tissues (ranging from 10(5) to 10(6) ng/g in sclera and choroid and 10(2) to10(3) ng/g in retina) over 48 hours with all the formulations studied. Low vitreous topotecan lactone levels (approximately 5 ng/mL) were found in animals receiving concomitant local vasoconstriction and high load implants. Topotecan lactone concentrations in plasma and in contralateral eyes were minimal or undetectable as a marker of tissue selectivity of the proposed strategy. Conclusions. These studies may contribute to improving the efficacy and safety of chemotherapy treatments for retinoblastoma and may support the role of the local vasculature and tissues promoting drug clearance and local accumulation during transscleral drug delivery.

Retinoblastoma

“…A few translational studies have resulted in changes in retinoblastoma clinical practice. 203 Innovative delivery systems to target small-volume subretinal tumours and vitreous seeding include episcleral implants 204 and nanoparticles 205 . Approaches adjusting chemotherapy schedules and dose intensity (metronomic therapy) 206 may particularly play an important role in palliative care for retinoblastoma.…”

Efficacy of methotrexate-loaded poly(ε-caprolactone) implants in Ehrlich solid tumor-bearing mice

“…This cascade of events presents an unregulated pattern that can induce cell lesion and necrosis. The efficacy of MTX-loaded PCL implants in decreasing necrosis and growth of the Ehrlich solid tumor on mice paw was attributed to the following reasons: (1) The biphasic pattern of release of the MTX from the implants contributed to the inhibition of the tumor growth, because higher local concentration of the drug can be immediately achieved, as an attack dose; and the long-lasting release of MTX at a slower rate might be important in recruiting more tumor cells at the S-phase of the cycle (Carcaboso et al, 2010). It was previously mentioned that MTX induces a strong S-phase block, and this alteration in tumor cell cycle provides its antitumor activity.…”

“…These thermal properties were capitalized to fabricate drug delivery systems by means of processes such as melt molding (Ayres et al, 2007), extrusion (Bourges et al, 2006) without risking neither the polymer nor the drug molecular integrity due to an aggressive heating treatment (Sprockel et al, 1997;Lemmouchi et al, 1998;Carcaboso et al, 2010). Recently, the pharmaceutical companies have adopted the injection molding as a technique for designing polymeric drug delivery systems, due to the possibility to manufacture in large scale (Altpeter et al, 2004).…”

“…For example, the melt-molding compression technique has been applied to manufacture topotecanloaded PCL implants. These episcleral implants contributed to understand the active role of the ocular tissues, sclera and choroid in the clearance of topotecan during its transient path toward the intraocular compartments (Carcaboso et al, 2010). Hydrophilic 5-fluorouracil (Hou et al, 2011) and bis(maltolato)oxovanadium (Jackson et al, 1997) loaded PCL implantable devices were fabricated by melt molding compression technique and injection molding techniques, respectively.…”

Aplicaciones de la tecnología de radiación de microondas en la síntesis de biomateriales

“…(-60°C) y la T m no suele superar 60-65°C, por lo que se pueden producir implantes empleando procesos poco drásticos tales como el moldeo en estado fundido y la compresión, sin comprometer la estabilidad química del fármaco encapsulado y del polímero [61,62].…”