Hydrogel implants for transscleral diffusion delivery of topotecan: In vivo proof of concept in a rabbit eye model

Hobzová, Radka; Kodetova, Martina; Pochop, Pavel; Uhlı́k, Jir̆ı́; Dunovská, Kateřina; Švojgr, Karel; Hraběta, Jan; Feriančiková, Barbara; Cocârță, Ana-Irina; Širc, Jakub

doi:10.1016/j.ijpharm.2021.120832

Cited by 10 publications

(12 citation statements)

References 31 publications

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“…The lens-shaped pHEMA and pEOEMA layers of the hydrogel implant were characterized by equilibrium swelling in water (38% for pHEMA and 2% for pEOEMA), weight in the swollen state (220 and 200 mg), and central thickness in the swollen state (1.8 and 0.8 mm). The details of these results are described elsewhere [ 40 ].…”

Section: Resultsmentioning

confidence: 99%

“…Preparation: The hydrogel implant is composed of two parts, an inner part made from pHEMA material and outer part of pEOEMA material, which were prepared separately and coupled together before implantation. Preparation of the individual implant parts and their characterization has previously been described in detail [ 40 ]. Briefly, the hydrogels were prepared by thermal radical crosslinking polymerization of a mixture of monomers of HEMA or EOEMA, the crosslinker EDMA (0.5 wt% relative to monomer), and initiator the AIBN (0.5 wt% relative to monomer and crosslinker).…”

Section: Methodsmentioning

confidence: 99%

“…Total TPT concentrations were determined by the HPLC-MS/MS method using an Agilent technologies 1290 Infinity II system, including an autosampler, binary pumps, and a thermostated column compartment with 6470 Triple Quad (Agilent technologies, Santa Clara, CA, USA). Processing of plasma and vitreous samples for HPLC-MS/MS analysis and details of the HPLC-MS/MS method are described elsewhere [ 40 ].…”

Section: Methodsmentioning

confidence: 99%

“…Measured TPT vitreous concentrations were normalized to eyeball volume, while TPT plasma levels were normalized to body weight. Non-detectable TPT levels (levels under the detection limit of 0.5 ng/mL [ 40 ]) were treated in the analysis as zero levels. The area under the TPT concentration–time curve from zero to infinity (AUC 0–∞ ) was calculated as AUC 0-last (up to the last measurable concentration) + AUC last–∞ (estimation from the last measured concentration to infinity).…”

Section: Methodsmentioning

confidence: 99%

“…Our implant is composed of two methacrylate-based layers: an inner hydrophilic drug reservoir made from poly(2-hydroxyethyl methacrylate) (pHEMA), which delivers low molecular weight hydrophilic drugs such as TPT, and an outer hydrophobic layer of poly(2-ethoxyethyl methacrylate) (pEOEMA), which is impermeable and thus suppresses the release of the drug into the surrounding vascularized tissue; the drug is almost exclusively released towards the sclera. In vitro properties and in vivo proof of concept in a rabbit eye model have been reported [ 38 , 39 , 40 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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A sensitive bioanalytical ultra‐high‐performance liquid chromatography‐tandem mass spectrometry method for the simultaneous quantitation of lactone and carboxylate forms of topotecan in plasma and vitreous

Mudrova,

Hrabakova,

Kozlik

et al. 2024

J of Separation Science

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Topotecan (TPT) is used in the treatment of retinoblastoma, the most common malignant intraocular tumor in children. TPT undergoes pH‐dependent hydrolysis of the lactone ring to the ring‐opened carboxylate form, with the lactone form showing antitumor activity. A selective, and highly sensitive ultra‐high‐performance liquid chromatography‐tandem mass spectrometry method was developed for the determination of both forms of TPT in one mobile phase composition in plasma and vitreous humor matrices. The method showed an excellent linear range of 0.375–120 ng/mL for the lactone. For the carboxylate, the linear range was from 0.75 to 120 ng/mL. The matrix effect and the recovery for the lactone ranged from 98.5% to 106.0% in both matrices, for the carboxylate form, it ranged from 94.9% to 101.2%. The dynamics of the transition between TPT lactone and TPT carboxylate were evaluated at different pH environments. The stability of TPT forms was assessed in plasma and vitreous humor at 8 and 37°C and a very fast conversion of lactone to carboxylate form occurred at 37°C in both matrices. The method developed facilitates the investigation of TPT pharmacodynamics and the release kinetics in the development of the innovative local drug delivery systems.

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Implantable sustained-release drug delivery systems: a revolution for ocular therapeutics

et al. 2023

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Hydrogel implants for transscleral diffusion delivery of topotecan: In vivo proof of concept in a rabbit eye model

Cited by 10 publications

References 31 publications

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

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

A sensitive bioanalytical ultra‐high‐performance liquid chromatography‐tandem mass spectrometry method for the simultaneous quantitation of lactone and carboxylate forms of topotecan in plasma and vitreous

Implantable sustained-release drug delivery systems: a revolution for ocular therapeutics

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