Development of Chitosan and Polylactic Acid Based Methotrexate Intravitreal Micro-Implants to Treat Primary Intraocular Lymphoma: An In Vitro Study

Abstract

Primary intraocular lymphoma (PIOL) is an uncommon but clinically and pathologically distinct form of non-Hodgkin's lymphoma. It provides a therapeutic challenge because of its diverse clinical presentations and variable clinical course. Currently available treatments for PIOL include intravenous multiple drug chemotherapy, external beam radiation therapy, and intravitreal methotrexate (MTX) injection. Each intravitreal injection of MTX is associated with potentially toxic peaks and subtherapeutic troughs of intraocular MTX concentration. Repetitive injections are required to maintain therapeutic levels of MTX in the eye. A sustained release drug delivery system is desired for optimized therapeutic release (0.2-2.0 μg/day) of MTX for over a period of 1 month to achieve effective treatment of PIOL. This study reports development of a unique intravitreal micro-implant, which administers therapeutic release of MTX over a period of 1 month. Chitosan (CS) and polylactic acid (PLA) based micro-implants are fabricated for different MTX loadings (10%, 25%, and 40% w/w). First, CS and MTX mixtures are prepared for different drug loadings, and lyophilized in Tygon® tubing to obtain CS-MTX fibers. The fibers are then cut into desired micro-implant lengths and dip coated in PLA for a hydrophobic surface coating. The micro-implant is characterized using optical microscopy, scanning electron microscopy (SEM), time of flight-secondary ion mass spectroscopy (ToF-SIMS), and differential scanning calorimetry (DSC) techniques. The release rate studies are carried out using a UV-visible spectrophotometer. The total release durations for 10%, 25%, and 40% w/w uncoated CS-MTX micro-implants are only 19, 29, and 32 h, respectively. However, the therapeutic release durations for 10%, 25%, and 40% w/w PLA coated CS-MTX micro-implants significantly improved to 58, 74, and 66 days, respectively. Thus, the PLA coated CS-MTX micro-implants are able to administer therapeutic release of MTX for more than 50 days. The release kinetics of MTX from the coated micro-implants is explained by (a) the Korsmeyer-Peppas and zero order model fit (R2 ∼ 0.9) of the first 60% of the drug release, which indicates the swelling of polymer and initial burst release of the drug; and (b) the first order and Higuchi model fit (R2 ∼ 0.9) from the tenth day to the end of drug release, implying MTX release in the therapeutic window depends on its concentration and follows diffusion kinetics. The PLA coated CS-MTX micro-implants are able to administer therapeutic release of MTX for a period of more than 1 month. The proposed methodology could be used for improved treatment of PIOL.

Noninvasive Electroretinography Assessment of Intravitreal Sustained-Release Methotrexate Microimplants in Rabbit Eyes

“…Accordingly in a subsequent study, our group developed a chitosan (CS) and polylactic acid (PLA)-based MTX intravitreal microimplant device that was able to sustain MTX release between 0.2 and 2 mg/day in vitro for more than 50 days. 4 The fabrication of the microimplant, along with the MTX-release characteristics from the microimplant, was described in detail in that report. 4 In addition, the potential benefits, limitations, and risks of MTX administration from an intravitreal MTX microimplant in comparison with those of systemic MTX administration or repeated intravitreal injections of MTX were discussed in detail in that report.…”

“…4 The fabrication of the microimplant, along with the MTX-release characteristics from the microimplant, was described in detail in that report. 4 In addition, the potential benefits, limitations, and risks of MTX administration from an intravitreal MTX microimplant in comparison with those of systemic MTX administration or repeated intravitreal injections of MTX were discussed in detail in that report. 4 In our recent preclinical trials in rabbit eyes involving the same PLA-coated CS-MTX microimplant containing *400 mg of MTX (similar dosage of MTX present in an intravitreal MTX injection), a sustained release of MTX (0.1-1 mM) was observed for more than 30 days.…”

“…4 In addition, the potential benefits, limitations, and risks of MTX administration from an intravitreal MTX microimplant in comparison with those of systemic MTX administration or repeated intravitreal injections of MTX were discussed in detail in that report. 4 In our recent preclinical trials in rabbit eyes involving the same PLA-coated CS-MTX microimplant containing *400 mg of MTX (similar dosage of MTX present in an intravitreal MTX injection), a sustained release of MTX (0.1-1 mM) was observed for more than 30 days. 5 Furthermore, histopathological analysis of the study eyes showed no evidence of histological retinal toxicity of the microimplants.…”

“…Therefore, such a device may be preferred over repetitive intravitreal injections of MTX if the safety of such an intravitreal device can be assured. During the past several years, our group developed a biodegradable slowrelease device 4 for intravitreal delivery of sustained therapeutic doses of MTX and performed pharmacokinetic studies of intravitreal dose levels over time and histopathological studies of rabbit eyes, in which one of these microimplants had been inserted. 5…”

Polydopamine – A Versatile Coating for Surface‐Initiated Ring‐Opening Polymerization of Lactide to Polylactide

“…The coverage of various surfaces with poly(lactic acid) (PLA) is of great importance in particular in medical applications. This strategy is used, for example, to cover implants in order to render corrosion resistance or to make them biocompatible . Since PLA is degraded under biological conditions, the material can be used for drug delivery systems as well as for temporary coating of materials.…”