New platform for controlled and sustained delivery of the EGF receptor tyrosine kinase inhibitor AG1478 using poly(lactic-co-glycolic acid) microspheres

Abstract

Inhibition of the epidermal growth factor receptor (EGFR) has been shown to reduce tumor growth and metastases and promote axon regeneration in the central nervous system. Current strategies for inhibiting EGFR include the administration of reversible or irreversible small-molecule tyrosine kinase inhibitors (TKIs). However, to be effective in vivo constant and sustained delivery is required. This study explored the feasibility of encapsulating the tyrphostin 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) in poly(lactic-co-glycolic acid) (PLGA) microspheres to achieve sustained delivery of the TKI. We characterized microspheres prepared using three different emulsion methods: solid-in-oil-in-water, oil-in-water, and oil-in-water with co-solvent. Addition of a co-solvent increased the loading and release of AG1478, and significantly (P<0.001) decreased the size of the microspheres which facilitates administration of the spheres. On average, sustained delivery of AG1478 from microspheres was achieved for six months. However, the addition of a co-solvent prolonged release for over nine months (266 days). In addition, AG1478 retained its bioactivity upon delivery, and inhibited EGFR in both immortalized rat fibroblasts and in EGFR-amplified human carcinoma cells. These results demonstrate that AG1478 can be encapsulated in PLGA and retain bioactivity; thereby providing a new platform for controlled administration of EGFR TKIs.

Nanospheres Delivering the EGFR TKI AG1478 Promote Optic Nerve Regeneration: The Role of Size for Intraocular Drug Delivery

“…Encapsulation of AG1478 in nanospheres resulted in an increase in loading (23.3 ± 0.693 μg/mg polymer vs 21.8 ± 0.250 μg/mg polymer, mean ± SD) and encapsulation efficiency (79 ± 12% vs 67 ± 1.5%, mean ± SD) compared to microspheres. As previously reported, microspheres formulated as described can sustain release for over six months . Nanospheres prepared in a similar manner also sustained release for over six months (182 days) (Figure a, b).…”

“…Previously, we investigated formulation parameters for PLGA encapsulation of AG1478 in microspheres. 14 PLGA microspheres have been successfully delivered intravitreally in a number of animal models with no apparent side effects. 15,16 In the present study we developed PLGA nanospheres delivering AG1478 and compared the administration of microspheres and nanospheres to the vitreous of adult rat eyes after optic nerve crush injury and examined its effects on nerve regeneration at two weeks and four weeks.…”

Increased amphiregulin expression as a biomarker of cholesteatoma activity

“…Recent advances in U.S. Food and Drug Administration-approved inhibitors of EGFR and overexpression of components of the EGFR signaling pathway in CHLST make this molecular network a compelling target for future studies of treatment options for CHLST. Development of topical delivery systems for anti-EGFR therapeutics 16 (e.g., monoclonal antibodies, tyrosine kinase inhibitors, ligand-toxin conjugates, or antisense oligonucleotides) may be efficacious for inhibiting CHLST progression in nonsurgical candidates or preventing recurrence of disease.…”

Specific delivery of kinase inhibitors in nonmalignant and malignant diseases

“…The microspheres were capable of releasing drug during up to 9 months in vitro, depending on the microsphere composition. The drug remained bioactive during this period and inhibited EGFR activity in several cell types [77]. This formulation could thus provide a slow-release form of the drug, avoiding peak concentrations that can often cause side effects.…”

“…To date erlotinib, gefitinib [77] and the multi-inhibitors lapatinib and vandetanib [78,79] are FDA-approved drugs. Their use, however, is associated with side effects, and no specific delivery forms of these drugs are approved for use.…”