Self-assembled phenylalanine-α,β-dehydrophenylalanine nanotubes for sustained intravitreal delivery of a multi-targeted tyrosine kinase inhibitor.
Current standard of care for sustained back of the eye drug delivery is surgical placement or injection of large, slow release implants using a relatively large 22 gauge needle. We designed novel dipeptide (phenylalanine-α,β-dehydrophenylalanine; Phe-∆Phe) based nanotubes with a diameter of ~15-30 nm and a length of ~1500 nm that could be injected with a 33 gauge needle for sustained intravitreal delivery of pazopanib, a multi-targeted tyrosine kinase inhibitor. The drug could be loaded during nanotube assembly or post-loaded after nanotube formation, with the former being more efficient at 25% w/w pazopanib loading and ~55% loading efficiency. Plain and peptide loaded nanotube were non-cytotoxic to retinal pigment epithelial cells even at a concentration of 200 μg/ml. Following intravitreal injection of fluorescently labeled nanotubes using a 33 gauge needle in a rat model, the nanotube persistence and drug delivery were monitored using noninvasive fluorophotometry, electron microscopy and mass spectrometry analysis. Nanotubes persisted in the vitreous humor during the 15 days study and pazopanib levels in the vitreous humor, retina, and choroid-RPE at the end of the study were 4.5, 5, and 2.5-folds higher, respectively, compared to the plain drug. Thus, Phe-∆Phe nanotubes allow intravitreal injections with a small gauge needle and sustain drug delivery.
International Centre for Genetic Engineering and Biotechnology, New Delhi 110067 India; Nanomedicine and Drug Delivery Laboratory, Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States.
Jiban J
JJ
Panda
Sarath
S
Yandrapu
Rajendra S
RS
Kadam
Virander S
VS
Chauhan
Uday B
UB
Kompella
D000818:Animals; D003692:Delayed-Action Preparations / Q000737:chemistry*; D007191:Indazoles; D058449:Intravitreal Injections; D043942:Nanotubes / Q000737:chemistry*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051381:Rats; D012160:Retina / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014822:Vitreous Body / Q000378:metabolism
D003692:Delayed-Action Preparations; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D010649:Phenylalanine; C018632:phenyldehydroalanine; C516667:pazopanib; D011505:Protein-Tyrosine Kinases
Dipeptide nanotubes; Drug delivery; Noninvasive ocular fluorophotometry; Pazopanib; Self-assembly