Sustained Drug Release in Nanomedicine: A Long-Acting Nanocarrier-Based Formulation for Glaucoma

Abstract

Therapeutic nanomedicine has concentrated mostly on anticancer therapy by making use of the nanosize for targeted therapy. Such nanocarriers are not expected to have sustained release of the bioactive molecule beyond a few days. There are other conditions where patients can benefit from sustained duration of action following a single instillation, but achieving this has been difficult in nanosized carriers. An important prerequisite for sustained delivery over several months is to have sufficiently high drug loading, without disruption or changes to the shape of the nanocarriers. Here we report on successful development of a drug-encapsulated nanocarrier for reducing intraocular pressure in a diseased nonhuman primate model and explain why it has been possible to achieve sustained action in vivo. The drug is a prostaglandin derivative, latanoprost, while the carrier is a nanosized unilamellar vesicle. The mechanistic details of this unique drug-nanocarrier combination were elucidated by isothermal titration calorimetry. We show, using Cryo-TEM and dynamic light scattering, that the spherical shape of the liposomes is conserved even at the highest loading of latanoprost and that specific molecular interactions between the drug and the lipid are the reasons behind improved stability and sustained release. The in vivo results clearly attest to sustained efficacy of lowering the intraocular pressure for 120 days, making this an excellent candidate to be the first truly sustained-release nanomedicine product. The mechanistic details we have uncovered should enable development of similar systems for other conditions where sustained release from nanocarriers is desired.

Probing suitable therapeutic nanoparticles for controlled drug delivery and diagnostic reproductive health biomarker development

“…Table 1. It could be seen that binding of NPs to human sperm sample provide ITC thermograms with exothermic and endothermic binding that are consistent with previous publication [43].…”

“…Uptake mechanism and penetration kinetics studied with highly reliable and sophisticated method ITC demonstrates the raw data for the heat rates of nanoparticles (Fe 3 O 4 , MWCNT and GPN) (μcal/s) vs. time obtained by titrating NPs into human sperm cell [43]. As observed from the thermogram, the Fe 3 O 4 , MWCNT and GPN NPs binding with sperm cell was exothermic, endothermic and exothermic respectively.…”

“…The instrument consists of a reference and a sample cell that holds a sample volume of 1.45 ml, while the syringe burette holds a volume of 282 μl. The titrations were carried out with sequential injections of the samples from the syringe burette into the sample cell with continuous mixing [42][43]. Different injection parameters can be controlled with the online software interface provided.…”

Antioxidant Gallic Acid-Functionalized Biodegradable in Situ Gelling Copolymers for Cytoprotective Antiglaucoma Drug Delivery Systems

“…2 More recently, Natarajan et al have developed a latanoprostencapsulated liposomal nanocarrier that achieves long-acting (i.e., 120 days) IOP-lowering effect in a diseased nonhuman primate model. 3 In our laboratory, the gelatin and poly(Nisopropylacrylamide) (PNIPAAm) graft copolymers are synthesized to be used for the preparation of a new intracameral drug delivery system. 4 As compared to either eye drop instillation or free drug injection, the intraocular administration of proposed biodegradable in situ gelling composition containing pilocarpine can more effectively improve the therapeutic outcomes for glaucomatous rabbits.…”

Therapeutic nanomedicine surmounts the limitations of pharmacotherapy

“…Approximately 5%-10% of all cancer drugs that are in clinical use today are nanodrugs. The solution to various infectious diseases has also been sought using nanotechnology, and they include endocrine/exocrine disorders, skin regeneration, cardiac/ vascular disorders, corrective cochlear and retinal implants, degenerative disorders [10], increased efforts in sustained drug release in treating glaucoma [79,80] improve heart function, and improved antimicrobials [81]. Most of the currently registered clinical trials (Table 4) in nanomedicine primarily focus on therapeutic approaches in managing malignant solid tumors.…”