Background
Alzheimer’s disease (AD) is an irreversible, progressive neurological brain disorder that slowly destroys the memory and thinking skills in people, and, eventually, their ability to carry out the simplest tasks. Estimates vary, but experts suggest that more than 5.5 million Americans, most of them age 65 or older, may have dementia caused by Alzheimer’s. Currently there is no known cure or preventative measure for this disease.
Approach
The approach for this project is to formulate drug-loaded, stable, blood-brain barrier (BBB) targeting liposome formulations and to develop experimental in-vitro models and computational models that can precisely evaluate the delivery of those liposome-nanoparticles based on the interaction of the BBB and liposome-nanoparticles.
Accomplishments
The following project metrics are briefly summarized here:
Goal: Prepare stable, nano-sized liposomes from biocompatible materials.
Metric: Formulations with submicron sizes that remain size stable, +/- 10 %, after 2 weeks.
Level of Success: COMPLETED- <200 nm sized liposomes were prepared, and the particle size remained stable under refrigeration for at least 2 weeks.
Goal: Prepare functionalized liposomes to selectively pass the blood-brain barrier.
Metric: Functionalized formulations that transport at least 2x greater than unfunctionalized formulations
Level of Success: COMPLETED- Numerous formulations with various functionalizations were successfully prepared and tested. Liposomes with PEG functionalization had greater permeation rates than solutions of gallic acid alone. In addition, liposomes with holo-transferrin functionality permeated faster than liposomes without holo-transferrin via the cell based in-vitro tests.
Goal: Prepare liposomes with ADAM-10 activators known to inhibit amyloid beta formation and, thus, inhibit/reverse AD.
Metric: Payloads of at least 10 % gallic acid encapsulation efficacy/
Level of Success: COMPLETED—Liposome formulations with greater than 10 % gallic acid efficiency was observed for several formulations
Goal: Development and integration of in-vitro BBB assays.
Metric: For both a non-cellular and cellular model, be able to reproducibly generate data using standards and demonstrate differentiation between formulations.
Level of Success: SIGNIFICANT- Massive amounts of effort went into screening both a non-cellular and cellular based in-vitro tests for permeation. Good, observable delineation was observed between differing formulations.
Goal: Develop/validate a computational model for liposome transport across the BBB.
Metric: Trends in in-vitro results correlate with predictive factors in the computational model.
Level of Success: PARTIAL—Advancements were made in both hardware and software. A number of 2D and 3D models had been designed and tested. The COMSOL model captured the scale of the process, but still requires additional development.