This award by the Biomaterials program in the Division of Materials Research to University of California-San Diego is to investigate magnetic remote spatio-temporal control of biomaterials and their payloads. Magnetic nanocapsules containing therapeutics could provide a viable means to remotely control the release of therapeutics to cell aggregates, through the blood vessels and blood-brain barrier. The magnetic nanocapsules respond to remotely applied magnetic fields to release drugs on-demand. To experimentally demonstrate the concept of spatio-temporal control of biomaterial response, the investigators will design and construct nanocapsules with innovative on-off switchable drug delivery approaches. The nature and dimension of these capsulated magnetic materials with therapeutics will be varied to understand the effects of these parameters on biomaterial characteristics and their drug release behavior. The anticipated impacts are expected to be significant in the drug delivery area that will benefit clinically challenging central nervous system disorders as well as cancer treatments. Graduate students will be trained with the multidisciplinary facets of this research project, and involves highly interdisciplinary fields such as materials science, biology, bioengineering, chemistry and chemical engineering. The educational outreach plan of this project will involve Annual San Diego Science Festival (Science Week San Diego) and Teacher Training and Professional Development programs that are organized by the BioBridge Science Outreach Initiative, a community based partnership among University of California, San Diego, San Diego School districts and industry.
This research project aims to investigate smart drug release systems based on magnetic nanocapsules containing therapeutic drug payloads. Such a controllable drug delivery techniques could provide viable means to treat Alzheimer's disease and other central nervous system disorders, and various types of cancers using on-demand release of drugs. To experimentally demonstrate the concept of remote spatio-temporal control of biomaterial response, the investigators will design and construct nanocapsules, and the nature and dimension of the capsule materials and magnetic materials will be varied to understand the effects of these parameters on biomaterial characteristics and efficiency of drug release behavior. The new technique can also be applied broadly to many other therapeutic areas to benefit large patient populations, and also provide opportunities for broader economic stimulus. The new approach will also stimulate many scientists and engineers in the materials science and bioengineering field for further innovations and understanding of biomaterials design, behavior and applications. This highly multidisciplinary research project will also emphasize the educational aspects for graduate, undergraduate, and high school students, including under-privileged high school students.
There is a need and challenge to create new regimes of on-demand, drug release techniques with targeting strategy. Current drug delivery systems with constant-rate, zero-order release can not meet the cyclic or irregular drug requirement in human body. Therefore, it is highly desirable to provide drug molecules within drug-delivery capsules which will release the payload only when the capsules reach the targeted organs, tissues or cells, thus minimizing toxic or systemic side effects. For controlled drug release, external stimuli such as temperature, electric field, and magnetic field, light, pH have been explored, however, a much needed complete on-off switchable release using remote, external activation with spatial and temporal control has not been fully addressed. For drugs to be efficient, placement or delivery of the drug-containing vehicles to the diseased region is essential. Nanotechnology is an exciting and rapidly advancing field with a significant impact on diagnosis and therapeutics for treatment of human diseases . Nanoparticle based delivery is of particular interest for the central nervous system (CNS) because of the "Blood Brain Barrier (BBB)". Use of nanoparticles to enhance drug delivery across BBB has been actively pursued in recent years, albeit no reliable controls. For treatment of cancer tumor cells, there is a major issue of drugs, even small molecule drugs, being able to penetrate only several cell layers thick. A new technique to allow better drug penetration into tumor aggregates is highly desirable. We have successfully designed and fabricated hollow nanocapsules containing intentionally trapped magnetic nanoparticles and defined anticancer drugs, and investigated the fundamental effect of materials and processing parameters that influence the drug delivery characteristics. These nanocapsules have been prepared to provide a powerful magnetic vector under moderate gradient magnetic fields, and the nanocapsules can penetrate into the interior of tumors and allow a controlled on-off switchable release of the drug cargo via remote RF field. This smart drug delivery system is compact as all the components can be self-contained in 80~150 nm capsules. In vitro as well as in vivo results indicate that these nanocapsules can be enriched near the mouse breast tumor and are effective in reducing tumor cell growth. We have also utilized the magnetic drug capsules for delivery of therapeutic or diagnostic agents across an intact blood-brain barrier (BBB). The BBB crossing remains a major challenge in the therapeutics for CNS (Central Nervous system) area. We have demonstrated in a mouse model that magnetic nanocapsules can cross the normal BBB when subjected to an external magnetic field. Following a systemic administration, an applied external magnetic field mediates the ability ofmagnetic nanocapsules to permeate the BBB and accumulate in a perivascular zone of the brain parenchyma. Direct tracking and localization inside endothelial cells and in the perivascular extracellular matrix in vivo was established using fluorescent nanoparticles. These magnetic nanocapsules are inert and associated with low toxicity, using a non-invasive reporter for astrogliosis, biochemical and histological studies. Atomic force microscopy demonstrated that MNCs were internalized by endothelial cells, suggesting that trans-cellular trafficking may be a mechanism for the magnetic nanocapsules crossing of the BBB observed. These nanocapsules allow on-demand drug release via remote RF magnetic field. Together, these results establish an effective strategy for regulating the biodistribution of magnetic nanocapsules in the brain through the application of an external magnetic field. It has also been demonstrated in this project that triggerable magnetic nanocapsules with biodegradable PLGA PLGA (Poly(lactic-co-glycolic acid) polymer coating can reduce the involuntary seepage of drug, so as to further improve the drug delivery characteristics of the magnetic nanocapsules. The outcome of this project is useful for broad drug and biological agents delivery in a controlled and on-off switchable manner, which can be utilized for many types of biomedical and therapeutic applications. The methodology and structures of nanocapsule design and processing also contribute to fundamental understanding of the nanoscience, and advance nanotechnology including related technological areas such as capsuled delivery of chemical, biological, catalytic or enzymatic materials in a controlled manner, using a remote control technique.
