This is the fourth article in our series entitled “Nanomedicine: A Vast Horizon on a Molecular Landscape”. We have already briefly reviewed the major research and entrepreneurial development of nanomedicine and related patents in Part I and Part II. In our last installment (Part III), we introduced one of the diagnostic applications of nanomedicine, the so-called: “Organ-on-a-chip”. Here, I discuss the therapeutic applications of nanomedicine for drug delivery.
For clinical therapeutics, there is a great need to develop new approaches to fight chronic and incurable diseases and further improve the efficiency of medical treatments. The current research focus and opportunities for nanomedicine in therapeutics include the development of rapid and accurate analytical techniques, safe and targeted drug delivery systems, improved controlled drug release systems, and the discovery of alternative and innovative therapeutic methods. In this article, I will specifically discuss the use of nanoparticles for drug delivery.
Nanoparticles for Drug Delivery
Nanoparticles refer to materials with structures roughly in the size regime from 1 nm up to several hundred nanometers in at least one dimension. The particle can be developed by either top-down or bottom-up engineering of individual components. Nanoparticles have unique physical and chemical properties, such as an ultra small size, large surface area to mass ratio, and high reactivity. These properties provide advantages for nanoparticles as novel drug delivery carriers to specifically transfer agents to desired therapeutic targets and to control the release of the drugs.
The first nanotechnology drug delivery systems were lipid vesicles, also called liposomes, developed in the 1960s by the research group of Dr. Bangham from England. Following this, a variety of other organic and inorganic nanomaterials have been developed for drug delivery. Dr. Langer and Dr. Folkman at Harvard Medical School reported the first controlled macromolecule release system based on polymeric materials (US patent 4,164,560). Later on, a “smart-drug” system was reported by Dr. Yatvin at the Weizmann Institute of Science in Israel for preferential intracellular drug delivery. This system uses pH-sensitive liposomes, which can trigger drug release according to changes in pH. However, there are two major challenges in nanoparticle drug delivery. One is non-site-specific targeting, leading to undesired systemic side effect. Two research groups reported the success of specific cell targeting by antibody-conjugated liposome systems almost at the same time. One group is Dr. Heath and his colleague at University of California, San Francisco (US patent 4,598,051). The other is Dr. Weinstein at NIH and his collaborators in France. The other major challenge is the short circulation half-life due to the elimination of these nanocarriers by the reticuloendothelial system, which results in frequent administrations. In order to overcome this issue, polyethylene glycol (PEG) had been introduced to shield both liposomes (Dr. Huang, University of Tennesse, US patent 5,043,164) and polymeric nanoparticles (Dr. Langer, Harvard Medical School, US patent 5,543,158) to increase the circulation time. Doxil (doxorubin liposomes), developed based on this technique, is the first nanoparticle drug delivery product approved by the FDA in 1995 for the treatment of AIDS-associated Kaposi’s Sarcoma. However, these developments relate to “soft” nanomaterials. In contrast to “soft” nanomaterials, “hard” nanomaterials, i.e., metallic oxide (Fe3O4), mesoporous silica, have been proposed to be promising drug delivery candidates due to the high surface to volume ratio and special intrinsic properties. Dr. Perez-Pariente’s group in Spain first introduced the surfactant coated MCM-41 mesoporous silica nanoparticles to deliver the drug, Ibuprofen. Dr. Jon’s group in South Korea described using magnetic fields to actually “steer” or direct drug-loaded iron oxide nanoparticles to the desired location in the body for combined cancer imaging and therapy in vivo.
In the past two decades, there have been over two dozen nanoparticle drug delivery products approved for clinical use and on the stage of clinical trial. For example, DaunoXome, Gilead Science, for HIV-related Kaposi’s sarcoma (approved); Pegasys, Hoffmann-La Roche, for Hepatitis B, Hepatitis C (approved); Neulasta, Amgen, for neutropenia associated with cancer chemotherapy (approved); Paliperidone, J&J, for Schizophrenia (approved). Currently, there is also a great increase in the number and variety of drug delivery nanoparticles on the pre-clinical research stage. Dr. Langer’s group at MIT developed a docetaxel-encapsulated nanoparticles formulated with biocompatible and biodegradable copolymer and surface functionalized with RNA aptamers that target one of the well-known surface antigen of prostate cancer cells: the extracellular domain of the prostate-specific membrane antigen (PSMA) (US patent 8,709,483). Dr. Saltzman and Dr. Fahmy at Yale discovered a novel vaccine delivery system for inducing an immune response by using polymeric nanoparticles and functional surface elements (US patent 8,889,117). Dr. Brinker at University of New Mexico working with Sandia National Laboratories to use a core-shell nanostructure: silica porous nanoparticle core surrounded by a shell of lipid bilayer, to targeted delivery drugs to cancer cells (US patent 8,992,984). Dr. Weissleder at Massachusetts General Hospital developed variable polymer-magnetic nanoparticle conjugations for targeted drug delivery and imaging contrast (US patent 8,569,078).
Drug delivery systems have been developed for a great number of important diseases including solid tumors, cardiovascular diseases, neurological disorders, and immunological diseases, etc.. Currently there are over 5000 patents issued in US relating to nanoparticle drug delivery. Each year, we are also expecting lots of applications regarding to new material and compound design, new method for this field. To take a close look at the state-of-art in this field, we will focus on the nanoparticle drug delivery in cancer therapy in the next article.
Table 1. Key Nanoparticle for Drug Delivery Patents
|4,164,560||Systems for the controlled release of macromolecules||NA||Moses J. Folkman, Robert S. Langer|
|4,598,051||Liposome conjugates and diagnostic methods therewith||The Regents of the University of California||Demetios P. Papahadjopoulos, Timothy D. Heath|
|5,043,164||Blood-stable, cholesterol-free liposomes||The University of Tennessee Research Corporation||Leaf Huang, Dexi Liu|
|5,543,158||Biodegradable injectable nanoparticles||Massachusetts Institute of Technology||Ruxandra Gref, Yoshiharu Minamitake, Robert S. Langer|
|8,709,483||System for targeted delivery of therapeutic agents||Massachusetts Institute of Technology, The Brigham and Women’s Hospital, Inc.||Omid C. Farokhzad, Jianjun Cheng, Benjamin A. Teply, Robert S. Langer, Stephen E. Zale|
|8,889,117||Modular nanoparticles for adaptable vaccines||Yale University||Ira S. Mellman, Tarek M. Fahmy, William Mark Saltzman, Michael J. Caplan|
|8,992,984||Protocells and their use for targeted delivery of multicomponent cargos to cancer cells||STC.UNM; Sandia Corporation||C. Jeffrey Brinker, Carlee Erin Ashley, Xingmao Jiang, Juewen Liu, David S. Peabody, Walker Richard Wharton, Eric Carnes, Bryce Chackerian, Cheryl L. Willman|
|8,569,078||Magnetic-nanoparticle conjugates and methods of use||The General Hospital Corporation||Lee Josephson, Ralph Weissleder, J. Manuel Perez|