Delivery Systems @ MMI
A Delivery System for Binding and Release of Growth Factors
IN A NUTSHELL: A polymer delivery system for the in vivo binding and release of growth factors, preferably orthobiologic GF, comprising a polymer, preferably a polyurea hyperbranched polymer (HBP) having anionic phosphorous groups. The HBP may be cross-linked to form a network. Especially preferred are hydrogel coatings crosslinked through reaction with the telechelic acrylate groups of TEGDA. The HBP coating may be applied when the device is manufactured or applied to the device just prior to use.
BENEFITS: Total joint replacement is an effective treatment for relieving pain and restoring function for patients with damaged joints. This treatment involves the replacement of damaged or troubled joints with orthopedic implants and prostheses Orthopedic implants are generally constructed of metals such as stainless steel, cobalt-chromium alloy, titanium alloy, pure titanium or tantalum, as well as plastics such as polyethylene. Some variants are cemented into place, while others are pressed to fit, and bone is allowed to grow into the implant for strength. For the majority of patients initial results following surgery are excellent. However, some of the prostheses may have to be revised within 5–15 years of the initial surgery because of the disappearance of bone around the implant (e.g., prosthesis-induced osteolysis). Surgery to replace failures is more difficult to perform, is costly, and has a poorer outcome than the original joint replacement surgery.
One way to make bone grow into the implant and thereby improve osseointegration is to deliver bone growth factors at the implant site. Growth factors are polypeptides which bind to receptors on the cell surface, with the primary result of activating cellular proliferation and/or differentiation. Such tissue growth promoting factors have been shown to promote bone formation both in vitro and in vivo.
However, achieving sustained in situ delivery of growth factor at the optimal rate is a significant challenge. Covalent linkage of growth factor to an appropriate carrier material often results in loss of bioactivity and difficulty of release. On the other hand, if it is non-covalently associated with the carrier it may be released too quickly. MMI’s hyperbranched polyurea is designed as an easy to coat, crosslinkable, rugged polymer with a high density of anionic phosphonate groups located at its periphery. The base polyurea composition, as well as the the peripheral phosphonate groups have excellent compatibility with both artificial joint replacement materials and natural bone. Positively charged growth factor proteins associate with the negatively charged phosphonate groups through strong non-covalent interactions, and as a consequence of this, are delivered in situ through a slow, sustained release mechanism, over the course of at least 24 hours.
THE STATE OF TECHNOLOGY: To achieve selective drug targeting and eliminate malignant tumors without destroying healthy tissue, various approaches based on differences in the physiology of normal and cancerous cells have been explored. Some of the most prominent of these include: (a) the use of high molecular weight polymer-drug conjugates which, because of their size, preferentially penetrate the porous cancerous tissue rather than the healthy, normal one, (b) the use of drug-carrier systems in which the drug-carrier bonds break under the pH or thermal conditions found in the cancerous environment to release the drug molecules, and (c) the use of systems in which the carrier contains targeting functional groups that can selectively bind to the overexpressed receptors or antigens on the surface of cancer cells allowing the system to deliver its drug content into the tumor only. An ideal drug delivery system should perform a combination of the features listed above, so as to maximize the curing function while minimizing the systemic toxicity of the cancer therapeutics to the healthy parts of the body, and it must remain water soluble (i.e., compatible with bodily fluids) in spite of the highly hydrophobic nature of the delivering drug molecule.
Polyamidoamine (PAMAM) dendrimers have attracted exceptional research attention for the development of such systems because they have an ideal combination of chemical, physical and physiological properties to satisfy this purpose. Among others, these unique properties include: (1) a branched polypeptide composition which is highly hydrophilic and compatible with physiological media and processes in the human body, (2) globular molecular shapes and nanoscopic sizes which do not trigger an immunological reaction and make them easily excretable through the kidneys, (3) some of the highest density of exo-presented molecular functionality known to chemistry (particularly at higher dendrimer generations) that enables covalent attachment of a large number and variety of different functional groups to the molecular carrier skeleton, including targeting groups, drug molecules, surface modifiers, etc., (4) availability in a number of end-group modifications that exhibit no, or very little toxicity and do not cause irritation, (5) high level of synthetic control that enables the preparation of very high quality products required for in vivo biomedical applications, and (6) convenient availability in a variety of grades, types, generations and commercial quantities from Dendritech, Inc.
STAGE OF DEVELOPMENT: Initial studies have focused on the synthesis of the HBP, and optimizing its composition and coating properties. Proof of principle in vitro experiments with Balb/c-3T3 cells demonstrated sustained release of rhPDGF-BB from polymer coated titanium disks over at least 24 hours, with the largest release apparently occurring towards the end of the 24 hour window.
NEXT STEPS: Follow-on research quantifying the binding and release of growth factor, the effect of coating thickness, release behavior over a longer time window, and toxicity studies of all polymer compositions.