A recombinant human enzyme for enhanced interstitial transport of therapeutics.

Subcutaneously injected therapeutics must pass through the interstitial matrix of the skin in order to reach their intended targets. This complex, three-dimensional structure limits the type and quantity of drugs that can be administered by local injection. Here we found that depolymerization of the viscoelastic component of the interstitial matrix in animal models with a highly purified recombinant human hyaluronidase enzyme (rHuPH20) increased the dispersion of locally injected drugs, across a broad range of molecular weights without tissue distortion. rHuPH20 increased infusion rates and the pattern and extent of appearance of locally injected drugs in systemic blood. In particular, rHuPH20 changed the pharmacokinetic profiles and significantly augmented the absolute bioavailability of locally injected large protein therapeutics. Importantly, within 24 h of injection, the interstitial viscoelastic barriers were restored without histologic alterations or signs of inflammation. rHuPH20 may function as an interstitial delivery enhancing agent capable of increasing the dispersion and bioavailability of coinjected drugs that may enable subcutaneous administration of therapeutics and replace intravenous delivery.

Nerve growth factor delivery systems.

Growth factors encourage tissue regeneration and differentiation, accelerate wound healing, and modulate neural repair. Thus, growth factor administration may become a useful treatment for neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease, which are characterized by the degeneration of neuronal cell populations. Controlled-release polymer delivery systems may be an important technology in enabling the prevention of neuronal degeneration, or even the stimulation of neuronal regeneration, by providing a sustained release of growth factors to promote the long-term survival of endogenous or transplanted cells.

Localized delivery of proteins in the brain: can transport be customized?

Certain central nervous system (CNS) diseases are characterized by the degeneration of specific cell populations. One strategy for treating neurodegenerative diseases is long-term, controlled delivery of proteins such as epidermal growth factor (EGF) and nerve growth factor (NGF). Since proteins permeate through brain capillaries very slowly, local administration using polymeric implants, continuous infusion pumps, or transplanted, protein-secreting cells may be required to achieve therapeutic concentrations in the tissue. The efficiency of local distribution, and hence effectiveness of local therapy, depends on the rate of protein migration through tissue. The rate of dispersion of molecules in a quiescent, isotropic medium can be characterized by the molecular diffusion coefficient, D, which can be measured by techniques such as quantitative autoradiography, iontophoresis, and fluorescence photobleaching recovery (FPR). These methods are reviewed, with an emphasis on their application to measurement of D for proteins in the brain. Biophysical techniques yield quantitative descriptions of local protein distribution and may enable discrimination of mechanisms of protein transport in the brain. This capability suggests a new paradigm for design of protein therapies, in which proteins and delivery systems are collectively customized to provide sustained protein availability over predetermined volumes of tissue.