ReviewBarriers to carrier mediated drug and gene delivery to brain tumors
Introduction
An estimated 17,200 individuals in the United States are diagnosed with malignant CNS tumors per year [1]. Despite aggressive surgery, radiotherapy, and chemotherapy, the average 1 year survival has increased little over the past three decades [1], [2]. This is related to the fact that brain tumors, upon diagnosis, are usually already 30 to 60 cm3 in volume, approximately 3–6 × 1010 cells. The tumor cell number must be reduced to about 105 cells before the immune system can control it [3]. Though surgery and radiation therapy can reduce the tumor cell burden by 1000 fold, chemotherapy is not yet up to the task of a further two orders of magnitude reduction in tumor cell number [3]. Biochemical and delivery challenges slow the development of effective brain tumor drug therapies.
Current drug development to treat brain diseases is directed towards low molecular weight, lipid-soluble molecules that readily diffuse across the blood–brain barrier (BBB) to reach diseased parenchymal tissue [4]. Although a number of low molecular weight molecules are helpful for the treatment of receptor or transporter-related diseases such as depression, low molecular weight drugs have had limited success for the treatment of Alzheimer's disease, Huntington's disorder, stroke or brain cancer. Macromolecular drugs may be particularly useful to treat these types of CNS diseases because they reach novel targets with a high specificity. However, the pursuit of macromolecular drugs to treat brain diseases is often abandoned because of difficulties delivering macromolecules to the parenchymal space of the brain.
A number of reviews have summarized the current challenges to brain drug delivery and technologies to improve the drug's access to the brain [5], [6], [7], [8], [9]. In this review, we will describe strategies to increase delivery into the brain parenchyma in the context of the barriers related to fluid and solute transport into, through and from the brain with a focus on liposome and polymer drug carriers.
Section snippets
Brain physiology and anatomy
The brain is an integral part of the central nervous system, acting as a major regulating and communicating organ to maintain the body's homeostasis in response to changes in both the external and internal environment. The primary cells of the brain include nerve cells (neurons) and supporting glial cells (glia); an adult human has approximately 100 billion neurons and 1 trillion glial cells [10]. The neurons and glial cells organize into specialized structures within the brain that can be
Small animal models of brain tumors
The development of appropriate small animal models of brain tumors is integral to the development of chemotherapy studies. It is necessary to consider what animal and tumor type to use, how and where the tumor will be induced, and the appropriate dosing schedule to evaluate the treatment protocol [44].
Brain tumor models can be spontaneous or artificially implanted into the animal. Spontaneous models can be induced by repeated exposure to carcinogens or to sarcoma viruses. However, these models
Drug delivery to the brain
Current strategies to deliver drugs to brain tumors include methods that exploit the following routes of administration: intravenous, intra-arterial, intraventricular, intrathecal, and intraparenchymal. These methods introduce drug in different spatial locations in the ISF/CSF fluid flow pathway; hence, they distribute the drug in different regions of the brain based on the volume of the compartment and the rate of the fluid production and drainage (Fig. 8). The route of administration can
Modeling
Compartmental models have been used to describe the distribution of drug within the brain since the mid-1970s. For example, Levin et al. [212] modeled drug distribution from the blood into a spherical tumor containing three regions: a poorly perfused low permeability center, a well-perfused high permeability outer shell, and an outermost shell with intermediate perfusion and permeability. This model could be used to predict the drug area under the curve (AUC) in the tumors with different blood
Summary
Although a number of strategies have been developed to deliver drugs into the brain, patients with brain tumors continue to face a poor prognosis and limited treatment options that are unlikely to be resolved even as effective novel anticancer drugs are devised. This is because the physiology of the brain presents unique challenges, including tight regulation of what can enter the brain space, limited distribution of substances along ECF flow pathways, and clearance from the tissue by
Acknowledgements
We thank Dr. J. Andrew MacKay for his assistance in the writing of this review. Funding has been provided by NIH R01 CA107268-01 NIH CA-85356, and NIH NS42927. GH Huynh is a recipient of a predoctoral fellowship from the Whitaker Foundation.
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