Delivery of Therapy to Brain Tumors: Problems and Potentials

This chapter includes an accompanying lecture presentation that has been prepared by the authors: .

Key Concepts

  • A combination of tight junctions and neighboring astrocytes in the blood-brain barrier (BBB) creates a significant obstacle in the effective delivery of chemotherapeutics to brain tumors.

  • Modification of drugs into lipophilic analogues or in conjunction with lipophilic carriers can potentiate passive diffusion through the BBB, but high tissue clearance rates can result in limited distribution.

  • Active transport also plays a factor in preventing effective drug distribution through the BBB through the expression of high levels of drug efflux pumps.

  • Modification of drugs into lipophilic analogues or prodrugs have demonstrated increased penetration through the BBB.

  • Delivery into the brain parenchyma can also be achieved through disruption of the BBB, which can be accomplished through numerous methods; the most promising include MRI-guided ultrasonography and laser thermal therapy.

  • Convection-enhanced delivery through direct intraparenchymal injection is a promising technique but has been hindered by limitations in the design of delivery catheters.

Malignant gliomas are the most common type of primary brain tumors in adults; approximately 20,000 new cases are diagnosed each year. Treatment of gliomas represents one of the most formidable challenges in oncology. Despite treatment with surgery, radiotherapy, and chemotherapy, the prognosis for patients with high-grade gliomas remains poor, particularly for those with glioblastomas, for which the median length of survival is 12 to 15 months. After recurrence, further treatment provides an additional median length of survival of only approximately 6 to 8 months. The infiltrative nature of these tumors eliminates the possibility of curative surgical resection. Even at initial presentation, infiltration by tumor cells extends at least 2 cm away from the radiographic contrast-enhancing mass. ,

The success of targeted chemotherapy, although considered by most authorities to be a promising strategy, is impaired by the presence of the blood-brain barrier (BBB; see Chapter 68 ) and the partially functional blood-tumor barrier, which prevent the effective delivery of potentially active chemotherapeutic compounds. Numerous research efforts are underway focusing on the design of new approaches that will improve drug delivery to brain tumor cells with limited systemic toxicity. In this chapter, we summarize the methods that have been developed for overcoming the multiple physical and physiologic barriers that shield brain tumor cells from effective treatment.

Physiologic Barriers to Delivery

The Blood-Brain Barrier

The BBB consists of a layer of endothelial cells that line the blood vasculature throughout the brain. These endothelial cells are held together by tight junctions , and are supported by neighboring astrocytes. Certain molecules, particularly large water-soluble molecules, are prevented from diffusing through the gaps between these cells. Small, lipophilic molecules passively diffuse, but their distribution is also limited because of high tissue clearance rates. The BBB limits the delivery of many common chemotherapeutic agents to the CNS, and its permeability to most molecules can be predicted on the basis of each agent’s octanol/water partition coefficient and the unidirectional transfer coefficient (K in ). The octanol/water partition coefficient is a measure of solute lipophilicity, whereas K in is a quantitative measure of the ability of a drug to pass from the plasma into the brain. K in is determined largely by lipid solubility because agents must first dissolve in the lipid membranes of the BBB to cross by lipid-mediated diffusion. K in can be plotted against the partition coefficient, and 20 reference permeability markers that bind minimally to plasma proteins and cross the BBB by passive diffusion are used to formulate the plot ( Fig. 141.1 ). In this plot, many of the chemotherapeutic agents fall below the line predicted for BBB passive diffusion.

Figure 141.1, Relationship between blood-brain barrier permeability and the octanol/water partition coefficient of chemotherapeutic agents.

Active or facilitated transport is used for substances with low partition coefficients. This type of transport is dependent on ion channels, specific transporters, energy-dependent pumps, and receptor-mediated endocytosis. Glucose, amino acids, and small intermediate metabolites are carried into the brain via facilitated transport, whereas substances with larger molecules, such as insulin and transferrin, are carried across the endothelial layer via receptor-mediated endocytosis.

Specific factors contribute to the poor chemotherapeutic uptake across the BBB; these include plasma protein binding, solute molecular weight, and active efflux transport. Most chemotherapeutic agents are bound to plasma proteins, which reduce the free fraction of the drug in the plasma that is available to cross the BBB. The molecular weights of most of these agents exceed 400 Da, which is significantly larger than what normally would leak passively through the BBB. , Another component of the BBB that makes it difficult for chemotherapeutics to function is its expression of high levels of drug efflux pumps, such as P-glycoprotein. These pumps actively remove chemotherapeutic drugs from the brain. A number of newer chemotherapeutic agents, such as gemcitabine, docetaxel, pemetrexed, irinotecan, and topotecan, show promising antitumor activity against systemic tumors but have limited delivery across the BBB because of active efflux transport and plasma protein binding. The tyrosine kinase inhibitor imatinib binds heavily to plasma proteins and is a substrate for active efflux pumps, which is also suspected to be the case for erlotinib and gefinitib.

The organic anion transporters and glutathione-dependent multidrug resistance–associated proteins (MRPs) also contribute to the efflux of organic anions from the brain and CSF. Receptor-mediated transport modulation, vasomodulators, nanoparticle delivery methods, and osmotic BBB disruption are all techniques that have been used to increase BBB permeability for chemotherapeutics. Unfortunately, these techniques do not ensure specific delivery to tumor tissue alone, and neurotoxicity can occur as a consequence of the enhanced CNS penetration of some of these agents. Interstitial drug administration via convection-enhanced delivery (CED) is another CNS delivery method; it circumvents the BBB, thereby potentially avoiding systemic toxicity while enabling delivery to targeted areas of the brain.

The Blood-Tumor Barrier

The endothelial tight junction component of the BBB can be compromised significantly in the enhancing part of a glioma, which results in the hallmark of contrast enhancement on CT or MRI; however, other remaining physiologic barriers (and additional physical barriers related to tumor microarchitecture) can restrict drug delivery to brain tumors. In comparison with the normal, orderly vasculature of healthy tissues, blood vessels in tumors are often highly abnormal; for example, distended capillaries with leaky walls and sluggish flow render drug delivery inconsistent. , “Leaky” tumor vasculature may impose higher drug clearance that extends radially into normal brain tissue, which in turn results in shunting of drug away from the tumor itself. Studies have shown that targeting vascular endothelial growth factor with the drug bevacizumab may decrease interstitial pressure, thereby enabling greater entry of drug into the tumor. Highly irregular blood flow results in localized hypoxia, which subsequently leads to tumor resistance to certain anticancer agents as well as to radiotherapy. Increased bioreductive enzyme expression is an adaptive strategy for solid tumors to detoxify anticancer drugs, and the hypoxic environment further contributes to the increased reduction in the activity of tumors.

The Blood–Cerebrospinal Fluid Barrier

The specialized tight junctions of epithelial cells in the choroid plexus (the blood-CSF barrier), which separate the CSF from blood, also are responsible for barrier function. The tight junctions of the blood-CSF barrier, in comparison with the BBB, are between the epithelial cells of the choroid plexus rather than at the endothelial layer. By sealing neighboring epithelial choroidal cells continuously together, the tight junctions strongly restrict the paracellular movement of solutes and thus considerably limit the diffusion of polar drugs into the CNS via the choroid plexus. The fenestrated choroid plexus capillaries provide little resistance to the movement of small molecules. However, the blood-CSF barrier does not contribute significantly to drug entry into brain parenchyma because the surface area of the blood-CSF barrier is approximately 1000-fold smaller than the surface area of the BBB. Like the BBB, however, the blood-CSF barrier contains drug-metabolizing enzymes, which are located within the choroid plexus and in some circumventricular organs, and these play a primarily protective role against exogenously administered molecules.

Drug Modifications For Enhanced Drug Delivery to Brain Tumors

Lipophilic Analogues

The BBB allows the diffusion of small, nonionic, lipid-soluble molecules, whereas larger, ionic, more water-soluble molecules do not readily cross it ( Table 141.1 ). To improve drug delivery to brain tumors, certain strategies have been formulated in which lipophilic analogues are used to enable passive drug uptake into the brain. Carmustine is an alkylating agent used to treat brain tumors and other well-known malignancies. Multiple carmustine analogues studied in clinical trials have demonstrated decreased alkylating activity and increased dose-limiting toxicity in comparison with carmustine. This result was probably caused by factors affecting drug-receptor interactions or increased binding to plasma proteins, which resulted in lower drug concentrations available for diffusion into the brain. Moreover, lipophilic analogues are less soluble in the brain interstitial fluid, which limits their activity against tumor cells. Although the use of lipophilic analogues has met a number of obstacles, , the concept of lipophilic transport across the BBB has been expanded upon in the form of liposomal and nanoparticle transport, , cellular transport, and vector-mediated transport strategies. ,

TABLE 141.1
Mechanisms of Drug Delivery to Brain Tumors
Drug Type Advantages Disadvantages
Drug Modifications
Lipophilic analogues Allow passage of large, polar molecules Limited activity against tumor cells
Lipophilic prodrugs Allow better penetration than that of parent drug Chemical transformation necessary to achieve active form
ADEPT/GDEPT Enhance prodrug activity
More specific targeting
Antigen/antibody counteraction
Difficulty in achieving selective gene delivery to a sufficient number of tumor cells
Receptor-/vector-mediated drug targeting Improves brain uptake by coupling drugs to vectors Imposed limitation by the immune system
Causes transient inflammation upon injection
Intranasal applications Noninvasive
Rapid delivery
Avoid hepatic drug metabolism
Further investigation still required
Barrier Disruption Strategies
Osmotic BBBD Increases drug concentrations in tumor cells Potential for neurotoxicity
Biochemical BBBD More precise time window for drug delivery to the brain Potential for neurotoxicity
Ultrasound-mediated BBBD Localized and reversible image-guided disruption of BBB Necessitates craniotomy
Direct Delivery Methods
Catheter with pump systems Direct drug delivery Infection
Catheter obstruction
Inadequate drug distribution
Implanted polymers Continuous drug delivery Local neurotoxicity
Poor wound healing
Limited drug penetration
CED Achieves both local and regional drug delivery
Bypasses BBB
Enables use of tumor-targeted drugs, which may have systemic toxicity
Necessitates implanting catheters into brain
Inconsistency in distribution and potential for backflow
Current approaches have not enabled imaging of distribution
Other Approaches for Delivery
Intraventricular/intrathecal Effective for leptomeningeal spread Poor delivery to brain parenchyma
Intra-arterial Improved efficacy when used with targeting strategies Limited efficacy as stand-alone therapy
Liposomal drug encapsulation Can be modified to better target tumor cells Highly unstable
Nanoparticulate systems Natural polymers
Controlled drug delivery
Transport of drugs across BBB depends on outer coating
Magnetic microspheres Tumor targeting enhanced by retention of cationic particles External magnetic field necessary
ADEPT, Antibody-directed enzyme prodrug therapy; BBB, blood-brain barrier; BBBD, blood-brain barrier disruption; CED, convection-enhanced delivery; GDEPT, gene-directed enzyme prodrug therapy.


As alternatives to analogues, prodrugs require a chemical or biochemical transformation to achieve the active form within the body. , Prodrugs are designed to overcome pharmaceutical and pharmacokinetic limitations of the parent molecule to better penetrate the BBB. Lipophilic ester prodrugs of the anticancer agent chlorambucil have been developed to increase efficacy in the treatment of brain tumors After equimolar doses of chlorambucil and chlorambucil–tertiary butyl ester, the brain delivery of the ester was 35-fold greater than that of chlorambucil. However, despite an enhanced CNS delivery ratio, none of the prodrugs demonstrated anticancer activity superior to that of the equimolar administration of chlorambucil against a brain-sequestered carcinosarcoma in rats. Other examples of lipophilic prodrugs have shown excellent CNS and glioma penetration in animal models. A different strategy for prodrug conversion consists of using stem cell–mediated conversion. Neural stem cells transduced with cytosine deaminase have been shown to effectively convert the prodrug 5-fluorocytosine to 5-fluorouracil following direct intracranial administration in recurrent high-grade glioma patients.

Antibody- and Gene-directed Enzyme Prodrug Therapy

To enhance prodrug activity at the site of action with minimal systemic toxicity, antibody-directed enzyme prodrug therapy (ADEPT) can be utilized. With ADEPT, enzymes that activate prodrugs are directed to human tumor xenografts by conjugating them to tumor-selective monoclonal antibodies. Once the enzyme is conjugated with an antitumor antibody, it is delivered to the tumor via intravenous infusion. When the conjugate is cleared from the blood, a prodrug is then delivered. The prodrug can now be activated by the tumor-associated enzyme.

Unfortunately, this strategy has limitations, and most directed prodrug therapy is being pursued in the form of gene-directed enzyme prodrug therapy (GDEPT). With GDEPT, an inactive prodrug can be activated to release a cytotoxic drug by an enzyme that has been delivered to the tumor for expression. Specific enzymes utilized include thymidine kinase, nitroreductase, cytosine deaminase, and cytochrome P-450. One example is the thymidine kinase gene, which is inserted into the herpes simplex virus and whose administration is followed by combination treatment with the prodrug ganciclovir. The cytotoxicity of these prodrug/enzyme combinations can be quite effective under in vitro conditions. However, this approach does not specifically target the invasive tumor cell populations. Improving the efficacy of delivery of these so-called suicide genes to infiltrating tumor cells has been one goal associated with research into stem cell or viral vector delivery systems. This combination of GDEPT with cell-targeting technologies exemplifies the synergistic approach to neuro-oncology that is evolving. A phase 2 study in which thymidine kinase introduced via viral vectors in conjunction with valacyclovir into high-grade gliomas in conjunction with the standard of care has been shown to demonstrate survival benefit.

Receptor- and Vector-mediated Drug Targeting

In carrier-mediated drug delivery, the facilitative endogenous transport systems that are present in brain endothelial cells are used. Specific transport systems for the brain include those of glucose, amino acids, choline, vitamins, low-density lipoproteins, and nucleosides. Glucose and the large neutral amino acids have a high transport capacity, so they are mostly used for drug delivery to the brain. Several amino acid–mimetic drugs in clinical use, such as levodopa, α-methyldopa, and baclofen, are readily taken up into the brain by these transport systems. The coupling of nontransportable therapeutic molecules to a drug-transport vector has improved CNS delivery significantly.

Similarly, drugs targeted for transport through olfactory and respiratory epithelium are receiving increased attention, with promising results in early phase 1 and phase 2 clinical trials. Intranasal delivery is a practical, noninvasive method for delivering therapeutic agents to the brain because of the unique anatomic connection provided by the olfactory and trigeminal nerves. Intranasally administered drugs reach the parenchymal tissues of the brain and spinal cord or CSF within minutes via an extracellular route through perineural channels. In addition to its bypassing the BBB, the advantages of intranasal delivery include rapid delivery to the CNS, avoidance of hepatic first-pass drug metabolism, and elimination of the need for systemic delivery, which thereby reduce systemic side effects. Various molecules have been investigated as vectors to facilitate the intranasal route whereby lipid solubility is relied on in addition to intraneural and perineural transport mechanisms. ,

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