**4. Convection‐enhanced delivery**

#### **4.1. Basic concepts**

Convection‐enhanced delivery (CED) is a catheter‐based direct drug microperfusion technique, which was introduced by Bobo (50). CED continuously infuses soluble therapeutic

agents into targeted site in CNS through fine catheters implanted either by surgery or stereotaxis. The hydrostatic pressure gradient (bulk flow) in CED is generated through a motor‐driven pump connected to the catheters. CED has several advantages as compared with other drug delivery methods. First of all, CED bypasses BBB and targets tumor bed through the implantation of catheters. The local concentration achieved by CED can be orders of magnitude higher than that produced via intravenous injection, while the systemic toxicity is minimal. Secondly, the pressure‐driven CED creates a homogeneous distribution of infused agents in a large region in brain while the diffusion‐driven drug delivery such as polymeric wafers usually leads to a limited penetration from the diffusive interface. A dramatic drop‐ off (250‐ to 1000‐fold decrease) in concentration was observed with the polymeric delivery in the tissue 1–2 mm away from the surface (51). Thirdly, a very large volume of infusion can be achieved via CED. It has been demonstrated that a volume of 200 ml infusion into brain did not cause irreversible neurological deficits in patients with brain tumors (52). Finally, various agents with different molecular weights such as conventional chemotherapeutical drugs, small molecular inhibitors, and immunotoxins can be readily infused through CED. Whereas sophisticated technologies are required to integrate those agents into polymeric system.

## **4.2. Determining variables for infusate distribution**

Several critical factors will influence the distribution of infusate delivered by CED. These include (i) infusion rate and volume; (ii) catheter features; (iii) anatomical structure and interstitial fluid pressure; (iv) intrinsic characteristics of infusate.

The concentration differential is the key driving force for diffusion‐driven drug delivery such as polymeric chemotherapy. By contrast, CED is a method to deliver agents mainly depend‐ ent on pressure gradient in the interstitial space. As a result, the distribution volume of infusate is mainly determined by infusion volume and rate. In an animal model, the distribution volume correlates with infusion volume in a linear manner. However, this dependence of infusate distribution on volume of infusion disappears due to the infusate reflux along the catheter/ brain interface (backflow) when the infusion rate reaches a threshold (e.g., >0.5 μl/min). Therefore, the optimal infusion rate and volume facilitate a better distribution of infusate.

Backflow is one of the major barriers for the clinical usage of CED. The reflux of infusate not only reduces the concentration of delivered drugs in the target location but also increases the risk of adverse effects such as chemical meningitis due to the leakage of the agents into the subarachoid spaces. The properties of the implanted catheters such as shape and size, and the implantation method of the catheters are associated with the incidence of backflow in CED. At the early stage of CED, the open‐ended straight catheters were used, but the backflow was frequently observed even at a relatively low infusion rate. A systemic analysis demonstrated that the diameter of catheters positively correlates with the backflow (53). Catheters with the diameter of <1 mm significantly minimize the backflow and achieve better drug distribution (54). It has been suggested that a smaller size of the catheter introduces less tissue displace‐ ment and trauma, consequently reducing the backflow. Fiandaca and colleagues modified the shape of the catheter by developing a step design. The step catheter consists of 0.2 mm needle with a glued‐in, internal silica tube (0.102‐mm inner diameter) that extends beyond the end of the needle by 5–10 mm (55). The authors demonstrated that the step catheter was reflux‐ resistant even when the infusion rate increased to as high as 5 μl/min. Gill and colleagues (56) evaluated the performance of CED with a recessed‐step catheter, which incorporates an indwelling catheter with adjustable winged stop within a guide tube. This novel design showed a superior control of backflow in comparison with the conventional step catheter. Other catheter designs such as hollow fiber catheter, multiple port catheter, and balloon‐tipped catheter have also been developed to minimize reflux and improve drug distribution (57).

agents into targeted site in CNS through fine catheters implanted either by surgery or stereotaxis. The hydrostatic pressure gradient (bulk flow) in CED is generated through a motor‐driven pump connected to the catheters. CED has several advantages as compared with other drug delivery methods. First of all, CED bypasses BBB and targets tumor bed through the implantation of catheters. The local concentration achieved by CED can be orders of magnitude higher than that produced via intravenous injection, while the systemic toxicity is minimal. Secondly, the pressure‐driven CED creates a homogeneous distribution of infused agents in a large region in brain while the diffusion‐driven drug delivery such as polymeric wafers usually leads to a limited penetration from the diffusive interface. A dramatic drop‐ off (250‐ to 1000‐fold decrease) in concentration was observed with the polymeric delivery in the tissue 1–2 mm away from the surface (51). Thirdly, a very large volume of infusion can be achieved via CED. It has been demonstrated that a volume of 200 ml infusion into brain did not cause irreversible neurological deficits in patients with brain tumors (52). Finally, various agents with different molecular weights such as conventional chemotherapeutical drugs, small molecular inhibitors, and immunotoxins can be readily infused through CED. Whereas sophisticated technologies are required to integrate those agents into polymeric system.

Several critical factors will influence the distribution of infusate delivered by CED. These include (i) infusion rate and volume; (ii) catheter features; (iii) anatomical structure and

The concentration differential is the key driving force for diffusion‐driven drug delivery such as polymeric chemotherapy. By contrast, CED is a method to deliver agents mainly depend‐ ent on pressure gradient in the interstitial space. As a result, the distribution volume of infusate is mainly determined by infusion volume and rate. In an animal model, the distribution volume correlates with infusion volume in a linear manner. However, this dependence of infusate distribution on volume of infusion disappears due to the infusate reflux along the catheter/ brain interface (backflow) when the infusion rate reaches a threshold (e.g., >0.5 μl/min). Therefore, the optimal infusion rate and volume facilitate a better distribution of infusate.

Backflow is one of the major barriers for the clinical usage of CED. The reflux of infusate not only reduces the concentration of delivered drugs in the target location but also increases the risk of adverse effects such as chemical meningitis due to the leakage of the agents into the subarachoid spaces. The properties of the implanted catheters such as shape and size, and the implantation method of the catheters are associated with the incidence of backflow in CED. At the early stage of CED, the open‐ended straight catheters were used, but the backflow was frequently observed even at a relatively low infusion rate. A systemic analysis demonstrated that the diameter of catheters positively correlates with the backflow (53). Catheters with the diameter of <1 mm significantly minimize the backflow and achieve better drug distribution (54). It has been suggested that a smaller size of the catheter introduces less tissue displace‐ ment and trauma, consequently reducing the backflow. Fiandaca and colleagues modified the shape of the catheter by developing a step design. The step catheter consists of 0.2 mm needle with a glued‐in, internal silica tube (0.102‐mm inner diameter) that extends beyond the end of

**4.2. Determining variables for infusate distribution**

326 Neurooncology - Newer Developments

interstitial fluid pressure; (iv) intrinsic characteristics of infusate.

The tissue structure and pathology at the targeting site are critical factors that influence the topography and the drug distribution achieved in CED. Normal brain tissues have signifi‐ cant heterogeneity and anisotropy in architecture and permeability for fluid flow. Anatomi‐ cally, grey matter is mainly composed of glial cells and neuron somas, and the effective diffusivity is generally isotropic in grey matter. Whereas, white matter comprises bundles of axons connecting various grey matter areas to each other in brain. The permeability varies in white matter, primarily depending on the density and directional alignment of axon fibers (58). The diffusion of infusate is anisotropic in white matter. In addition, morphological analysis and mathematical models revealed that extracellular space is more easily extended by infusion fluid in white matter than that in grey matter (59, 60). As a result, white matter is more susceptible to extracellular bulk flow and infusate can travel a longer distance because of the higher permeability along the white matter. In pathological tissues such as gliomas, the bulk flow can be less predictable due to the heterogeneous cytoarchitecture and the treatment‐ related changes. GBM is characterized with the thriving growth of tumor cells, pseudopali‐ sading necrosis, and glomeruloid vascular proliferation in histology (61). Interstitial fluid pressure (IFP) has been found to increase in intracranial tumors in preclinical models and patients (62). The leaky vasculature coupled with the resistance to bulk flow in the tortuous interstitial space of the surrounding grey and white matter is suggested to be the underlying mechanism for the increased IFP in GBMs (63). More importantly, IFP varies in different areas of the tumor. IFP elevates in the tumor center and dramatically drops toward the tumor periphery or the surrounding normal brain tissue. The outward pressure gradient restrains infusate to enter the tumor core, and the leaky tumor vasculature facilitates the rapid efflux of infused drugs into systemic circulation. Treatment‐induced changes may also complicate the drug delivery in CED. For example, postoperative inflammatory reaction decreases the diffusion of drug with a larger molecular weight in extracellular spaces (64). In addition, to treat a residue tumor surrounding the resection cavity, which directly communicates with the subarachnoid space or ventricle, makes it more difficult to deliver drugs via CED. The numbers and placement of catheters should be carefully planned according to the postoperative tumor characteristics.

Besides, the intrinsic features such as the physical and chemical properties of infusate are highly related to the efficiency of CED. Drugs with small molecular weight can be employed in CED, but their faster clearance from CNS limits their diffusion. Agents that easily cross the BBB are not good choices for CED because they can be readily eliminated from the CNS and transported into the systemic circulation. Similarly, drugs that are rapidly taken up or metabolized in the CNS may reduce the distribution of the infusates. Viscosity is also an important factor for bulk flow in CED. Intuitively, the less viscous the infusate is, the more smoothly it diffuses in the extracellular space. Subsequently, a larger diffusion volume is expected from the low‐viscosity drugs. However, Mardor and colleagues (65) demonstrated in a rat model that agents with high viscosity tend to have an increased volume of diffusion because they are more resistant to backflow. Therefore, when a drug is chosen as a candi‐ date for CED, its physico‐chemical characteristics such as molecular weight, viscosity, clearance rate should be taken into account. In addition, novel strategies are explored to improve the efficacy of CED through delaying the degradation or clearance of agents in the target sites. To achieve this goal, drugs are conjugated or encapsuled with nanoparticles or liposomes (66, 67).

## **4.3. Agents for convection‐enhanced delivery**

A wide range of therapeutic agents, such as conventional chemotherapies, targeted toxins, viruses and oligonucleotides, have been investigated on CED for the safety and efficacy in the treatment for gliomas in clinical trials.
