Selected Techniques for Delivery of Drugs to the Brain

Number: 0731

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses selected techniques for delivery of drugs to the brain.

Experimental, Investigational, or Unproven

Aetna considers the following drug delivery techniques to the brain (not all-inclusive list) as experimental, investigational, or unproven because the safety and effectiveness of these approaches have not been established:

• Convection-enhanced delivery (CED) of drugs into brain parenchyma;
• Low-intensity MR-guided focused ultrasound (MRgFUS) mediated disruption of the blood-brain barrier for enhanced delivery of drugs into the brain.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
CPT codes not covered for indications listed in the CPB:
0947T	Magnetic resonance image guided low intensity focused ultrasound (MRgFUS), stereotactic blood-brain barrier disruption using microbubble resonators to increase the concentration of blood-based biomarkers of target, intracranial, including stereotactic navigation and frame placement, when performed
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C71.0 - C71.9	Malignant neoplasm of brain
C79.31, C79.49	Secondary malignant neoplasm of brain and other parts of nervous system
G30.0 - G30.9	Alzheimer's disease
G40.001 - G40.909	Epilepsy and recurrent seizures
R56.1	Post traumatic seizures
R56.9	Unspecified convulsions

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Background

Convection-enhanced delivery (CED) is a method of directly administering drugs into the brain to enhance the distribution of drugs throughout the brain parenchyma. It involves the stereotactic placement of several catheters into brain parenchyma through cranial burr holes and the subsequent infusion of antineoplastic agents or other therapeutic agents via a micro-infusion pump.

This technique has been described in published pre-clinical and early clinical studies. Although CED has primarily been evaluated for administering antineoplastic drugs, this technique can also be used for a wide range of agents, such as for the treatment of Alzheimer’s disease and epilepsy.

Standard methods of local delivery of most drugs into the brain, either by intravenous injection and passage through the blood-brain barrier (BBB) or intraventricular injection, have relied on diffusion, which results in a non-homogeneous distribution of most agents. Intravenous administration of drugs to the brain has been hampered by the BBB, which prevents the passage of large molecules. The BBB is characterized by tight junctions between vascular endothelial cells, which prevent or impede various naturally occurring and synthetic substances (including anti-cancer drugs) from entering the brain.

Blood-brain barrier disruption (BBBD) techniques have been used in the chemotherapy of brain tumors to disrupt the BBB in order to increase the concentration of chemotherapy drugs delivered to the tumor and prolong the drug-tumor contact time. Chemotherapy may be administered in conjunction with mannitol to cause osmotic disruption of the BBB, or disruption may be attempted through other mechanisms with other substances.

Although BBBD techniques have been used for over 20 years, the efficacy of this technique has been questioned (ICSI, 2001; CMS, 2007), as the long-term effects of BBBD chemotherapy are unknown, and no randomized controlled trials have established the superiority of BBBD chemotherapy over conventional chemotherapy. In addition, BBBD with chemotherapy is associated with a higher risk of complications than conventional chemotherapy. Complications associated with BBBD include seizures, obtundation, focal neurologic deficits, cerebral herniation, strokes, death, as well as the side effects related to the chemotherapeutic agents themselves. Based on a review of the evidence, CMS has issued a National Coverage Determination stating that the use of osmotic BBBD is not reasonable and necessary when used as part of a treatment regimen for brain tumors (CMS, 2007).

In contrast to techniques that rely on diffusion, CED uses a pressure gradient established at the tip of an infusion catheter to push a drug into the extracellular space. The intention is to distribute the drug more evenly, at higher concentrations, and over a larger area than when administered by diffusion alone.

Convection-enhanced delivery of anti-neoplastic agents may occur after craniotomy with tumor resection, once the patient is stable. A separate hospital admission (apart from admission for tumor resection) is expected for CED for catheter placement and infusion of the therapeutic agent by means of a micro-infusion pump. Once the infusion is complete, the catheters are removed, and the patient is discharged.

Novel, targeted anti-neoplastics are in development for brain tumors. However, their administration has been hampered by the BBB, which prevents the passage of large molecules.

1. interleukin-13, which binds to receptors on tumor cells; and
2. pseudomonas exotoxin (PE), a cytotoxin, which causes destruction of the tumor cell once the molecule is absorbed.

Interleukin-13 receptors are present in substantial numbers on malignant glioma cells, but only a minimal amount on healthy brain cells. Hence, cintredekin besudotox has the potential to target tumor cells, with minimal impact on surrounding normal brain tissue.

Because of its large size, cintredekin besudotox can not cross the BBB. In clinical studies, cintredekin besudotox has been administered by CED. Catheters are placed following tumor resection, in areas of microscopic tumor spread or at risk of tumor spread around the tumor resection cavity. Because of the need to achieve homogenous distribution of cintredekin besudotox throughout the tumor infiltrated tissue, the catheters can not be placed in any previous resection cavity.

Once the patient is stable, approximately two weeks following craniotomy with tumor resection, the patient is admitted for catheter placement and anti-neoplastic infusion. Catheters are strategically placed by neurosurgeons, taking into account the location of residual non-resectable tumor, brain anatomy, and fluid dynamics. Between two to four catheters are placed during a surgical procedure lasting several hours. Cintredekin besudotox is then slowly infused through the catheter directly into the brain over 96 hours.

Available phase I/II clinical studies of cintredekin besudotox suggest that this is a promising agent for the treatment of recurrent glioblastoma multiforme. A phase III trial (PRECISE) is currently underway. Cintredekin besudotox has been granted fast-track development designation and orphan drug designation by the U.S. Food and Drug Administration (FDA), and may be approved by the FDA as early as 2007.

At present, the pharmacokinetics of CED are poorly understood (Sampson et al., 2006). More research is needed to determine the optimal catheter location to distribute a drug to target tumor cells within the tumor mass and in the infiltrated adjacent parenchyma. Optimal catheter design is being researched to minimize backflow, maximize distribution in the brain, and account for the need to maintain patient mobility.

Raghavan et al. (2006) explained that, although CED has been under investigation since the early 1990s, "this technique remains experimental because of both the absence of approved drugs for intraparenchymal delivery and the difficulty of guaranteed delivery to delineated regions of the brain."

Sampson et al. (2008) determined the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and intra-cerebral distribution of a recombinant toxin (TP-38) targeting the epidermal growth factor receptor in patients with recurrent malignant brain tumors using the intra-cerebral infusion technique of CED. A total of 20 patients were enrolled and stratified for dose escalation by the presence of residual tumor from 25 to 100 ng/ml in a 40-ml infusion volume. In the last 8 patients, co-infusion of (123)I-albumin was performed to monitor distribution within the brain. The MTD was not reached in this study. Dose escalation was stopped at 100 ng/ml due to inconsistent drug delivery as evidenced by imaging the co-infused (123)I-albumin. Two DLTs were observed, both of which were neurological. Median survival after TP-38 was 28 weeks (95% confidence interval: 26.5 to 102.8). Of the 15 patients treated with residual disease, 2 (13.3%) demonstrated radiographical responses, including 1 patient with glioblastoma multiforme who had a nearly complete response and remains alive for over 260 weeks after therapy. Co-infusion of (123)I-albumin demonstrated that high concentrations of the infusate could be delivered over 4 cm from the catheter tip. However, only 3 of 16 (19%) catheters produced intra-parenchymal infusate distribution, while the majority leaked infusate into the cerebrospinal fluid spaces. Intra-cerebral CED of TP-38 was well-tolerated and produced some durable radiographical responses at doses less than or equal to 100 ng/ml. The authors concluded that CED has significant potential for enhancing the delivery of therapeutic macromolecules throughout the human brain. However, the potential efficacy of drugs delivered by this technique may be severely constrained by ineffective infusion in many patients.

Fiandaca and colleagues (2008) stated that CED of substances within the human brain is becoming a more frequent experimental treatment option in the management of brain tumors, and more recently in phase I trials for gene therapy in Parkinson's disease (PD). Benefits of this intracranial drug-transfer technology include a more efficient delivery of large volumes of therapeutic agents to the target region when compared with more standard delivery approaches (i.e., biopolymers, local infusion). These researchers developed a reflux-resistant infusion cannula that allows increased infusion rates to be used. They also described their efforts to visualize the CED process in vivo, using liposomal nanotechnology and real-time intra-operative MRI. In addition to carrying the MRI contrast agent, nanoliposomes also provide a standardized delivery vehicle for the convection of drugs to a specific brain-tissue volume. This technology provides an added level of assurance via visual confirmation of CED, allowing intra-operative alterations to the infusion if there is reflux or aberrant delivery. These investigators proposed that these specific modifications to the CED technology will improve efficacy by documenting and standardizing the treatment-volume delivery. Furthermore, they believe that this image-guided CED platform can be used in other translational neuroscience efforts, with eventual clinical application beyond neuro-oncology and PD.

In a review on novel drug delivery strategies in neuro-oncology, Bidros and Vogelbaum (2009) stated that an important impediment to finding effective treatments for malignant gliomas is the presence of the BBB, which serves to prevent the delivery of potentially active therapeutic compounds. Multiple efforts are focused on developing strategies to effectively deliver active drugs to brain tumor cells. Convection-enhanced delivery and BBBD have emerged as leading investigational delivery techniques for the treatment of malignant brain tumors. Clinical trials using these methods have been completed, with mixed results, and several more are being initiated.

Bidros et al. (2010) stated that CED has emerged as a leading investigational delivery technique for the treatment of brain tumors. Clinical trials utilizing these methods have been completed, with mixed results, and several more are being initiated. However, the potential effectiveness of drugs delivered by CED may be severely constrained by poor drug distribution.

Sampson et al. (2010) retrospectively analyzed the expected drug distribution based on catheter positioning data available from the CED arm of the PRECISE trial. BrainLAB iPlan Flow software was used to estimate the expected drug distribution. Only 49.8% of catheters met all positioning criteria. Still, catheter positioning score (hazard ratio 0.93, p = 0.043) and the number of optimally positioned catheters (hazard ratio 0.72, p = 0.038) had a significant effect on progression-free survival. Estimated coverage of relevant target volumes was low, however, with only 20.1% of the 2-cm penumbra surrounding the resection cavity covered on average. Although tumor location and resection cavity volume had no effect on coverage volume, estimations of drug delivery to relevant target volumes did correlate well with catheter score (p < 0.003), and optimally positioned catheters had larger coverage volumes (p < 0.002). Only overall survival (p = 0.006) was higher for investigators considered experienced after adjusting for patient age and Karnofsky Performance Scale score. The authors concluded that the potential effectiveness of drugs delivered by CED may be limited by ineffective delivery in many patients.

Buonerba et al. (2011) stated that glioblastoma multiforme (GBM) is the most frequent and aggressive malignant glioma, with a median survival time of 12 to 15 months, despite current best treatment based on surgery, radiotherapy, and systemic chemotherapy. Many potentially active therapeutic agents are not effective by systemic administration because they are unable to cross the BBB. As intra-cerebral administration bypasses the BBB, it increases the number of drugs that can be successfully delivered to the brain, with the possibility of minor systemic toxicity and better effectiveness. These researchers summarized the results of extensive clinical research conducted on intra-cerebral therapy. Biodegradable drug carriers, implantable subcutaneous reservoirs, and CED represent the main techniques for intra-cerebral delivery, while conventional chemotherapy agents, radiolabeled antibodies, and receptor-targeted toxins are the main classes of drugs for intra-cerebral therapy. At present, biodegradable carmustine wafers, commercialized as Gliadel, are the only FDA-approved treatment for intra-cerebral chemotherapy of malignant gliomas, but intra-cavitary delivery of mitoxantrone and radiolabeled anti-tenascin antibodies via implantable reservoirs has yielded promising results in uncontrolled trials. The pressure-driven flow generated by CED can potentially distribute convection-enhanced drugs over large volumes of the brain, independent of their intrinsic diffusivity. Nevertheless, prominent technical problems, like back-flow, are yet to be properly addressed and have contributed to the disappointing results of two phase III trials that investigated CED of cintredekin besudotox and TransMid in patients with recurrent GBM.

In a prospective, dose-escalation phase Ib study, Bruce et al. (2011) examined the safety profile of topotecan via CED in the treatment of recurrent malignant gliomas and assessed radiographical response and survival. Significant anti-tumor activity, as described by radiographical changes and prolonged overall survival with minimal drug-associated toxicity, was demonstrated. An MTD was established for future phase II studies. The authors concluded that topotecan delivered by CED has significant anti-tumor activity at concentrations that are non-toxic to normal brain. The potential for the use of this therapy as a generally effective treatment option for malignant gliomas will be tested in subsequent phase II and phase III trials.

Lam et al. (2011) stated that CED is a promising neurosurgical technique for the delivery of potential therapeutic agents to the Parkinson's disease (PD)-affected striatum. CED utilizes stereotactic insertion of a catheter to the striatum and continuous infusion to distribute agents in the brain parenchyma. Insufficient attention to the details of CED may have contributed to early failures in translating candidate therapeutic agents from the laboratory to PD patients. A literature review was performed to examine the factors that govern CED in the laboratory as well as translation in PD, and these researchers found that although there have been significant developments in implant design, infusion parameters, and infusate composition, there have not been enough comparative trials of different technologies. Further optimization of CED is needed before it can be applied in the clinical setting, and this will require a step-by-step breakdown of the different elements of delivery for independent testing. The authors concluded that CED is a promising technique for delivering therapeutic agents to the striatum for the treatment of PD, but further refinements are necessary for successful clinical translation.

Barua et al. (2012) examined whether the peri-vascular distribution of solutes delivered by CED into the striatum of rats is affected by the molecular weight of the infused agent, co-infusion of a vasodilator, alteration of infusion rates, or use of a ramping regime. These investigators also aimed to make a preliminary comparison of the distribution of solutes with that of nanoparticles. They analyzed the peri-vascular distribution of 4, 10, 20, 70, and 150 kDa fluorescein-labeled dextran and fluorescent nanoparticles at 10 minutes and 3 hours following CED into rat striatum. They investigated the effect of local vasodilation, slow infusion rates, and ramping on the peri-vascular distribution of solutes. Co-localization with peri-vascular basement membranes and vascular endothelial cells was identified by immunohistochemistry. The uptake of infusates by peri-vascular macrophages was quantified using stereological methods. Widespread peri-vascular distribution and macrophage uptake of fluorescein-labeled dextran was visible 10 minutes after cessation of CED, irrespective of molecular weight. However, a significantly higher proportion of peri-vascular macrophages had taken up 4, 10, and 20 kDa fluorescein-labeled dextran than 150 kDa dextran (p < 0.05, ANOVA). Co-infusion with a vasodilator, slow infusion rates, and the use of a ramping regime did not alter the peri-vascular distribution. CED of fluorescent nanoparticles indicated that particles co-localize with peri-vascular basement membranes throughout the striatum but, unlike soluble dextrans, are not taken up by peri-vascular macrophages after 3 hours. The authors concluded that the findings of this study suggested that widespread peri-vascular distribution and interaction with peri-vascular macrophages is likely to be an inevitable consequence of CED of solutes. The potential consequences of peri-vascular distribution of therapeutic agents, particularly cytotoxic chemotherapies delivered by CED, must be carefully considered to ensure safe and effective translation to clinical trials.

White et al. (2012) described a single-center, phase I, dose-escalation clinical trial of carboplatin administered by CED to patients with recurrent or progressive GBM despite full standard treatment. This trial will incorporate six cohorts of three patients each. Cohorts will be treated in a sequential manner with increasing doses of carboplatin, subject to dose-limiting toxicity not being observed. This protocol should facilitate the identification of the maximum-tolerated infused concentration of carboplatin by CED into the supratentorial brain. This should facilitate the safe application of this technique in a phase II trial, treating patients with GBM, as well as for the treatment of other forms of malignant brain tumors, including metastases.

Anderson et al. (2013) noted that CED for the treatment of malignant gliomas is a technique that can deliver chemotherapeutic agents directly into the tumor and the surrounding interstitium through sustained, low-grade positive-pressure infusion. This allows for high local concentrations of drug within the tumor while minimizing systemic levels that often lead to dose-limiting toxicity. Diffuse intrinsic pontine gliomas (DIPGs) are universally fatal childhood tumors for which there is currently no effective treatment. In this report, the authors described CED of the topoisomerase inhibitor topotecan for the treatment of DIPG in two children. As part of a pilot feasibility study, the authors treated two pediatric patients with DIPG. Stereotactic biopsy with frozen section confirmation of glial tumor was followed by placement of bilateral catheters for CED of topotecan during the same procedure. The first patient underwent CED 210 days after initial diagnosis, after radiation therapy and at the time of tumor recurrence, with a total dose of 0.403 mg in 6.04 ml over 100 hours. Her Karnofsky Performance Status (KPS) score was 60 before CED and 50 post-treatment. Serial MRI initially demonstrated a modest reduction in tumor size and edema, but the tumor progressed, and the patient died 49 days after treatment. The second patient was treated 24 days after the initial diagnosis prior to radiation with a total dose of 0.284 mg in 5.30 ml over 100 hours. Her KPS score was 70 before CED and 50 post-treatment. Serial MRI similarly demonstrated an initial modest reduction in tumor size. The patient subsequently underwent fractionated radiation therapy, but the tumor progressed, and she died 120 days after treatment. Topotecan delivered by prolonged CED into the brainstem in children with DIPG is technically feasible. In both patients, high infusion rates (greater than 0.12 ml/hour) and high infusion volumes (greater than 2.8 ml) resulted in new neurological deficits and a reduction in the KPS score, but lower infusion rates (less than 0.04 ml/hour) were well-tolerated. While serial MRI showed moderate treatment effect, CED did not prolong survival in these two patients. The authors concluded that more studies are needed to improve patient selection and determine the optimal flow rates for CED of chemotherapeutic agents into DIPG to maximize safety and efficacy.

Barua et al. (2014) stated that CED describes a direct method of drug delivery to the brain through intra-parenchymal micro-catheters. By establishing a pressure gradient at the tip of the infusion catheter to exploit bulk flow through the interstitial spaces of the brain, CED offers a number of advantages over conventional drug delivery methods—bypassing the BBB, targeting distribution through large brain volumes, and minimizing systemic side effects. Despite showing early promise, CED has yet to fulfill its potential as a mainstream strategy for the treatment of neurological diseases (e.g., Alzheimer's disease, high-grade glioma, and Parkinson's disease). Substantial research effort has been dedicated to optimizing the technology for CED and identifying the parameters that govern successful drug distribution. It seems likely that the successful clinical translation of CED will depend on suitable catheter technology being used in combination with drugs with optimal physicochemical characteristics, and on neuropathological analysis in appropriate pre-clinical models.

Xia and colleagues (2014) examined a novel drug delivery system for the treatment of malignant brain gliomas; doxorubicin (DOX) complexed with nano-diamonds (ND-Dox), administered via CED. Drug retention and toxicity were examined in glioma cell lines, and distribution, retention, and toxicity were examined in normal rat parenchyma. Efficacy was assessed in a bioluminescence rodent tumor model. NDs markedly enhanced DOX uptake and retention in glioma cells. ND-Dox delivered via CED extended DOX retention and localized DOX toxicity in normal rodent parenchyma and was significantly more efficient at killing tumor cells than un-complexed DOX. The authors concluded that outcomes from this work suggested that CED of ND-Dox is a promising approach for brain tumor treatment.

Aparicio-Blanco and Torres-Suarez (2015) stated that epidemiological data on central nervous system disorders highlight the need to address the major barrier to brain drug delivery, the blood-central nervous system barriers. Without overcoming this challenge, there is little chance of improving the short-term survival of patients with diseases such as glioblastoma (GBM), which is associated with significant years of life lost. Targetable nanocarriers for treating malignant gliomas offer a unique approach to overcoming low chemotherapeutic levels at target sites while avoiding systemic toxicity. These researchers described the currently available targetable nanocarriers, focusing particularly on one of the newest types, lipid nano-capsules. They discussed various strategies that lipid nano-capsules may exploit to bypass blood-central nervous system barriers, including recent targeting approaches (such as targeting mesenchymal cells) and novel administration routes (like convection-enhanced delivery, CED), along with their notable achievements in glioma-implanted animal models. The authors concluded that while these systems are promising, much research remains to be done in this field.

Zhou and colleagues (2017) noted that CED is a technique designed to deliver drugs directly into the brain or tumors. Its ability to bypass the blood-brain barrier (BBB) has made it a promising drug delivery method for treating primary brain tumors. Several clinical trials utilizing CED of various therapeutic agents have been conducted to treat patients with supratentorial high-grade gliomas, and significant responses have been observed in certain patients across these trials. However, the insufficient ability to monitor drug distribution and pharmacokinetics hampers CED from achieving its full potential on a larger scale. Brainstem CED for treating diffuse intrinsic pontine glioma (DIPG) is appealing because this tumor is compact and lacks definitive treatment options. The safety of brainstem CED has been established in both small and large animals, and recently in early-stage clinical trials. There are ongoing clinical trials of brainstem CED in treating DIPG patients using targeted macromolecules such as antibodies and immunotoxins. Future advances for CED in DIPG treatment will come from several directions, including selecting the right agents for infusion, developing better agents and regimens for DIPG infusion, improving instruments and techniques for easier and more accurate surgical targeting, allowing multi-session or prolonged infusion to implement optimal timing, and better understanding and controlling drug distribution, clearance, and timing. The authors concluded that CED-based therapies for DIPG will continue to evolve with new insights into the technique and the disease.

Jahangiri and colleagues (2017) noted that glioblastoma is the most common malignant brain tumor and carries an extremely poor prognosis. Attempts to develop targeted therapies have been hindered because the BBB prevents many drugs from reaching tumor cells. Additionally, the systemic toxicity of drugs often limits their therapeutic potential. A number of alternative delivery methods have been developed, one of which is CED. The authors described CED as a therapeutic measure and reviewed pre-clinical studies and the most prominent clinical trials of CED in the treatment of glioblastoma. They outlined numerous technical challenges that need to be addressed to overcome the issues encountered with CED to treat glioblastoma to date. Another important consideration is that durable CED efficacy might require long-term convection at set intervals for months, similar to what is often required for systemically administered chemotherapy to be effective for non-brain tumors. The success of such a strategy may necessitate implantable ports that can be cannulated to receive CED in an outpatient setting. Furthermore, they stated that before evaluating the effectiveness of an agent delivered via CED, technical reproducibility must be achieved. The authors concluded that discouraging results from the two randomized phase III studies conducted to date revealed technical shortcomings that need to be addressed to allow CED to fulfill its therapeutic potential; CED holds promise for treating glioblastoma and warrants further pre-clinical and clinical development.

Saito and Tominaga (2017) noted that CED circumvents the BBB by delivering agents directly into the tumor and surrounding parenchyma, achieving large volumes of distribution through continuous positive-pressure infusion. Although promising as an effective drug delivery method in concept, the administration of therapeutic agents via CED is not without challenges. Limitations of distribution remain a problem in large brains, such as those of humans. Accurate and consistent delivery of an agent is another challenge associated with CED. Similar to the difficulties caused by immunosuppressive environments associated with gliomas, several mechanisms complicate effective local drug distribution in malignant gliomas. These investigators discussed methods for local drug application targeting gliomas, with special emphasis on CED. The authors concluded that although early clinical trials have failed to demonstrate the efficacy of CED against gliomas, CED has the potential to serve as a platform for translating the molecular understanding of glioblastomas achieved in the laboratory into effective clinical treatments. They noted that several clinical studies using CED of chemotherapeutic agents are ongoing, and successful delivery of effective agents should prove the efficacy of CED in the near future.

Sasaki and colleagues (2020) examined the efficacy of the enhancer of zeste homolog-2 (EZH2) inhibitor by CED against human DIPG xenograft models. The concentration of the EZH2 inhibitor (EPZ-6438) in the brainstem tumor was evaluated using liquid chromatography-mass spectrometry (LC/MS). These researchers treated mice bearing human DIPG xenografts with EPZ-6438 using systemic (intraperitoneal) or CED administration. Intracranial tumor growth was monitored by bioluminescence imaging, and the therapeutic response was evaluated by animal survival. LC/MS analysis showed that the concentration of EPZ-6438 in the brainstem tumor was 3.74% of serum concentration following systemic administration. CED of EPZ-6438 suppressed tumor growth and significantly extended animal survival compared to systemic administration of EPZ-6438 (p = 0.0475). The authors concluded that the findings of this study indicated that CED of an EZH2 inhibitor is a promising strategy to bypass the BBB and increase the efficacy of an EZH2 inhibitor for the treatment of DIPG.

Bander and associates (2020) reported on the safety and experience in a group of pediatric patients who received sequential CED into the brainstem for the treatment of DIPG. Patients in this study were enrolled in a single-center, phase I clinical trial using the 124I-8H9 monoclonal antibody (124I-omburtamab) administered by CED. A retrospective chart and imaging review was conducted to examine demographic data, CED infusion data, and post-operative neurological and surgical outcomes. MRI scans were analyzed using iPlan Flow software for volumetric measurements. Target and catheter coordinates, as well as radial, depth, and absolute error in MRI space, were calculated with the ClearPoint imaging software. A total of seven patients underwent two or more sequential CED infusions. No patients experienced Clinical Terminology Criteria for adverse events (AEs) of grade 3 or greater deficits; one patient had a persistent grade 2 cranial nerve deficit after a second infusion. No patient experienced hemorrhage or stroke post-operatively. There was a statistically significant decrease in radial error (p = 0.005) and absolute tip error (p = 0.008) for the second infusion compared with the initial infusion. Sequential infusions did not result in significantly different distribution capacities between the first and second infusions (volume of distribution determined by the PET signal/volume of infusion ratio [mean ± SD]: 2.66 ± 0.35 versus 2.42 ± 0.75; p = 0.45). The authors concluded that the findings of this study demonstrated the ability to safely carry out sequential CED infusions into the pediatric brainstem. Previous treatments did not negatively influence the procedural workflow, technical application of the targeting interface, or distribution capacity. These researchers stated that this limited experience provided a foundation for using repeat CED for oncological purposes.

In a retrospective review, Szychot and co-workers (2021) described their clinical experience and what they learned regarding the safety and feasibility of treating DIPG with intermittent CED of carboplatin and sodium valproate to the pons via the Renishaw Drug Delivery System (RDDS). This study reviewed children with DIPG who, following radiotherapy, received compassionate treatment commencing 3.3 to 10 months post-diagnosis (median of 4.9 months). They received up to seven cycles of three to six weekly pontine infusions of carboplatin (0.12 to 0.18 mg/ml) and sodium valproate (14.4 to 28.8 mg/ml). A total of 13 children aged 3 to 19 years (mean of 6.9 years) were treated. There were no surgical complications. With the exception of infusion channels blocking in one device, there were no adverse device effects; two patients developed persistent sixth nerve palsies, which led to drug concentration reduction in the combination therapy. Subsequently, infusion/drug-related toxicities were transient. Tumor control in the pons was achieved in 10 of 13 patients. The median progression-free survival (PFS) was 13.0 months, while median overall survival (OS) was 15.3 months. The authors concluded that the use of the RDDS was safe and well-tolerated in all 13 patients, and treatment improved control of pontine disease, resulting in longer PFS and OS, meriting further evaluation in a clinical trial.

Wang et al. (2021) noted that in patients with glioblastoma, resistance to the chemotherapeutic temozolomide (TMZ) limits any survival benefits conferred by the drug. These researchers showed that CED of nanoparticles containing disulfide bonds (which are cleaved in the reductive environment of the tumor) and encapsulating an oxaliplatin pro-drug and a cationic DNA intercalator inhibited the growth of TMZ-resistant cells from patient-derived xenografts and hindered the progression of TMZ-resistant human glioblastoma tumors in mice without causing any detectable toxicity. Genome-wide RNA profiling and metabolomic analyses of a glioma cell line treated with the cationic intercalator or with TMZ showed substantial differences in the signaling and metabolic pathways altered by each drug. The authors concluded that the findings of this study suggested that the combination of anti-cancer drugs with distinct mechanisms of action, selective drug release, and CED may represent a translational strategy for the treatment of TMZ-resistant gliomas.

Sunli et al. (2021) stated that in recent years, combination therapy has emerged as the cornerstone of clinical practice in the treatment of GBM; however, their ability to trigger and leverage the body's adaptive immunity has rarely been studied. Tumor heterogeneity, the presence of the BBB, and an immunosuppressive tumor microenvironment play crucial roles in the 90% local tumor recurrence post-treatment. These researchers described an improved combination therapy approach capable of stimulating an immune response that uses light-responsive antigen-capturing oxygen generators (LAGs). The engineered LAGs, loaded with a non-genotoxic molecule, Nutlin-3a, and a photosensitizer, protoporphyrin IX, can release the payload on-demand when exposed to light of a specific wavelength. The in-situ oxygen generation capability of LAGs enhances tumor oxygenation, alleviating tumor hypoxia and enhancing the efficacy of chemo-photodynamic therapy (PDT). Furthermore, by modulating the surface properties of LAGs, these researchers demonstrated that the tumor-derived protein antigens released can be captured and retained in-situ, improving antigen uptake and presentation by antigen-presenting cells. Dual drug-loaded LAGs (DD-LAGs) up-regulated the expression of cell surface CD83 maturation and CD86 co-stimulatory markers on monocyte-derived dendritic cells, suggesting intrinsic immune adjuvancy. In the presence of three-dimensional (3D) printed hypoxic U87 spheroids (h-U87), DD-LAGs induced cancer cell death, up-regulated IL-1β, and down-regulated IL-10, resulting in CD3+, helper CD4+, and cytotoxic CD8+ proliferation. Finally, the authors examined CED as a potential route of administration for DD-LAGs. These investigators stated that their work presents a novel strategy to induce tumor cell death both during and post-treatment, thereby reducing the possibility of recurrence.

Lambride et al. (2022) noted that brain cancer therapy remains a formidable challenge in oncology, and CED is an innovative and promising local drug delivery method for the treatment of brain cancer, overcoming the challenges of systemic drug delivery to the brain. To improve the understanding of the effectiveness of CED and drug transport, these investigators presented an in-silico methodology for simulating brain cancer CED treatment. To achieve this, a 3D finite element (FE) formulation was used that employed a brain model representation from clinical imaging data to predict drug deposition in CED regimes. The model encompasses biofluid dynamics and the transport of drugs in the brain parenchyma. Drug distribution was studied under various pathophysiological conditions of the tumor, in terms of tumor vessel wall pore size and tumor tissue hydraulic conductivity, as well as for drugs of various sizes, spanning from small molecules to nanoparticles. Through a parametric study, these researchers reported the impact of the size of the vascular wall pores and that of the therapeutic agent on drug distribution during and after CED. The authors concluded that the in-silico findings provided useful insights into the spatiotemporal distribution and average drug concentration in the tumor, contributing to effective treatment of brain cancer.

These investigators stated that it is important to acknowledge the simplifications and limitations of the current model. For the sake of simplicity, the drug was considered a spherical particle, and the vessel wall openings were modeled as perfect cylindrical pores; thus, the theory for hindered transport of rigid solutes via liquid-filled pores could be applied to describe drug transport across the tumor vessel walls. Furthermore, to simplify the modeling procedure, the flow physics of the catheter domain were disregarded. This modeling approach was substantially less challenging, as it minimized the complexity (in terms of the extra differential equations and the additional model parameters and boundary conditions) and the considerable computational burden (solving the Navier-Stokes equations and coupling these with the biphasic finite element formulation). The catheter jet flow was modeled by taking appropriate boundary conditions at the interface between the catheter and the (tumor or host) tissue to simulate drug administration during CED. After CED administration, a zero-flux boundary condition was used on the outlet surface of the catheter, neglecting any drug amount that could diffuse from the catheter to the tumor tissue. Regarding the model limitations, it incorporates only the biomechanical properties of the gray and white matter, while it does not account for other components of the brain, such as the thalamus, internal capsule, corpus callosum, putamen, ventricles, and cavities. How the predictive results would be affected by the incorporation of these other brain components is not intuitive; therefore, detailed simulations would have to be performed. Additionally, according to the literature, drug transport efficiency varies greatly in different regions of the brain, as the effective diffusivity in gray matter is isotropic, whereas white matter diffusion is anisotropic. Hence, diffusion tensor imaging (DTI) data could be considered to provide estimates of tissue anisotropy within the entire brain, thereby reducing these uncertainties.

Brady et al. (2022) stated that limitations have previously existed for the use of brain infusion catheters with extended delivery port designs to achieve larger distribution volumes using CED, due to poor transmittance of materials and uncontrolled backflow. These researchers examined a novel brain catheter designed to allow for extended delivery and larger distribution volumes with limited backflow of fluid. It was characterized using a broad range of therapeutic pore sizes, both for transmittance across the membranes to address possible occlusion and for distribution in short-term infusion studies, both in vitro in gels and in vivo in canines. Brain catheters with pore sizes of 10, 12, 15, 20, and 30 µm were examined using three infusates prepared in 0.9% sterile saline with diameters approximating 2, 5, and 30 nm, respectively. Magnevist was chosen as the small molecule infusate to mimic low-molecular-weight therapeutics. Galbumin served as a surrogate for an assortment of proteins used for brain cancer and Parkinson's disease. Gadoluminate was used to evaluate the distribution of large therapeutics, such as adeno-associated viral particles and synthetic nanoparticles. The transmittance of the medium and large tracer particles via catheters of different pore sizes (15, 20, and 30 µm) was measured by MRI and compared with the measured concentration of the control. Infusions into 0.2% agarose gels were carried out to examine differences in transmittance and distribution of the small, medium, and large tracer particles via catheters with different pore sizes (10, 12, 15, 20, and 30 µm). In vivo infusions were conducted in canines to examine the ability of the catheter to infuse the small, medium, and large tracer particles into brain parenchyma at high flow rates through catheters with different pore sizes (10, 15, and 20 µm). Two catheters were inserted stereotactically into the brain for infusion, one per hemisphere, in each animal (n = 6). The transmittance of Galbumin and Gadoluminate across the catheter membrane surface was 100% to within the accuracy of the measurements. There was no evidence of blockage or retardation of any of the infusates. Catheter pore size did not appear to significantly affect transmittance or distribution in gels of any of the molecule sizes in the range of catheter pore sizes tested. Differences in the distributions between the different tracer molecules were observed: Magnevist produced relatively large distributions, followed by Gadoluminate and Galbumin. These investigators observed no instances of uncontrolled backflow in a total of 12 in vivo infusions. Furthermore, several of the infusions resulted in substantial amounts remaining in tissue. They expected the in-tissue distributions to be significantly improved in the larger human brain. The new porous brain catheter performed well in terms of both backflow and intra-parenchymal infusion of molecules of varying sizes in the canine brain under CED flow conditions. The authors concluded that the data presented in this report support the notion that the novel porous brain catheter can deliver therapeutics of varying sizes at high infusion rates in the brain parenchyma and resist backflow that can compromise the effectiveness of CED therapy. Moreover, these researchers stated that further investigation is needed to characterize the brain catheter, including animal toxicity studies of chronically implanted brain catheters to lay the foundation for its use in the clinic.

Rechberger et al. (2023) noted that despite much progress, the prognosis for H3K27-altered diffuse midline glioma (DMG, formerly known as diffuse intrinsic pontine glioma) when located in the brainstem remains dark and dismal. Extensive research over the last 10 years has revolutionized the understanding of the molecular basis of DMG, revealing potential targetable vulnerabilities for the treatment of this lethal childhood cancer. However, obstacles to the successful clinical implementation of novel therapies remain, including effective delivery across the BBB to the tumor site. These investigators reviewed relevant literature and clinical trials and discussed direct drug delivery via CED as a promising treatment modality for DMG. They outlined a comprehensive molecular, pharmacological, and procedural approach that may offer hope for afflicted patients and their families. The authors concluded that challenges remain in successful drug delivery to DMG. While CED and other techniques offer a chance to bypass the BBB, the variables influencing successful intra-tumoral targeting are numerous and complex. These researchers discussed these variables and potential solutions that could lead to the successful clinical implementation of pre-clinically promising therapeutic agents.

Intra-Cerebral Delivery of rhFGF20 via Heparin-Poloxamer Hydrogel for the Treatment of Ischemic Stroke

Ye et al. (2025) noted that ischemic stroke is a significant health threat.  fibroblast growth factor (FGF)20 is involved in the repair of CNS diseases; however, it has the shortcomings of short half-life and inability to penetrate the BBB. To overcome the limitations of recombinant human FGF20 (rhFGF20) and examine its role in ischemic stroke, the effects of intra-cerebral administration of rhFGF20 by heparin-poloxamer hydrogel (HP-rhFGF20 [heparin-poloxamer hydrogel-encapsulated rhFGF20]) in a rat stroke model were the focus of this study. A rat model of middle cerebral artery (MCA) occlusion/re-perfusion and oxygen-glucose deprivation-reoxygenation models were established to mimic ischemic stroke in-vivo and in-vitro, respectively. Endogenous FGF20 levels were measured in patients, ischemic rats, and oxygen-glucose deprivation-reoxygenation-injured neurons. To examine the therapeutic potential, rhFGF20 was administered intra-cerebrally via heparin-poloxamer hydrogel implants (1 mg/ml, 20 μL) on day 5 post-stroke. 2,3,5-triphenyltetrazolium chloride (TTC) staining, neurobehavioral tests (including the Modified Neurological Severity Score (mNSS), the corner test, the rotarod test, the cylinder test, and the Morris water maze test), and Nissl staining were carried out to assess neurological recovery. Immunofluorescence and Western blotting were carried out to evaluate the brain repair processes (neurogenesis, neuronal re-modeling, and angiogenesis). High expression of FGF20 was detected in the serum of patients with ischemic stroke, the cortex of ischemic rats, and oxygen-glucose deprivation-reoxygenation-injured neurons. Heparin-poloxamer increased the stability and bioavailability of rhFGF20. HP-rhFGF20 attenuated neurobehavioral deficits and infarct volume in ischemic stroke rats. HP-rhFGF20 inhibited neuronal cell death, microglial activation, and glial scar formation on day 7 post-implantation. Moreover, HP-rhFGF20 promoted the proliferation, migration, and differentiation of neural stem cells and improved neuronal plasticity and angiogenesis in ischemic stroke rats. The authors concluded that HP-rhFGF20 promoted functional recovery in ischemic stroke rats by enhancing neurogenesis and angiogenesis. These researchers stated that the combination of growth factors and biomaterials provided a promising therapeutic strategy for CNS diseases.

Low-Intensity MR-Guided Focused Ultrasound Mediated Disruption of the Blood-Brain Barrier

Meng et al. (2018) stated that low-intensity MR-guided focused ultrasound (MRgFUS) combined with intravenously injected micro-bubbles (MBs) is a promising platform for drug delivery to the central nervous system (CNS) past the blood-brain barrier (BBB), which is a key bottleneck for cancer therapeutics due to limited inter- and intra-cellular transport. Additionally, drugs that cross the BBB when delivered in a spatially non-specific manner can result in adverse effects on normal brain tissue, and high concentrations may increase risks to peripheral organs. Therefore, various anti-cancer drugs that have been developed or will be developed in the future would benefit from a non-invasive, temporary, and repeatable method of targeted opening of the BBB to treat metastatic brain diseases. MRgFUS presents a potential solution to these design requirements. The safety, feasibility, and preliminary effectiveness of MRgFUS-aided delivery have been reported in various animal models. These researchers discussed the pre-clinical evidence, mechanisms of focused ultrasound-mediated BBB opening, and translational efforts to neuro-oncology patients. The authors stated that although still in the early investigational stages, this minimally invasive technology for targeted BBB opening has the potential to revolutionize the care of neuro-oncology patients.

Olsman et al. (2021) noted that the BBB is a major obstacle to treating several brain disorders. Focused ultrasound (FUS) combined with intravascular MBs increases BBB permeability by opening tight junctions, creating openings in endothelial cells, improving endocytosis, and increasing transcytosis. These investigators examined whether combining FUS and micro-bubbles with transferrin receptor-targeting liposomes would enhance delivery to the brain of post-natal rats compared with liposomes lacking the BBB-targeting moiety. Increased BBB permeability was observed following FUS treatment in all animals. A 40% increase in the accumulation of transferrin receptor-targeting liposomes was noted in the FUS-treated hemisphere, whereas isotype immunoglobulin G liposomes showed no increased accumulation. Confocal laser scanning microscopy of brain sections revealed that both types of liposomes were primarily observed in endothelial cells in the FUS-treated hemisphere. The authors concluded that the findings of this study demonstrated that FUS and MB treatment combined with BBB-targeting liposomes could be a promising approach to enhance drug delivery to the brain.

Rodríguez et al. (2023) stated that brain neurodegenerative diseases are CNS afflictions typically common in the elderly. A new therapeutic approach for these conditions involves providing specific drugs to the CNS via blood circulation; however, the BBB prevents almost 100% of neurotherapeutics from reaching the brain. There are indications that FUS, when temporarily applied to the BBB, can achieve a controlled increase in temperature at its focus, allowing for temporary, localized, and reversible opening of the BBB, which facilitates the temporary delivery of specific drugs. These researchers presented a FUS-based protocol for the local, temporary, and reversible opening of the BBB in Wistar rats. The proposed protocol specified certain power levels, treatment times, and duty cycles to controllably increase the temperature at the region of interest, specifically the substantia nigra. Numerical simulations using commercial software based on the finite element method were performed to determine the optimal size of the craniotomies for nearly full acoustic transmission. Experiments in rats were conducted with the parameters used during computational simulations to assess the adequate opening of the BBB. For this, craniotomies of different sizes were made at coordinates of the substantia nigra, and FUS was applied externally. The opening of the BBB was examined using Evans Blue (EB) as an indicator of the dye's crossing from blood vessels to brain tissue. Numerical simulations revealed a greater distance reached by the ultrasound focus with a larger diameter. Experimental results demonstrated the local, temporary, and reversible opening of the BBB via a 10-mm diameter craniotomy, which effectively allowed placement of the ultrasound focus over the substantia nigra, unlike a 6-mm diameter craniotomy, which resulted in a deviation of the focus through that window. Furthermore, these results indicated that the disruption of the BBB was reversible, with an opening duration of 6 hours after FUS application. The authors stated that the experimental work developed in this study resulted in a minimally invasive method for the temporary opening of the BBB. They also noted that preliminary findings showed that this FUS protocol enabled safe and efficient gene delivery by a synthetic nano-vector to dopaminergic neurons of the substantia nigra in Wistar rats; thus, this protocol can aid in implementing drug or gene delivery approaches in pre-clinical studies of Parkinson's disease.

Rouhi et al. (2024) noted that Alzheimer's disease (AD) is characterized by progressive neurodegeneration, memory loss, and cognitive impairment, ultimately resulting in dementia and death. The BBB prevents the delivery of drugs into the brain, which can limit their therapeutic potential in treating AD; thus, there is a need to develop new approaches to bypass the BBB for appropriate treatment of AD. Recently, FUS has been reported to disrupt the BBB, allowing therapeutic agents to penetrate the brain. Furthermore, MBs, as lipophilic carriers, can cross the BBB and deliver active drugs into brain tissue. Therefore, when combined with FUS, drug-encapsulated MBs can pass through the ultrasound-disrupted zone of the BBB and diffuse into brain tissue. The authors stated that further clinical data must be collected to confirm the application of FUS/MBs in humans; thus, future research employing FUS/MBs-based delivery to the brain should focus on improving safety, precise targeting, and pharmacokinetic properties. These researchers concluded that FUS/MBs-based sonogenetics approaches have notable therapeutic potential for AD.

Nose to Brain Delivery of Nano-Structured Lipid Carriers Loaded with Rivastigmine and Nilotinib for the Treatment of Alzheimer's Disease

Khan et al. (2025) stated that Alzheimer's disease (AD) is a complex neurodegenerative that affects over 55 million individuals globally, a number expected to double by 2050 due to aging populations. This growing prevalence imposes immense societal as well as economic burdens on healthcare systems and caregivers. AD is challenging to treat with monotherapy, making combination therapy a more effective approach. These researchers focused on delivering rivastigmine tartrate (RIV) and nilotinib hydrochloride monohydrate (NIL) to the brain to achieve synergistic effects against AD. The optimal ratio of the drug combination was determined using the combination index that was carried out using the Neuro2a cells line. It was found to be 1:1; emphasizing the synergistic effect against the cell lines. Thus, nano-structured lipid carriers (NLCs) were loaded with RIV and NIL, both individually and in combination, developed and optimized in this study. These formulations were characterized for globule size, poly-dispersity index (PDI), as well as entrapment efficiency (EE) for each drug and the combination. The globule size was greater than 200 nm, PDI greater than 0.3; EE less than 85% in all the developed formulations. On performing an in-vitro cell availability study it was found that developed NLCs showed a 1.3 to 1.4-fold increase in the viability of the cells. On performing an in-vivo study, the concentration in the brain following administration of different formulations was in the order of RIV-NIL-NLC > NIL-NLC > RIV-NLC > RIV-NIL SUS > NIL-SUS > RIV-SUS. There was a 3.5- to 5-fold increase in the concentration of RIV and NIL in the brain when administered as RIV-NIL-NLC. The authors concluded that the NLCs with combined drugs demonstrated promising results, enhancing drug permeability via the intra-nasal route; thus, could be used for the treatment of AD.

Thermo-Responsive Solid Lipid Nano-Particles for the Treatment of CNS Tumor

Bera et al. (2025) stated that nano-particulate drug delivery systems have significantly enhanced the effectiveness of many drugs for the treatment of various diseases. Recently, stimuli-responsive drug delivery systems have been used in the treatment of various diseases/conditions, specifically cancer therapy. Thermo-responsive drug delivery systems are most frequently employed for cancer treatment as they can be combined with hyperthermia or radiation therapy (RT). The tumors of the CNS are considered one of the difficult-to-treat cancers due to the limitation of BBB penetration. Thermo-responsive solid lipid nano-particles have the additional advantage of easy BBB penetration. These researchers focused on the potential use of thermos-responsive solid lipid nano-particles in CNS tumor therapy. They summarized various types of solid lipids that can be used for thermos-responsive solid lipid nano-particle formulation; and discussed the methods for preparing thermos-responsive solid lipid nano-particles. These investigators also addressed the mechanisms of drug release from the thermos-responsive solid lipid nano-particles. The authors provided the readers with a more profound knowledge of thermos-responsive solid lipid nano-particle formulations, emphasizing the research on these thermos-responsive solid lipid nano-particles to establish their role in enhanced outcomes of CNS cancer therapy.

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