Convection Enhanced Drug-Loaded Nanocarrier Delivery for Glioma Therapy

B. Anderson, M. Leggas, P. Hardy

Convection Enhanced Delivery (CED) may improve drug delivery to GBMs while sparing the normal systemic and CNS tissues. CED has several advantages for the treatment of gliomas:

1. it can deliver high drug concentrations directly to the tumor;
2. drug infusion is driven by a positive pressure pump to overcome the high interstitial tumor pressure;
3. the catheter –pump combination allows precise control over the concentration profile inside and outside the tumor.

Although advantageous in terms of localized delivery, CED of chemotherapy in the brain may not be optimal for highly permeable, lipophilic drugs that can be readily taken up by capillaries and removed by the blood. Given the steep concentration gradients away from the site of administration, drug may be cleared before it can reach cancer cells in diffuse gliomas. An alternative approach would be to entrap drug in nanocarriers, such as liposomes for sufficient length of time to utilize CED and create a broad distribution profile of drug-loaded carrier. Provided that a controlled and tunable drug release can be achieved from these broadly distributed particles, it is possible that better drug exposure will be achieved in diffuse gliomas.

Trainees involved in this program will work with Leggas to implement a xenograft glioma model in nude rats. Stereotactic techniques will be used to inject luciferin expressing U87 glioblastoma cells intracranially. Tumor growth will be monitored using an IVIS 100 system (Xenogen Corp). Nanocarrier liposomes loaded with the highly lipophilic camptothecin analog AR-67 or other drugs will be prepared under the direction of Anderson. Drug loading using metal salts will be used to achieve tunable release rates. Multifunctional particles with either iron or gadolinium complexes will also be considered for therapeutic and diagnostic purposes. Trainees will work with Leggas and Hardy to administer the nanocarriers and to co-infuse contrast agents which would allow monitoring particle dispersion during the infusion. Alternatively, multifunctional particles may be used for monitored particle dispersion. Detailed studies will be carried out to optimize infusion parameters, catheter placement, flow rate, and total infusion volume. The overall goal would be to achieve increased drug exposure in these tumors and minimize systemic toxicity. Trainees will also be exposed to ongoing studies to understand and model drug release kinetics, optimize liposome size for optimal CED based treatment.