R. Bellamkonda, Georgia Institute of Technology
Gliomas are highly invasive and diffuse; hence, surgical resection, radiation and local delivery of drugs have not been effective treatments, resulting in an extremely poor prognosis for patients diagnosed with high-grade gliomas. Nanocarrier mediated therapy of gliomas has promise because multi-functional nanocarriers can theoretically be designed not only to carry a range of chemotherapeutic or anti-invasive agents (and not just low molecular weight, uncharged lipophilic drugs), but also to both passively and actively target intracranial tumors such as gliomas. However, targeting nanocarriers to tumors has not been very effective due to increased clearance of nanocarriers from circulation due to the presence of targeting ligands compared to non-targeted nanocarriers.
This project proposes an innovative strategy to use long polyethylene glycol (PEG) chains to "mask" the targeting ligands (folate, targeting the folate receptor over-expressed in gliomas) while the nanocarriers are in circulation, protecting them from accelerated clearance. PEG-lipid conjugates will be synthesized with a link that can be "cleaved" using a safe trigger such as cysteine. The targeting ligand can then be "unmasked" after the nanocarriers extravasate to the tumor using systemic administration of a safe level of exogenous cysteine to trigger active targeting of tumors. Cysteine, due to its small size, freely leaks into tumors from circulation, which has been confirmed experimentally and via mathematical modeling. Thus, the proposed strategy will exploit the advantages of active targeting which include increased tumor retention and more efficient drug uptake in the tumor, without sacrificing passive dosing of the nanocarriers to the tumor, a parameter critically dependent on circulation time of the nanocarriers. Additionally, liposomal nanocarriers can potentially carry a wide range of chemotherapeutic drugs (including doxorubicin as proposed in this study) as well as MR/CT contrast agents to facilitate real-time pharmacokinetics of systemically administered nanocarriers.
The current prognosis of a mean survival time of 9 months after diagnosis of high-grade glioma, and only a 2 month extension in life after treatment of local delivery of BCNU with Gliadel wafers is unacceptable. Given its invasive and diffuse nature, systemic chemotherapy is the best route to treat gliomas; however, due to blood brain barrier imposed limitations, even with leaky blood vessels resulting from the enhanced permeation effect, a very limited range of lipophilic, low molecular weight, uncharged set of chemotherapeutics are used for systemic chemotherapy today, and their impact is limited.
Multi-functional liposomal nanocarriers have the promise of delivering a wide range of chemotherapeutics, and lend themselves well to incorporation of MR and CT contrast agents for real-time pharmaco-kinetic tracking of carriers such that tumor dosing, retention time and distribution can be evaluated for patient-specific therapy. Additionally, by presenting targeting ligands to modulate the efficiency of cellular uptake, tumor retention times and distribution, liposomal nanocarriers can significantly enhance the capabilities of current generation of systemic chemotherapy options available to the clinician today. However, targeting ligands on the nanocarrier surface compromise the circulation time of nanocarriers, limiting the number of carriers that reach the tumor, offsetting any gains of active targeting. Therefore in proposing an innovative solution to preserving circulation time of nanocarriers and yet, not compromising their ability to actively target gliomas, the proposed research has implications for glioma prognosis, and for the use of nanocarriers as systemically delivered targeting agents in general. The PI's group's ability to combine contrast agents as well as chemotherapeutics in liposomal nanocarriers gives the potential to truly "personalize" systemic chemotherapy by observing tumor dosing and retention and efficacy in "real-time". Therefore, the research proposed is a functional piece of a larger effort to develop personalized, targeted nanotherapies for treating gliomas of the brain.