Hydroxyapatite-Tariquidar Long-Term Diminish Drug Clearance in Brain and Drug Resistance in Glioblastoma Multiforme

Glioblastomas (GBM) are one of the most aggressive tumor in the central nervous system (CNS) with a nearly 100% death rate without treatment. Even after advance treatments, an average of only 1-2 years life extend is expected. There are a few anticancer drugs that are able to use in the therapy of GBM, and Temozolomide (TMZ) is the first new chemotherapy agent approved in more than 20 years. It has good oral bioavailability with limited side effects, and is capable of penatrating through the blood brain barrier (BBB). However, the difficulty in GBM treatment lies both in the inherent complexity and numerous mechanisms of drug resistance. One of the important mechanism of drug resistance is GBM can include drug efflux by using varies transporters, which removes drugs out of the cancer cells, and even out of the brain, before they can take effects.An ideal small molecule chemotherapy agent should be retained in the primary target tumor site in the brain, of the exposed subject for sufficient periods to inhibit and kill cancer cells. However, many drugs will be cleared by specific transporters on the BBB. The principle of diminishing drug clearance and resistance has been employed pharmacologically for years to enhance drug action. We believe that we can markedly prolong the drug capacity of TMZ by inhibiting the P-glycoprotein (P-gp) transporter. We plane to employ a P-gp inhibitor, tariquidar (TQD), as a reference compound and show brain ratio of TMZ, are elevated and drug resistance is reduced. To match the daily oral uptake of TMZ, we plan to use a biodegradble nano-material, meso-porous hydroxyapatite (mesoHAP), to carrier TQD forming mesoHAP-TQD, and provide a long-term drug release through intramuscular (IM) injection. The release mechnisim of TQD is not based on concentration gradient like in most carriers; instead it is controlled by the endocytosis of macrophage, which transfers mesoHAP-TQD to the acid lysosome for dissolution, and releasing TQD to the blood stream to maintain drug concentation for long period of time. In the animal study, we will use TMZ and mesoHAP-TQD to treat mice with ALTS1C1 glioma cells implantion in the brain. The results will be evaluated by magnetic resonance imaging (MRI) according to the tumor size. This design may repurpose pharmacological agents that inhibit transporters responsible for the efflux transport of chemotherapy agents; offers an attractive avenue to enhance the efficacy of TMZ during GBM treatment.