X. Li, J. Rong, D. Su, J.Z. Zhou
Keywords: bone marrow, blood cancer, chemotherapy, radiation, myelosuppression, myelotoxicity, hematopoietic disorders, delivery system
Summary:Bone marrow is the primary hematopoietic organ. Conventional delivery of drugs into bone marrow relies on the systemic distribution of drug molecules that are introduced to the body by any common route of systemic administration. Availability of drugs in the bone marrow is relatively low because most of the administrated drugs either accumulate in other highly perfused tissues/organs or are cleared by the body’s metabolic/excretory system prior to reaching the bone marrow. Therefore, it always requires administering drugs at higher doses and/or more frequent dosing for reaching the effective therapeutic magnitude inside the bone marrow, which often leads to inevitable adverse effects. To improve the drug availability in bone marrow, several delivery strategies based on liposomes were developed relying on the modulation of their physiochemical properties to affect its distribution profile. Vyxeo is a long-circulating liposomal formulation of cytarabine and daunorubicin, which was approved as the first-line treatment of acute myeloid leukemia due to its ability to maintain the therapeutic concentrations of such two drugs in bone marrow for a long timeframe. Polymeric nanoparticles or micelles with passive targeting (by immune cells such as macrophages), vascular targeting, or bone surface-targeting profile were also demonstrated to be reasonably effective for enhanced bone marrow delivery. However, the off-tissue distribution of these nanoparticle drugs (e.g., in the spleen and liver) remained an unmet clinical problem for these strategies, which limited the delivery efficacy and caused side effects. Zymeron developed an advanced bone marrow-targeting delivery platform, which specifically transports cargo molecules into the bone marrow with a tunable controlled release profile. The principle of concept has been demonstrated by delivering an FDA-approved prophylactic small molecule drug to prevent the DNA damage of hematopoietic stem and progenitor cells in animal models. When delivered by Zymeron’s platform technology, 1) the therapeutic window of the drug was significantly extended in a tunable fashion to a practically favorable range between 6 and 24h after subcutaneous drug administration compared to that for the free small molecule drug of less than 30 minutes. 2) Moreover, 60 mg/kg of API equivalent dose achieved comparable therapeutic efficacy with the free small molecule drug dose of 300 mg/kg. 3) Importantly, it was also demonstrated that bone marrow was the only primary drug accumulation site (i.e., greater than 40%) compared to other organs, indicating predominant tissue-specific delivery effectiveness and lower off-tissue toxicity. It is anticipated that this novel bone marrow-targeting delivery platform could be used for an array of bone marrow-associated drugs with potential applications in treating blood cancers (e.g., acute myeloid leukemia, multiple myeloma), chemotherapy-induced myelosuppression, radiation-induced myelotoxicity among other hematopoietic disorders. Particularly, myelosuppression is a critical dose-limiting factor causing chemotherapy dose reduction, delay or even discontinuation. Zymeron is developing bone marrow-targeted myeloprotection therapeutics to improve outcomes (enhanced anti-tumor efficacy and reduced myelotoxicity) for patients undergoing chemotherapy.