由于难以达到和维持治疗药物在目标组织和细胞中的浓度，白血病仍然难以治愈。下一代药物针对多个细胞关卡，包括口服活性venetoclax（Bcl-2靶点）和zanubrutinib（BTK靶点），具有比传统的非靶向化疗更高的安全性和耐受性。然而，单一药物剂量的使用通常会导致药物耐药性；由于两种或更多口服药物的高峰和低谷时间，异步覆盖阻止了药物组合同时消除各自药物的靶点以维持白血病的抑制。更高剂量的药物可能通过饱和靶点占用来克服白血病细胞中异步药物暴露的困难，但更高剂量通常会导致剂量限制性毒性。为了同步多药靶向消除，我们已经开发并表征了一种药物组合纳米粒子（DcNP），它可以将两种短效、口服白血病药物（venetoclax和zanubrutinib）转化为长效纳米制剂（VZ-DCNPs）。VZ-DCNPs展示了venetoclax和zanubrutinib的同步和增强的细胞摄取和血浆暴露。两种药物都由脂质成分稳定，以产生悬浮液中的VZ-DcNP纳米颗粒（d ~ 40 nm）产品。VZ-DcNP制剂在不死白血病细胞（HL-60）中的两种药物（VZ）的摄取量比其自由药物对应物高三倍。此外，VZ的药物靶点选择性在过度表达每个靶点的MOLT-4和K562细胞中得到注意。在小鼠皮下给予时，venetoclax和zanubrutinib的半衰期分别比等效的自由VZ延长大约43倍和5倍。总体而言，这些数据表明，在白血病治疗中，VZ-DcNP中的VZ作为同步和长效药物组合的临床前和临床开发值得考虑。

Leukemia remains incurable partly due to difficulties in reaching and maintaining therapeutic drug concentrations in the target tissues and cells. Next-generation drugs targeted to multiple cell checkpoints, including the orally active venetoclax (Bcl-2 target) and zanubrutinib (BTK target), are effective and have improved safety and tolerability compared to conventional, nontargeted chemotherapies. However, dosing with a single agent frequently leads to drug resistance; asynchronous coverage due to the peak-and-trough time-course of two or more oral drugs has prevented drug combinations from simultaneously knocking out the respective drugs' targets for sustained leukemia suppression. Higher doses of the drugs may potentially overcome asynchronous drug exposure in leukemic cells by saturating target occupancy, but higher doses often cause dose-limiting toxicities. To synchronize multiple drug target knockout, we have developed and characterized a drug combination nanoparticle (DcNP), which enables the transformation of two short-acting, orally active leukemic drugs, venetoclax and zanubrutinib, into long-acting nanoformulations (VZ-DCNPs). VZ-DCNPs exhibit synchronized and enhanced cell uptake and plasma exposure of both venetoclax and zanubrutinib. Both drugs are stabilized by lipid excipients to produce the VZ-DcNP nanoparticulate (d ~ 40 nm) product in suspension. The VZ-DcNP formulation has enhanced uptake of the two drugs (VZ) in immortalized leukemic cells (HL-60), threefold over that of its free drug counterpart. Additionally, drug-target selectivity of VZ was noted with MOLT-4 and K562 cells that overexpress each target. When given subcutaneously to mice, the half-lives of venetoclax and zanubrutinib were extended by approximately 43- and 5-fold, respectively, compared to an equivalent free VZ. Collectively, these data suggest that VZ in VZ-DcNP warrant consideration for preclinical and clinical development as a synchronized and long-acting drug-combination for the treatment of leukemia.