Nanomedicines for Delivery of Cytarabine: Effect of Carrier Structure and Spacer on the Anti-Lymphoma Efficacy

High-dose therapy with cytarabine (araC) is a standard treatment for aggressive non-Hodgkin lymphomas, but its efficacy is limited by rapid enzymatic degradation. To overcome this, araC was conjugated to <i>N</i>-(2-hydroxypropyl)methacrylamide (HPMA) copolymers to form linear and star-like nanomedicines using six different spacers: 3-aminopropanoyl, 5-pentanoyl, 6-aminohexanoyl, 4-aminobenzoyl, glycyl, and diglycyl. The conjugates contained 12.5-14.7 wt% araC and exhibited distinct hydrolytic release profiles at pH 7.4. <b>LC1</b> (3-aminopropanoyl) and <b>LC6</b> (diglycyl) released the drug most rapidly (~80% bound after 72 h), and <b>LC2</b>, <b>LC3</b>, and the star conjugate <b>SC1</b> showed intermediate stability (~90%), while <b>LC4</b> (4-aminobenzoyl) was most stable (~95%). In vivo, all conjugates markedly suppressed tumor growth in patient-derived xenograft models of mantle cell and Burkitt lymphoma compared with free araC. <b>LC1</b> and <b>LC2</b> provided the most durable tumor control, delaying regrowth beyond 40 days, and <b>SC1</b> achieved comparable efficacy at a reduced araC-equivalent dose (2 mg/mouse vs. 3 mg/mouse for linear conjugates). These results demonstrate that spacer structure critically influences drug release and identify <b>LC1</b> and <b>LC2</b> as promising candidates for further development in lymphoma therapy.