Department of Biomedical Engineering, The University of Texas, Austin, TX 78712, USA.
J Control Release. 2011 Oct 30;155(2):184-92. doi: 10.1016/j.jconrel.2011.06.008. Epub 2011 Jun 21.
Patients with malignant non-Hodgkin's lymphomas (NHL) of B-cell lineages relapse despite initial anti-tumor response to chemotherapy or antibody treatments. Failure to eliminate the tumor is often because of inadequate priming, low cell numbers and suboptimal phenotype of effector T cells. Here we describe a new biomaterial-based controlled-release paradigm to treat weakly immunogenic NHLs by in-situ amplifying the number of functional, antigen-specific T-helper 1 (Th1) cells following immunotherapy. An injectable, synthetic immune priming center (sIPC) consisting of an in-situ crosslinking, chemokine-carrying hydrogel and both DNA- and siRNA dual-loaded microparticles, is reported. This sIPC chemo attracts a large number of immature dendritic cells (DCs) at the site of administration and efficiently co-delivers both DNA antigens and interleukin-10 (IL10)-silencing siRNA to those cells. Using a murine model of A20 B cell lymphoma, we demonstrate that combination of DNA-antigen delivery and IL10 silencing, synergistically activate recruited immature DCs and cause a strong shift towards Th1 response while suppressing Th2 and Th17 cytokines. sIPC-based immunotherapy showed 45% more CD8+ cytotoxic T cell (CTL) response and 53% stronger CD4+ CTL activity compared to naked DNA vaccine. In addition, in-vivo sIPC immunization induced significant protection (p<0.01) against subsequent tumor challenge. Such a multi-modal, injectable system that simultaneously delivers chemokines, siRNA and DNA antigens to DCs marks a new approach to in-situ priming and modulation during immunotherapy and could provide effective vaccination strategies against cancers and infectious diseases.
患有 B 细胞谱系恶性非霍奇金淋巴瘤（NHL）的患者尽管最初对化疗或抗体治疗有抗肿瘤反应，但仍会复发。肿瘤无法消除通常是由于初始刺激不足、效应 T 细胞数量低和表型不理想。在这里，我们描述了一种新的基于生物材料的控释范式，通过免疫治疗后在原位扩增功能、抗原特异性 T 辅助 1（Th1）细胞的数量来治疗弱免疫原性 NHL。报告了一种可注射的合成免疫启动中心（sIPC），由原位交联的趋化因子载体水凝胶和双载 DNA 和 siRNA 的微颗粒组成。这种 sIPC 化学物质会在给药部位吸引大量未成熟树突状细胞（DC），并有效地将 DNA 抗原和白细胞介素 10（IL10）沉默 siRNA 共同递送到这些细胞中。使用 A20 B 细胞淋巴瘤的小鼠模型，我们证明 DNA 抗原递送和 IL10 沉默的联合使用可协同激活募集的未成熟 DC，并导致强烈的 Th1 反应，同时抑制 Th2 和 Th17 细胞因子。与裸 DNA 疫苗相比，sIPC 为基础的免疫治疗显示出 45%更强的 CD8+细胞毒性 T 细胞（CTL）反应和 53%更强的 CD4+CTL 活性。此外，体内 sIPC 免疫接种可显著保护（p<0.01）免受随后的肿瘤挑战。这种多模式、可注射的系统可同时将趋化因子、siRNA 和 DNA 抗原递送至 DC，为免疫治疗中的原位启动和调节开辟了一条新途径，并可为癌症和传染病提供有效的疫苗接种策略。
