Role of chitosan co-formulation in enhancing interleukin-12 delivery and antitumor activity.
Role of chitosan co-formulation in enhancing interleukin-12 delivery and antitumor activity.
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DOI：
10.1016/j.biomaterials.2013.02.031
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发表时间：
2013-05
期刊：
影响因子：
14
通讯作者：
Zaharoff, David A.
中科院分区：
文献类型：
--
作者：
Yang, Lirong;Zaharoff, David A.
为了实现基于细胞因子的免疫疗法的潜力，需要在肿瘤微环境中提供持续、高浓度的抗肿瘤细胞因子的局部递送系统，同时最大限度地减少全身传播。最近，细胞因子与壳聚糖溶液的共同配方已被证明可以增加局部细胞因子的保留和生物活性。特别是，瘤内注射壳聚糖/IL-12可以消除已建立的肿瘤并产生肿瘤特异性免疫反应。本研究旨在探讨壳聚糖增强IL-12抗肿瘤活性的机制。壳聚糖/IL-12注射的位置对细胞因子的最佳递送至关重要。it注射消除了10例MC38腺癌中的9例，而对侧和瘤周注射延缓了肿瘤的生长，但不能消除肿瘤。微剂量研究表明，通过每日单独注射IL-12来模拟IL-12库，其效果不如每周注射壳聚糖/IL-12。50-75%的小鼠每日接受微量剂量的IL-12治疗，87.5%的小鼠每周接受壳聚糖/IL-12治疗，MC38肿瘤治愈。壳聚糖可使肿瘤和肿瘤引流淋巴结（tdln）中il -12介导的白细胞扩增分别增加40%和100%。免疫表型研究表明，壳聚糖共制剂放大了il -12诱导的肿瘤和tdln树突状细胞群中CD8+IFN-γ+和NKT细胞等重要效应细胞群的增加。在接受壳聚糖或壳聚糖/IL-12治疗的小鼠中，也观察到Gr-1+CD11b+肿瘤浸润显著增加。该人群不表现出抑制作用，可能促进局部抗肿瘤反应。目前的数据表明，壳聚糖介导的仓库形成和增强的局部细胞因子保留是显著的，但不是完全负责细胞因子生物活性的增加。
Local delivery systems that provide sustained, high concentrations of antitumor cytokines in the tumor microenvironment while minimizing systemic dissemination are needed to realize the potential of cytokine-based immunotherapies. Recently, co-formulations of cytokines with chitosan solutions have been shown to increase local cytokine retention and bioactivity. In particular, intratumoral (i.t.) injections of chitosan/IL-12 can eliminate established tumors and generate tumor-specific immune responses. In the present study, we explored the mechanisms by which chitosan potentiated IL-12’s antitumor activity. The location of chitosan/IL-12 injection was found to be critical for optimal cytokine delivery. I.t. injections eliminated 9 of 10 MC38 adenocarcinomas while contralateral and peritumoral injections delayed tumor growth but could not eliminate tumors. Microdosing studies demonstrated that IL-12 depots, simulated through daily i.t. injections with IL-12 alone, were not as effective as weekly i.t. chitosan/IL-12. 50–75% of mice receiving daily IL-12 microdoses and 87.5% of mice receiving weekly chitosan/IL-12 were cured of MC38 tumors. Chitosan was found to increase IL-12-mediated leukocytic expansion in tumors and tumor-draining lymph nodes (TDLNs) by 40% and 100%, respectively. Immunophenotyping studies demonstrated that chitosan co-formulation amplified IL-12-induced increases in important effector populations, such as CD8+IFN-γ+ and NKT cells, in tumors and dendritic cell populations in TDLNs. Remarkable increases in Gr-1+CD11b+ tumor infiltrates were also observed in mice receiving chitosan or chitosan/IL-12. This population does not appear be suppressive and may facilitate the local antitumor response. Presented data suggest that chitosan-mediated depot formation and enhanced local cytokine retention is significantly, but not entirely, responsible for increased cytokine bioactivity.
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影响因子：
45.3
作者：
FYFE, G;FISHER, RI;LOUIE, AC
通讯作者：
LOUIE, AC
DOI：
10.1111/j.1749-6632.1996.tb52676.x
发表时间：
1996-01-01
期刊：
INERLEUKIN 12: CELLULAR AND MOLECULAR IMMUNOLOGY OF AN IMPORTANT REGULATORY CYTOKINE
影响因子：
--
作者：
Brunda, MJ;Luistro, L;Palleroni, AV
通讯作者：
Palleroni, AV
影响因子：
5.5
作者：
McNeela, EA;Jabbal-Gill, I;Mills, KHG
通讯作者：
Mills, KHG
影响因子：
39.2
作者：
GROOPMAN, JE;GOTTLIEB, MS;VOLBERDING, PA
通讯作者：
VOLBERDING, PA
DOI：
10.2174/187153007782794335
发表时间：
2007-12-01
影响因子：
1.9
作者：
Egilmez, Nejat K.;Kilinc, Mehmet O.;Conway, Thomas F.
通讯作者：
Conway, Thomas F.