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一种作为抗肿瘤免疫调节剂的Toll样受体7/8激动剂的制剂及临床前评价

Formulation and preclinical evaluation of a toll-like receptor 7/8 agonist as an anti-tumoral immunomodulator.

作者信息

Lu Ruolin, Groer Chad, Kleindl Peter A, Moulder K Ryan, Huang Aric, Hunt Jordan R, Cai Shuang, Aires Daniel J, Berkland Cory, Forrest M Laird

机构信息

Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas, United States of America.

HylaPharm LLC, Lawrence, Kansas, United States of America.

出版信息

J Control Release. 2019 Jul 28;306:165-176. doi: 10.1016/j.jconrel.2019.06.003. Epub 2019 Jun 4.

DOI:10.1016/j.jconrel.2019.06.003
PMID:31173789
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6679596/
Abstract

The toll-like receptor 7 and 8 (TLR7/8) agonist Resiquimod (R848) has been recognized as a promising immunostimulator for the treatment of cutaneous cancers in multiple clinical trials. However, systemic administration of R848 often results in strong immune-related toxicities while having limited therapeutic effects to the tumor. In the present study, a prodrug-based nanocarrier delivery system was developed that exhibited high therapeutic efficiency. R848 was conjugated to α-tocopherol to constitute an R848-Toco prodrug, followed by formulating with a tocopherol-modified hyaluronic acid (HA-Toco) as a polymeric nano-suspension. In vitro evaluation showed that the delivery system prolonged the release kinetics while maintaining TLR agonist activities. When administered subcutaneously, the nano-suspension formed a depot at the injection site, inducing localized immune responses without systemic expansion. This formulation also suppressed tumor growth and recruited immune cells to the tumor in a murine model of head and neck cancer. In a preclinical canine study of spontaneous mast cell tumors, the treatment led to a 67% response rate (three partial remissions and one complete remission).

摘要

Toll样受体7和8（TLR7/8）激动剂瑞喹莫德（R848）在多项临床试验中已被公认为是一种有前景的用于治疗皮肤癌的免疫刺激剂。然而，全身性给予R848常常会导致强烈的免疫相关毒性，同时对肿瘤的治疗效果有限。在本研究中，开发了一种基于前药的纳米载体递送系统，该系统表现出高治疗效率。R848与α-生育酚缀合以构成R848-生育酚前药，随后与生育酚修饰的透明质酸（HA-生育酚）一起配制成聚合物纳米混悬液。体外评估表明，该递送系统延长了释放动力学，同时保持了TLR激动剂活性。当皮下给药时，纳米混悬液在注射部位形成储库，诱导局部免疫反应而无全身扩散。在头颈癌小鼠模型中，该制剂还抑制了肿瘤生长并将免疫细胞募集到肿瘤部位。在一项针对自发性肥大细胞瘤的临床前犬类研究中，该治疗导致67%的缓解率（3例部分缓解和1例完全缓解）。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9145/6679596/3612ec288570/nihms-1533054-f0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9145/6679596/f28ff587ee02/nihms-1533054-f0002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9145/6679596/b4df540dc1e0/nihms-1533054-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9145/6679596/32663d857b74/nihms-1533054-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9145/6679596/0e5689693d86/nihms-1533054-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9145/6679596/1020bd98afd8/nihms-1533054-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9145/6679596/eae9f2a2c1d7/nihms-1533054-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9145/6679596/5cb30c2c5d2d/nihms-1533054-f0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9145/6679596/6523998798d8/nihms-1533054-f0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9145/6679596/3612ec288570/nihms-1533054-f0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9145/6679596/f28ff587ee02/nihms-1533054-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9145/6679596/3083fd92582a/nihms-1533054-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9145/6679596/b4df540dc1e0/nihms-1533054-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9145/6679596/32663d857b74/nihms-1533054-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9145/6679596/0e5689693d86/nihms-1533054-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9145/6679596/1020bd98afd8/nihms-1533054-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9145/6679596/eae9f2a2c1d7/nihms-1533054-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9145/6679596/5cb30c2c5d2d/nihms-1533054-f0009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9145/6679596/3612ec288570/nihms-1533054-f0011.jpg

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