Delivery of Immunotherapeutic Nanoparticles to Tumors via Enzyme‐Directed Assembly. Issue 23 (30th October 2019)

• Record Type: Journal Article
• Authors: Battistella, Claudia; Callmann, Cassandra E.; Thompson, Matthew P.; Yao, Shiyin; Yeldandi, Anjana V.; Hayashi, Tomoko; Carson, Dennis A.; Gianneschi, Nathan C.
• Is Part Of: Advanced healthcare materials. Volume 8:Issue 23(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-10-30
• Subjects: drug delivery -- immunotherapeutic nanoparticles -- immunotherapeutics -- polymeric nanoparticles -- stimuli‐responsive materials; Biomedical materials -- Periodicals; 610.28
• DOI: 10.1002/adhm.201901105
• Languages: English
• ISSNs: 2192-2640

Abstract

Abstract: Amphiphilic diblock copolymers are prepared by ring opening metathesis polymerization, with one block containing hydrophobic Toll‐like receptor 7 (TLR7) agonists and one block containing hydrophilic peptides as substrates for matrix metalloproteinases (MMPs). A fluorescent label is incorporated into the polymer chains for in vivo imaging. Upon dialysis against aqueous solution, polymers form 15 nm spherical micelles. Subsequent exposure to MMP‐9 elicits a morphological change to yield immunostimulatory microscale assemblies. The intravenous (IV) administration of the formulation to mice bearing 4T1 breast cancer tumors results in nanoparticle accumulation in tumors, reduction in primary tumor growth, and inhibition of lung metastases, as compared to saline‐treated animals. Mice administered the parent immunotherapeutic small molecule (1V209) experience significantly increased plasma levels of proinflammatory cytokines IL‐6, IP‐10, and MCP‐1 at 2 h following IV administration, whereas the nanomaterial shows no increase over saline‐treated controls. These data suggest that covalently packaging low molecular weight immunotherapeutics at high weight percent loadings in enzyme‐responsive nanoparticles maintains drug efficacy while decreasing immunotoxicity, providing a platform for cancer immunotherapeutic delivery. Abstract : Enzyme‐responsive nanoparticles containing small molecule immunotherapeutics are synthesized as a drug delivery system to tumors. These nanoparticles can be safely injected intravenously without causing nonspecific immune upregulation and localize to tumor tissue. Furthermore, administration of these nanoparticles in an animal model of metastatic breast cancer results in suppressed primary tumor growth and fewer lung nodules, as compared to saline‐treated controls.