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Delivery of Immunotherapeutic Nanoparticles to Tumors via Enzyme‐Directed Assembly
Author(s) -
Battistella Claudia,
Callmann Cassandra E.,
Thompson Matthew P.,
Yao Shiyin,
Yeldandi Anjana V.,
Hayashi Tomoko,
Carson Dennis A.,
Gianneschi Nathan C.
Publication year - 2019
Publication title -
advanced healthcare materials
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.288
H-Index - 90
eISSN - 2192-2659
pISSN - 2192-2640
DOI - 10.1002/adhm.201901105
Subject(s) - in vivo , proinflammatory cytokine , materials science , pharmacology , nanoparticle , chemistry , cancer research , biophysics , nanotechnology , medicine , inflammation , immunology , biology , microbiology and biotechnology
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.