Delivery of Immunotherapeutic Nanoparticles to Tumors via Enzyme-Directed Assembly

Claudia Battistella, Cassandra E. Callmann, Matthew P. Thompson, Shiyin Yao, Anjana V. Yeldandi, Tomoko Hayashi, Dennis A. Carson, Nathan C. Gianneschi*

*Corresponding author for this work

Research output: Contribution to journalArticle

3 Scopus citations

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.

Original languageEnglish (US)
Article number1901105
JournalAdvanced Healthcare Materials
Volume8
Issue number23
DOIs
StatePublished - Dec 1 2019

Keywords

  • drug delivery
  • immunotherapeutic nanoparticles
  • immunotherapeutics
  • polymeric nanoparticles
  • stimuli-responsive materials

ASJC Scopus subject areas

  • Biomaterials
  • Biomedical Engineering
  • Pharmaceutical Science

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