UC San Diego

Targeted therapeutics should accumulate at disease sites in higher quantities relative to other locations in the body. In cancer therapy, one strategy towards this is to exploit features of the tumor microenvironment (TME) for drug delivery. Herein, drug delivery strategies focusing on the TME are investigated.

First, nanomaterials designed to respond to matrix metalloproteinases (MMPs) are explored for delivery of cytotoxins to tumors. Ring opening metathesis polymerization (ROMP) is employed to generate amphiphilic diblock copolymers containing paclitaxel (PTX) prodrugs and MMP-responsive peptides. These polymers form 20 nm nanoparticles that rearrange to microscale aggregates upon MMP exposure. This process is observed and efficacy evaluated in a fibrosarcoma xenograft model. Critically, these materials have equivalent efficacy to PTX at equivalent doses, but with a 16-fold higher maximum tolerated dose (MTD). Further, nanoparticles containing an MMP-responsive peptide together with platinum (Pt) drugs, 15N-labelled moieties, and near infrared (NIR) fluorophores are developed. These materials are evaluated for their therapeutic efficacy in vivo and the simultaneous, yet independent, tracking of carrier and drug is completed ex vivo using correlative microscopy techniques.

This platform is then extended to the delivery of immunotherapeutics. MMP-responsive nanoparticles containing an immunotherapeutic compound (1V209) are developed and assessed in vitro for immunogenicity and in vivo for efficacy. In a syngeneic orthotopic breast cancer model, 1V209-containing nanoparticles do not cause nonspecific cytokine upregulation and significantly inhibit lung metastasis formation relative to 1V209, non-responsive nanoparticles, and saline.

Dual-responsive nanomaterials are also explored that are designed to respond to two separate features of the TME. Polymers and nanoparticles are designed to release cargo only when both MMPs and reactive oxygen species (ROS) are present.

Finally, a biomaterial-based delivery strategy is explored using human serum albumin (HSA) as a drug carrier of long chain fatty acids (LCFAs) to the TME. Mono-functionalizing octadecanedioic acid (ODDA) with PTX affords a fatty acid-PTX ester prodrug that retains one carboxylic acid moiety to form stable electrostatic interactions with HSA in its natural binding sites for LCFAs. This prodrug is capable of binding to HSA and shows differentiated pharmacokinetics, as well as remarkable tolerability and efficacy in vivo, relative to clinical formulations in multiple xenograft models.