Intratumoral (IT) drug injections reduce systemic toxicity, but delivered volumes and distribution can be inconsistent. To improve IT delivery paradigms, porphyrin-phospholipid (PoP) liposomes were passively loaded with 3 hydrophilic cargos: SRB, a fluorophore; Gd-DTPA, a magnetic resonance (MR) agent; and oxaliplatin, a colorectal cancer chemotherapeutic. Liposome composition was optimized so that cargo was retained in serum and storage, but was released in less than one minute with exposure to near infrared (NIR) light. Light-triggered release occurred with PoP-induced photooxidation of unsaturated lipids and all cargos released concurrently. In subcutaneous murine colorectal tumors, drainage of released cargo was delayed when laser treatment occurred 24 hours after IT injection, at doses orders of magnitude lower than systemic ones. Delayed light-triggering resulted in substantial tumor shrinkage relative to controls a week following treatment, although regrowth occurred subsequently. MR imaging revealed that over this time frame, pools of liposomes within the tumor migrated to adjacent regions, possibly leading to altered spatial distribution during triggered drug release. Although further characterization of cargo loading and release is required, this proof-of-principle study suggests that multimodal theranostic IT delivery approaches hold potential to both guide injections and interpret outcomes, in particular when combined with chemophototherapy.

Surfactant-stripped, nanoformulated naphthalocyanines (nanonaps) can be formed with Pluronic F127 and low temperature membrane processing, resulting in dispersed frozen micelles with extreme contrast in the near infrared. Here, we demonstrate that nanonaps can be used for multifunctional cancer theranostics. This includes lymphatic mapping and whole tumor photoacoustic imaging following intradermal or intravenous injection in rodents. Without further modification, pre-formed nanonaps were used for positron emission tomography and passively accumulated in subcutaneous murine tumors. Because the nanonaps used absorb light beyond the visible range, a topical upconversion skin cream was developed for anti-tumor photothermal therapy with laser placement that can be guided by the naked eye.

In this work we investigate the mechanisms by which very long chain fatty acids (VLCFA) contribute to membrane permeabilization during necroptosis, a form of highly regulated necrotic cell death. We show that inactivating fatty acid elongase ELOVL7 prevents VLCFA accumulation and necroptotic cell death, while it's overexpression causes membrane permeabilization. We show that VLCFA can directly permeabilize lipid bilayers and investigate the basis of these effects by molecular dynamics simulations. Finally, we show that VLCFA can be used as substrates for protein fatty acylation during necroptosis, suggesting another potential mechanism by which VLCFA may mediate membrane permeabilization.