Abstract 820: Photo-activatable ON-OFF microparticles for on-demand pulsatile drug delivery in a breast cancer model

Abstract The ability to treat tumors with high efficacy in a local microenvironment, while mitigating the side effects of systemic toxicity is an area of active investigation. Towards this goal, designing a minimally-invasive local therapeutic modality, with a controlled, pulsatile drug release mechanism is an attractive proposition. In this study, a near-infrared (NIR) photo-activatable microparticle was developed for localized, pulsatile delivery of encapsulated anticancer drugs into the tumor with simultaneous thermal ablation, with controlled ON-OFF thermal cycles using NIR laser irradiation. The microparticles were fabricated using a poly(caprolactone) (PCL) matrix, containing 2D molybdenum disulfide (MoS2) nanosheets as the NIR-responsive photothermal agent, and doxorubicin or violacein, as hydrophilic and hydrophobic model anticancer drugs, respectively. Cubic microparticles of 200 µm size were fabricated by casting a polymer-MoS2-drug film on PDMS mold with loading efficiency of 2 μg MoS2 per particle, and 0.2-8 μg of drug per particle. A cytotoxicity assay was performed to test the efficacy of the loaded microparticles in reducing the viability of 4T1 murine-derived cell culture, using the ON-OFF laser switch mechanism. In order to select a suitable laser power and duration of treatment for in vivo studies, a Machine Learning algorithm based on a Random Forest classifier was trained, to arrive at the optimal treatment conditions: 0.4-0.5 W/cm2 of laser power at 808 nm, for 3 cumulative minutes of laser irradiation, to reach the target temperature of 50 °C, which activates PCL melting and subsequent drug release. The effect of pulsatile treatment was studied in vivo in a murine-derived 4T1 subcutaneous mouse model of breast cancer, using this photo-activatable ON-OFF switch mechanism, for up to 3 cycles of laser irradiation. As control groups, tumor only (no treatment), laser only (no drug or microparticle), drug only (no laser or microparticle), microparticles only (no drug or laser), and microparticles with laser (no drug) were studied. The cohorts receiving the photo-activated 3-cyclic treatment for both drugs showed increased median survival up to 40 days post tumor induction, compared to a median survival of 16 days for the control groups. Although one laser cycle was enough to trigger drug release, there was a significant shrinkage in the tumor volume noticed with 3 cycles, with eventual scarring and shedding of the tissue with no evidence of residual tumor at the primary site. While this cyclic drug release modality is very effective at treating the primary site, subsequent histopathology revealed that the aggressive tumor in some animals had metastasized to the liver and other organs. More work is ongoing to design better targeted approaches to deliver the drug-loaded microparticles to the site of metastatic tumors, to increase the survival prospects of this disease. Citation Format: Maria Kanelli, Neelkanth M. Bardhan, Morteza Sarmadi, Shahad Alsaiari, William Rothwell, Apurva Pardeshi, Angela M. Belcher, Ana Jaklenec, Robert S. Langer. Photo-activatable ON-OFF microparticles for on-demand pulsatile drug delivery in a breast cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 820.