Engineering Multifunctional Nanoparticles: Applied Nanoscale Therapeutics

Abstract

Decades of research towards the development of nanomedicines have, to date, yielded minimal clinical impact. Focused particularly on the treatment of cancer, the relatively low number of pursued technologies to reach the market can in part be attributed to the complex biological barriers and clearance mechanisms nanomedicines must overcome to reach their intended target. Together with a dynamic and heterogeneous disease landscape, the development of more sophisticated and multifunctional delivery systems may be required. Here, we leverage our ability to produce multifunctional nanoparticles through EHD co-jetting to engineer novel drug delivery systems.

Collaborative work first identified synergistic combinations of lapatinib and paclitaxel in HER2+ breast cancer. Findings yielded optimized synergistic drug ratios and revealed a dependence upon the temporal delivery of the two agents. Utilizing EHD co-jetting and the synthetic polymers PLGA and pH responsive acetalated dextran, a controlled and scheduled release of two compounds was achieved from a single particle architecture. Decoupled release kinetics exhibited dependence upon bulk polymer properties, rather than chemical structures of encapsulated materials. These properties were leveraged to engineer dual drug-loaded Janus particles capable of sequentially releasing lapatinib and paclitaxel. Ultimately, we demonstrate an ability to achieve controlled delivery and similar synergistic activities in HER2+ breast cancer cells, comparable to free-drug studies.

Inspired by nature, significant efforts were then directed at the development of synthetic protein nanoparticles (SPNPs). In moving away from synthetic polymers, we sought to develop more biocompatible particle systems capable of targeted delivery, rapid clearance from off-target organs, and to efficiently deliver therapeutics while minimizing harmful immune responses. We began by developing an extensive protein particle platform, evaluating a range of proteins and crosslinking macromers. The engineered particles were shown to be monodisperse, stable, responsive to pH, and capable of encapsulating therapeutic molecules with diverse physical properties. The result is a modular platform, designed to evolve, with the capacity to optimize particle properties to meet disease-specific challenges. Extending beyond the bulk properties of SPNPs, we demonstrate an ability to actively target particles through cell-specific interactions and alter biodistribution. Compared to untargeted SPNPs, YN1 (Anti-ICAM) SPNPs exhibit an 80-fold increase in lung targeting following systemic delivery.

Finally, we leverage the active targeting and drug delivery capacity of SPNPs towards the treatment of glioblastoma (GBM). An axis for tumor progression and immune response in GBM, STAT3 serves as an attractive therapeutic target; however, inability to effectively traverse the blood-brain barrier (BBB) has limited clinical translation. Challenged with the task of accessing the CNS, we demonstrate an ability to successfully deliver therapeutic doses of siRNA against STAT3 across the BBB. Combined with standard of care, ionized radiation, the targeted protein particles result in 87.5% of mice reaching the long-term survival point in a highly aggressive intracranial GBM model. In addition to increased median survival, we observe a robust immune response characterized by increased tumor-antigen specific CD8 T cells and decreased immune suppressive M2 macrophages within the brain. When rechallenged, all previously cured mice are found to reach a second long-term survival time point in the absence of further treatments, suggesting the development of an anti-GBM immune response.

Moving forward, we aim to apply these fundamental understandings and design parameters towards engineering more complex protein particle systems capable of delivering multiple agents directed at diverse therapeutic targets through the use of our novel bicompartmental particle architecture.