J15 - Peptide Amphiphile-Nanoparticle Assemblies for Mechano-Chemo Combination Therapy

Introduction: : Mechanical tumor ablation using focused ultrasound (FUS) offers minimally invasive ablation of solid tumors. However, mechanical tumor ablation requires highly intense FUS pulses, which may generate off-target effects. In addition, residual cancer cells that survive ablation can cause recurrence. Our lab develops robust ultrasound-responsive nanoparticles by engineering mesoporous silica nanoparticles (MSNs). To prepare these nanoparticles, we first hydrophobically modify the surfaces of MSNs to create a surface suitable for stabilizing gas pockets. Then, the hydrophobic MSNs (hMSNs) are coated with an amphiphilic layer, such as block copolymers or phospholipids, to disperse them in aqueous solutions. The gas pockets stabilized by these core-shell nanoparticles act as nucleation sites for acoustic cavitation when activated using low-intensity focused ultrasound (FUS) pulses. Recently, we showed that these nanoparticles enabled mechanical disintegration of tumor tissue under FUS insonation to significantly reduce (>90%) the tumor burden in mouse models. However, we observed that the ablated tumors usually relapse due to residual cells that survived FUS treatment.

Materials and

Methods: : In this study, to prevent recurrence after ablation, we developed a multifunctional coating that can stabilize hMSNs and allow for the sustained delivery of attached drugs into cancer cells. Specifically, the coating consisted of a zwitterionic peptide amphiphile (zPA). Lipid modification of zPA allows self-assembly with hMSNs and zwitterionic motif enables dispersibility in biological solutions. In addition, a cysteine was added to the zwitterionic motif to enable drug conjugation through maleimide thiol coupling. We conjugated a prodrug of a highly potent chemotherapy monomethyl auristatin E (MMAE) with a cathepsin B cleavable linker to the zPA.

Results, Conclusions, and Discussions:: We found that zPA coating of hMSN can assemble with cell membranes, enabling strong cellular internalization independent from nanoparticle uptake. A synergistic cell-killing effect was observed in vitro when A375 melanoma cells were treated with FUS and MMAE-zPA-coated hMSN. In vivo, a robust therapeutic response was observed in 60% of mice treated with MMAE-zPA-coated hMSN and FUS, with survival exceeding 40 days. In contrast, none of the mice in the regular nanoparticles and the FUS group survived after 25 days.

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