V33 - Peptide Amphiphile Coated Hydrophobic Nanoparticles for Controlled Drug Delivery

Friday, October 10, 2025

10:00 AM - 11:00 AM PDT

Location: Exhibit Hall F, G & H

Presenting Author(s)

PR

Pintu Rathod, Student

Ph.D. Student
Oregon Health & Science University, United States

Co-Author(s)

Li Xiang, Ph.D.

Postdoctoral Scholar
Oregon Health & Science University, United States
Michael I. Henderson, B.A.

Ph.D. Candidate
Oregon Health & Science University
Portland, Oregon, United States
KM

Kailin Mooney

Research Engineer
Oregon Health & Science University
Portland, Oregon, United States

Primary Investigator(s)

Adem Yildirim, Ph.D.

Assistant Professor
Oregon Health & Science University
PORTLAND, Oregon, United States

Introduction: : Focused ultrasound (FUS) is a non-invasive therapeutic modality that utilizes high-frequency acoustic waves to precisely target and treat tissue located deep within the body. The mechanical modality of FUS generates strong cavitation activity in tissue and is a promising approach to ablate solid tumors. However, incomplete ablation often leave viable tumor cells behind, leading to disease recurrence. To address this limitation, in a previous work, we engineered a dual-functional nanoparticle by assembling peptide amphiphiles (PAs) onto hydrophobically modified nanoparticles [1]. The hydrophobic core of the nanoparticles facilitates cavitation at lower FUS intensities, enhancing ablation efficiency. The peptide amphiphile coating exhibits dynamic interactions with both the hydrophobic nanoparticle surfaces and cellular membranes, thereby improving the tumor retention of the conjugated chemotherapeutic agent [1]. Building on these promising results, we are further engineering nanoparticle formulations by modulating the hydrophobicity of mesoporous silica nanoparticles (MSNs) and varying the lipid and amino acid sequences of peptide amphiphiles (PAs). In the preliminary studies, four distinct nanoparticle constructs were developed by combining two different hydrophobic surface modifications of mesoporous silica nanoparticles (MSNs) with two peptide amphiphiles (PAs) exhibiting varying degrees of hydrophobicity. The overall design is illustrated in Figure 1. Based on previous results, we hypothesize that these novel combinations will enhance intratumoral retention and cellular internalization, prevent the recurrence of ablated tissue, and reduce the systemic toxicity associated with chemotherapy.

Materials and

Methods: : Hydrophobically modified mesoporous silica nanoparticles (hMSNs) were synthesized by functionalizing bare MSNs as previously described [2]. Four different nanoparticles were generated by systematically varying the hydrophobic surface modifications of MSNs, as well as the lipid chain lengths and amino acid sequences of peptide amphiphiles (PAs). We have functionalized the surface of MSNs using hexamethyldisilazane (HMDS) and trichloro(octyl)silane (TOS) to modulate their surface hydrophobicity. Subsequently, the nanoparticles were coated with two different peptide amphiphiles (PAs): C18-G3-KE-C and C18-3L-G3-KE-C, as shown in Figure 1. To enable in vitro and in vivo fluorescence imaging, PAs were conjugated to the Cy5 dye. Nanoparticles were assembled by suspending hydrophobic MSNs (4mg/mL in ethanol) in PA solutions prepared in phosphate-buffered saline (PBS). To minimize fluorescence quenching, Cy5-labeled PAs were mixed with unlabelled PAs with a molar ratio of 5:95. Particle size distribution and acoustic responsiveness were characterized using dynamic light scattering (DLS) and a tandem imaging/focused ultrasound (FUS) transducer, respectively. The stability of PAs coating on the nanoparticles was evaluated by introducing 400 µL (5 mg/mL) of unlabeled PAs and monitoring the fluorescence intensity of the supernatant at different time points to assess potential PA-Cy5 displacement from nanoparticle surfaces due to assembly with excess PAs in solution.

Results, Conclusions, and Discussions:: We have successfully engineered a novel class of peptide amphiphile-coated nanoparticles capable of facilitating acoustic cavitation under low-intensity focused ultrasound (FUS) conditions. This approach enables effective tumor ablation while minimizing damage to surrounding healthy tissues [1]. All four nanoparticle formulations exhibited favourable particle size distributions, with average diameters ranging from 140 to 170 nm as determined by dynamic light scattering (DLS), and demonstrated strong acoustic responsiveness under focused ultrasound exposure, as shown in Figure 2. We evaluated the impact of hydrophobicity on dye release by performing in vitro release studies using Cy5-conjugated nanoparticles in phosphate-buffered saline (PBS), by adding an excess of unlabeled PAs to the solution to intentionally destabilize physical interactions with the hydrophobic nanoparticle surfaces and Cy5-labeled PAs. To assess potential peptide-Cy5 desorption from nanoparticle surfaces, we removed nanoparticles using centrifugation at various time points, up to 2 hours, and measured the fluorescence intensity of the supernatant. Among the tested formulations, TOS-modified MSNs coated with C18-3L-G3-KE-C exhibited enhanced stability and sustained release of the conjugated Cy5, as demonstrated in Figure 2. These findings suggest improved tumor retention and sustained release of the conjugated chemotherapeutic agent. Ongoing in vivo studies will evaluate the therapeutic efficacy and biosafety of this peptide-nanoparticle-mediated platform, which holds potential to effectively prevent the recurrence of ablated tissue through a sustained drug delivery approach.

Acknowledgements and/or References (Optional): :

References:
[1] L. Xiang, M. I. Henderson, S. Drennan, S. Sabuncu, J. M. Fischer, and A. Yildirim, “Peptide Amphiphile-Nanoparticle Assemblies for Mechano-Chemo Combination Therapy,” Nano Lett, vol. 25, no. 19, pp. 7875–7884, May 2025, doi: 10.1021/acs.nanolett.5c01112.
[2] S. Sabuncu et al., “Protein-Coated Biodegradable Gas-Stabilizing Nanoparticles for Cancer Therapy and Diagnosis Using Focused Ultrasound,” Adv Mater Interfaces, vol. 10, no. 2, Jan. 2023, doi: 10.1002/admi.202201543.