Award Abstract # 1845683
CAREER: Expandable sol-gel nanomaterials as therapeutic tools and imaging agents

NSF Org: DMR
Division Of Materials Research
Recipient: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Initial Amendment Date: May 20, 2019
Latest Amendment Date: April 24, 2023
Award Number: 1845683
Award Instrument: Continuing Grant
Program Manager: Nitsa Rosenzweig
nirosenz@nsf.gov
 (703)292-7256
DMR
 Division Of Materials Research
MPS
 Directorate for Mathematical and Physical Sciences
Start Date: June 15, 2019
End Date: November 30, 2024 (Estimated)
Total Intended Award Amount: $543,136.00
Total Awarded Amount to Date: $543,136.00
Funds Obligated to Date: FY 2019 = $110,650.00
FY 2020 = $103,372.00

FY 2021 = $102,776.00

FY 2022 = $110,912.00

FY 2023 = $115,426.00
History of Investigator:
  • Jesse Jokerst (Principal Investigator)
    jjokerst@ucsd.edu
Recipient Sponsored Research Office: University of California-San Diego
9500 GILMAN DR
LA JOLLA
CA  US  92093-0021
(858)534-4896
Sponsor Congressional District: 50
Primary Place of Performance: University of California-San Diego
CA  US  92093-0934
Primary Place of Performance
Congressional District:
50
Unique Entity Identifier (UEI): UYTTZT6G9DT1
Parent UEI:
NSF Program(s): BIOMATERIALS PROGRAM
Primary Program Source: 01001920DB NSF RESEARCH & RELATED ACTIVIT
01002021DB NSF RESEARCH & RELATED ACTIVIT

01002122DB NSF RESEARCH & RELATED ACTIVIT

01002223DB NSF RESEARCH & RELATED ACTIVIT

01002324DB NSF RESEARCH & RELATED ACTIVIT
Program Reference Code(s): 1045, 7237, 8614
Program Element Code(s): 762300
Award Agency Code: 4900
Fund Agency Code: 4900
Assistance Listing Number(s): 47.049

ABSTRACT

Technical Abstract
The long-term goal of this research is to develop novel biomaterials for medical imaging and therapy and to educate the public and future materials scientists about biomaterials research. The research objective is to create novel biomaterials with both imaging and therapeutic capabilities. Here, the PI will synthesize P2O5-CaO-Na2O phosphate sol-gel nanoparticles and will modulate the concentration of cations to control the structure-function properties including biodegradation time. One surprising feature of these materials is that they swell up to 500% larger during their biodegradation in aqueous environments. Thus, the PI hypothesizes that one can control this swelling by coating the nanoparticles with a responsive hydrophobic shell and use this size change to ablate cancer cells. By building the shell with site-selective cleavage sites, the nanoparticle core would be exposed to the cytosol and swell only in the presence of defined chemical cues. This swelling would then mechanically destroy the cells of interest. These materials also have an acoustic impedance mismatch with tissue and can report the cell killing process via ultrasound. The educational objective is to disseminate the research findings to the scientific community, graduate and undergraduate trainees, as well as high school students via focused seminars and hands-on training with a portable ultrasound scanner. The broader impacts of this CAREER award will focus on LGBTQ students who typically lack visibility and community in the STEM fields. The PI will offer mentorship connections, networking opportunities, and professional/leadership development for our LGBT STEM students.

Non-Technical Abstract

This project is creating a biomaterial based on phosphate ions, which are a very common type of salt in the human body. The PI will create very small particles of this phosphate-based biomaterial and use it to image and treat cancer. The remarkable feature of this biomaterial is that it swells when it degrades-size changes up to 5-fold were shown in preliminary data. This is useful because when these materials swell inside of cancer cells, they will destroy the dangerous tissue. This project will design the particles such that they only swell in the presence of biomarkers found on the surface of the cancer cells to prevent damage to other cells. A second important feature of this idea is that doctors can image the location of the particles with ultrasound. This is because sound waves will echo off the surface of the particles. Importantly, as the particles swell, even more sound waves will be reflected. Thus, doctors can use the images to understand the location of the particles and whether they have been activated by the cancer cells or not. The benefit to society will be a less traumatic and more effective cancer treatment, which includes an imaging signal physicians can use to customize treatment. These efforts will also educate the next generation of engineers and scientists using hands-on ultrasound modules in the teaching labs at UC San Diego.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH

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(Showing: 1 - 10 of 21)
Borum, Raina M. and Moore, Colman and Mantri, Yash and Xu, Ming and Jokerst, Jesse V. "Supramolecular Loading of DNA Hydrogels with DyeDrug Conjugates for RealTime Photoacoustic Monitoring of Chemotherapy" Advanced Science , v.10 , 2022 https://doi.org/10.1002/advs.202204330 Citation Details
Borum, Raina M. and Retout, Maurice and Creyer, Matthew N. and Chang, Yu-Ci and Gregorio, Karlo and Jokerst, Jesse V. "Self-assembled peptide-dye nanostructures for in vivo tumor imaging and photodynamic toxicity" npj Imaging , v.2 , 2024 https://doi.org/10.1038/s44303-024-00008-4 Citation Details
He, Tengyu and Bradley, David G. and Xu, Ming and Ko, Shu-Ting and Qi, Baiyan and Li, Yi and Cheng, Yong and Jin, Zhicheng and Zhou, Jiajing and Sasi, Lekshmi and Fu, Lei and Wu, Zhuohong and Zhou, Jingcheng and Yim, Wonjun and Chang, Yu-Ci and Hanna, Joh "Bio-Inspired Degradable Polyethylenimine/Calcium Phosphate Micro-/Nano-Composites for Transient Ultrasound and Photoluminescence Imaging" Chemistry of Materials , v.34 , 2022 https://doi.org/10.1021/acs.chemmater.2c00857 Citation Details
He, Tengyu and Bradley, David G. and Zhou, Jiajing and Jorns, Alec and Mantri, Yash and Hanna, John V. and Jokerst, Jesse V. "Hydro-Expandable Calcium Phosphate Micro/Nano-Particles with Controllable Size and Morphology for Mechanical Ablation" ACS Applied Nano Materials , 2021 https://doi.org/10.1021/acsanm.1c00285 Citation Details
He, Tengyu and Jokerst, Jesse V. "Structured micro/nano materials synthesized via electrospray: a review" Biomaterials Science , v.8 , 2020 https://doi.org/10.1039/D0BM01313G Citation Details
He, Tengyu and Wen, Jing and Wang, Wenjian and Hu, Zeliang and Ling, Chuxuan and Zhao, Zhongchao and Cheng, Yong and Chang, YuCi and Xu, Ming and Jin, Zhicheng and Amer, Lubna and Sasi, Lekshmi and Fu, Lei and Steinmetz, Nicole F. and Rana, Tariq M. and "PeptideDriven Proton Sponge NanoAssembly for Imaging and Triggering LysosomeRegulated Immunogenic Cancer Cell Death" Advanced Materials , 2024 https://doi.org/10.1002/adma.202307679 Citation Details
Jin, Zhicheng and Dridi, Narjes and Palui, Goutam and Palomo, Valle and Jokerst, Jesse V. and Dawson, Philip E. and Amy Sang, Qing-Xiang and Mattoussi, Hedi "Evaluating the Catalytic Efficiency of the Human Membrane-type 1 Matrix Metalloproteinase (MMP-14) Using AuNPPeptide Conjugates" Journal of the American Chemical Society , v.145 , 2023 https://doi.org/10.1021/jacs.2c12032 Citation Details
Jin, Zhicheng and Dridi, Narjes and Palui, Goutam and Palomo, Valle and Jokerst, Jesse V. and Dawson, Phillip E. and Sang, Qing-Xiang Amy and Mattoussi, Hedi "Quantum DotPeptide Conjugates as Energy Transfer Probes for Sensing the Proteolytic Activity of Matrix Metalloproteinase-14" Analytical Chemistry , v.95 , 2023 https://doi.org/10.1021/acs.analchem.2c03400 Citation Details
Jin, Zhicheng and Ling, Chuxuan and Yim, Wonjun and Chang, Yu-Ci and He, Tengyu and Li, Ke and Zhou, Jiajing and Cheng, Yong and Li, Yi and Yeung, Justin and Wang, Ruijia and Fajtová, Pavla and Amer, Lubna and Mattoussi, Hedi and ODonoghue, Anthony J. an "Endoproteolysis of Oligopeptide-Based Coacervates for Enzymatic Modeling" ACS Nano , v.17 , 2023 https://doi.org/10.1021/acsnano.3c04259 Citation Details
Moore, Colman and Wing, Ryan and Pham, Timothy and Jokerst, Jesse V. "Multispectral Nanoparticle Tracking Analysis for the Real-Time and Label-Free Characterization of Amyloid- Self-Assembly In Vitro" Analytical Chemistry , v.92 , 2020 https://doi.org/10.1021/acs.analchem.0c01048 Citation Details
Patel, Shiv H. and Yim, Wonjun and Garg, Anupam K. and Shah, Sahil H. and Jokerst, Jesse V. and Chao, Daniel L. "Assessing the Physiological Relevance of Cough Simulators for Respiratory Droplet Dispersion" Journal of Clinical Medicine , v.9 , 2020 https://doi.org/10.3390/jcm9093002 Citation Details
(Showing: 1 - 10 of 21)

PROJECT OUTCOMES REPORT

Disclaimer

This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.

Project Outcomes 

This project created innovative materials for biomedical applications by designing biodegradable nanomaterials capable of imaging, drug delivery, and cancer therapy. Our goal was to create systems that could address critical limitations in current diagnostic and therapeutic technologies—specifically, poor biodegradability, limited targeting capability, and insufficient immune activation. The outcome for taxpayers is cancer imaging agents and therapies that work better.

We focused on calcium phosphate-based materials, which are well-known for their biocompatibility and ability to dissolve safely in the body. One major breakthrough was the development of hydro-expandable calcium phosphate particles that can grow dramatically in size (up to 720% in volume) when hydrated. This swelling property enables a novel method of mechanically disrupting targeted cells or tissue, providing a non-toxic, localized alternative to conventional drug-based ablation. These particles are synthesized using a low-temperature sol-gel and electrospray process that enables precise control over their size and morphology—from flower-like to smooth spherical particles—unlocking new directions in particle-based therapies.

Another component of our work involved a bio-inspired approach that mimics natural processes like biosilicification in diatoms. We created a mild, solution-based method to synthesize degradable composites of polyethylenimine (PEI) and calcium phosphate. These composites could be tuned in size from nanometers to microns and demonstrated strong ultrasound and optical imaging signals. Importantly, these imaging agents degrade within 24 hours, overcoming the persistent toxicity associated with many inorganic imaging agents, and offering a transient but powerful tool for medical imaging.

We also engineered a series of “proton sponge nano-assemblies” that self-assemble to enhance surface charge and selectively rupture lysosomes inside cancer cells. These assemblies are built from small, low-toxicity components that become highly active only upon assembly—making them safer and more targeted. They triggered a form of cancer cell death known as immunogenic cell death, which not only destroys the tumor cells but also activates the immune system to recognize and attack the tumor. This approach offers a promising strategy to turn “immune-cold” tumors into “immune-hot” environments that are more responsive to immunotherapy.

Intellectual Merit

This work made foundational contributions to the chemistry and nanotechnology of biodegradable materials. We developed new methods for synthesizing tunable nano/micro structures using mild conditions compatible with biological molecules. We also provided the first detailed study of hydro-expansion in phosphate glasses and identified mechanisms of lysosome-triggered cell death using designer proton sponge assemblies. These findings contribute to the fundamental understanding of how structure, surface charge, and degradability affect the behavior of nanomaterials in biological environments.

Broader Impacts

The project has direct implications for improving healthcare outcomes. By creating biodegradable, non-toxic imaging agents and therapeutic systems, we provide alternatives to persistent inorganic materials that can cause long-term side effects. Our cancer-targeting materials offer potential improvements to immunotherapy by making tumors more responsive to treatment. These advances could lead to safer diagnostics, more effective localized therapies, and better patient outcomes.

The project also involved interdisciplinary training for graduate and undergraduate researchers in chemistry, bioengineering, materials science, and nanomedicine. Several publications resulted from this work, and the methodologies developed are now being applied to other diseases and delivery platforms. We volunteered at science fairs to teach elementary school children about how ultrasound works—this is important in the context of workforce development.

 


Last Modified: 03/21/2025
Modified by: Jesse V Jokerst

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