DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Nanoparticles for Effective and Targeted Ovarian Cancer Treatment


Posted September 8, 2020

Paula Hammond, Ph.D. Massachusetts Institute of Technology

Dr. Paula Hammond

Dr. Paula Hammond

Dr. Paula Hammond is a pioneer in nanotechnology. She has had great success in developing drug-delivery products in areas as diverse as ophthalmology, wound care, and tendon repair. The Ovarian Cancer Research Program awarded her the Teal Innovator Award in 2012, which provided funding to focus her innovative drug delivery system designs on ovarian cancer. With support from this award, Dr. Hammond’s laboratory developed the layer-by-layer (LbL) nanoparticle system to encapsulate and protect cancer treatments and selectively target them to ovarian tumors.

The LbL nanoparticle approach involves “layering” positively and negatively charged polymers around a core. The layered nanoparticle is also wrapped in an external “stealth” layer that can facilitate tumor targeting. This lessens the side effects caused by treatment toxicity in healthy cells and also protects the drug from clearance. Dr. Hammond and her team demonstrated that LbL nanoparticles formulated with Poly-L-Arginine and hyaluronic acid external layers selectively target receptors on ovarian cancer cells. Using this technique, a drug or treatment can reside in the core or layers of the nanoparticle and can be released after entering the cancer cell. The team has successfully shown the delivery of chemotherapies, small interfering RNA (siRNAs), and cytokines specifically to ovarian cancer cells.

Dr. Hammond examined the use of the LbL nanoparticle system in cancer chemotherapy administration, as more targeted methods would be helpful in minimizing the adverse side effects common in systemic chemotherapy treatment. Dr. Hammond’s team demonstrated the capability of incorporating cisplatin into the core and poly ADP-ribose polymerase (PARP) inhibitors into the polymer layers of the LbL nanoparticles. In mouse models of ovarian cancer, combination treatment with cisplatin and PARP inhibitors showed drastic reduction in tumor burden and prolonged survival compared to free combination drug. In addition, there were indications of increased toxicity in the mice treated with free drugs.

siRNA is a strong candidate for cancer treatment because it could reverse the chemoresistance seen in recurrent ovarian cancer by blocking the genes that enable the resistance to treatment. It is difficult to deliver siRNA directly to tumors, as it is quickly degraded outside the cell and is toxic at high doses. Using the LbL technique, Dr. Hammond’s team was able to form stable nanoplexes to package, protect, and deliver siRNAs to tumors. They tested their system on the protein kinase MK2 pathway, which is required for survival of cells deficient in the tumor suppressor, p53. Tumor suppressor p53 is the most frequently mutated gene in cancer, and its mutation is often connected to resistance to standard chemotherapies. In a mouse model of chemoresistant ovarian cancer, mice receiving both MK2 siRNA nanoplexes and chemotherapy exhibited the most dramatic decreases in tumor proliferation compared to either siRNA or chemotherapy alone. Thus, nanoplex-mediated silencing of the protein kinase MK2 profoundly sensitized ovarian tumors to chemotherapy.

Another exciting finding is that Dr. Hammond and her team were able to safely deliver cytokines within the LbL nanoparticles to tumor tissues to initialize an immune response against the cancer while maintaining the health of normal cells and tissues. Many commonly known immunotherapies are not as effective in ovarian cancer. Cytokines are a promising therapy for ovarian cancer treatment, but clinical use has been limited due to their toxicity for healthy tissue. The team focused on interleukin-12 (IL-12), which is a potent cytokine. IL-12 was packaged into the core of the LbL nanoparticle, and they were then tested in a mouse model of ovarian cancer. The team found that the LbL nanoparticles containing IL-12 greatly reduced toxicity and prolonged survival compared to both carrier-free IL-12 and a similar IL-12 loaded liposome lacking the LbL structure. This suggests that the LbL nanoparticle system can be used to systemically deliver potent cytokines to treat ovarian tumors while minimizing their systemic toxicities.

Dr. Hammond has made significant strides in designing the LbL nanoparticle system for the targeted treatment of ovarian cancer. She demonstrated numerous successful applications of the LbL nanoparticles in the delivery of combination small molecule drugs, siRNAs, and immune-activating proteins such as cytokines specifically to ovarian cancer cells. The potential of this is monumental, as it could provide more positive outcomes for ovarian cancer patients. This platform has the potential to offer personalized treatments in ovarian cancer that could better target the tumors while reducing toxicity and eliminating chemotherapy resistance. Dr. Hammond has received funding from the National Institutes of Health to continue these studies focused on ovarian cancer and further expand and improve this platform.

 

References:

Correa S, Boehnke N, Barberio AE, Deiss-Yehiely E, Oberlton B, Smith SG, Zervantonakis I, Dreaden EC, Hammond PT. 2020. Tuning Nanoparticle Interactions with Ovarian Cancer Through Layer-by-Layer Modification of Surface Chemistry. ACS Nano 2, 2224-2237.

Correa S, Boehnke N, Deiss-Yehiely E, Hammond PT. 2019. Solution Conditions Tune and Optimize Loading of Therapeutic Polyelectrolytes into Layer-by-Layer Functionalized Liposomes. ACS Nano 13, 5623-34.

Mensah LB, Morton SW, Li JH, Xiao HH, Ouadir MA, Elias KM, Penn E, Richson AK, Ghoroghchian PP, Liu J, Hammond PT. 2019. Layer-by-Layer Nanoparticles for Novel Delivery of Cisplatin and PARP Inhibitors for Platinum-Based Drug Resistance Therapy in Ovarian Cancer. Bioengineering & Translational Medicine 4, 2.

Dreaden EC, Kong YW, Quadir MA, Correa S, Suárez-López L, Barberio AE, Hwang MK, Shi AC, Oberlton B, Gallagher PN, Shopsowitz KE, Elias KM, Yaffe MB, and Hammond PT. 2018. RNA-Peptide Nanoplexes Drug DNA Damage Pathways in High-Grade Serous Ovarian Tumors. Bioengineering & Translational Medicine 3, 26-36.

Wu C, Li J, Wang W, Hammond PT. 2018. Rationally Designed Polycationic Carriers for Potent Polymeric siRNA-Mediated Gene Silencing. ACS Nano 12, 6504-6514.

Quadir MA, Morton SW, Mensah LB, Shopsowitz K, Dobbelaar J, Effenberger N, Hammond PT. 2017. Ligand-Decorated Click Polypeptide-Derived Nanoparticles for Targeted Drug Delivery Applications. Nanomedicine: Nanotechnology, Biology and Medicine 13, 1797-1808.

Dang X, Gu L, Qi J, Correa S, Zhang G, Belcher A, Hammond P. 2016. Layer-by-Layer Assembled Fluorescent Probes in Second Near-Infrared Window for Systemic Delivery and Ovarian Cancer Detection. Proceedings of the National Academy of Sciences of the United States of America 113, 5179-5184.

Wu C, Shopsowitz KE, Hammond PT. 2016. Engineering Periodic shRNA for Enhanced Silencing, Efficacy, Molecular Therapy. Journal of the American Society of Gene Therapy 24 (6), 1070-1077.

Shopsowitz, KE, Wu C, Liu G, Dreaden EC, Hammond PT. 2016. Periodic-shRNA Molecules Are Capable of Gene Silencing, Cytotoxicity, and Innate Immune Activation in Cancer Cells. Nucleic Acid Research 44 (2), 545-557.

Kong YW, Dreaden EC, Hammond PT, Yaffe MB. 2016. Exploiting Nanocarriers for Combination Cancer Therapy. Intracellular Delivery III, 1st Ed. Prokop A, Weissig V, Eds. Springer International, Switzerland. ISBN: 978-3-319-43525-1.

Links:

Public and Technical Abstracts: Nano-siRNA Particles and Combination Therapies for Ovarian Tumor Targeting 

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Last updated Tuesday, September 8, 2020