Polymers for Health 9
Specific Delivery of Nitric Oxide using Polymeric Nanoparticles
A/Prof Cyrille Boyer
Dr Hien Duong
Prof Tom Davis (Monash)
In 1992, nitric oxide (NO) was proclaimed “Molecule of the Year” by Science Magazine as it has been found to have wide ranging biological effects. NO is an important cellular signalling molecule and a deficiency of NO has been associated with a number of diseases, including diabetes, liver fibrosis, cardiovascular illness, neurodegenerative diseases and several cancers. NO delivery has been shown to effectively reduce the proliferation of several cancer cells. In addition, recent studies have shown the potential of the direct use of NO as a chemotherapy drug or in combination with chemotherapy agents (cisplatin and doxorubicin) to enhance their cytotoxicity in a variety of different cancer cell lines. Co-delivery of NO and chemotherapeutic agents can also overcome drug resistance in cancer. Finally, another potential application of co-delivery NO and drugs is to enhance EPR effect in tumor.
However, the delivery of NO is challenging, as non-systemic administration is relatively difficult. Currently, NO gas is used in the clinic for the treatment of respiratory distress syndrome (RDS) and persistent pulmonary hypertension of the newborn (PPHN). However, delivering NO to organs other than the lungs is relatively difficult, as NO is an extremely reactive molecule that can react with oxygen (and other gases) resulting in a short half-life time in the body (less than 5 minutes). To improve the administration of NO, a range of small-molecules capable of decomposition under specific conditions to release NO have been developed, including nitrate, nitroprusside, S-nitrosothiols (RSNOs) and N-diazeniumdiolates (NONOates) (Figure 1). Among these NO donors, RSNO and NONOates are the most widely used for NO delivery. Unfortunately, these small molecules lack both stability and specificity. For example, NONOate compounds have a half-life of just a few minutes at 25oC. To improve the bio-distribution and stability, NONOate donors have previously been conjugated to linear polymers or inorganic nanoparticles.
In this project, we prepared polymeric nanoparticles containing NO donors for the specific delivery of NO (Figure 2). The shape of the nanoparticle can be manipulated from spherical, rod-like to vesicle (Figure 3).
- Intracellular Nitric Oxide Delivery From Stable NO-Polymeric Nanoparticle Carriers, H. Duong, M. Jones, M. Kavallaris, T.P. Davis and C. Boyer (2013) Chemical Communication, 49, (39), 14 4190-4192.
- Polymerization-Induced Self-Assembly (PISA) – Control Over the Morphology of Nanoparticles for Drug Delivery Applications, B. Karagoz, L. Esser, H. T. Duong, J. S. Basuki, C. Boyer, T. P. Davis (2014), Polymer Chemistry, DOI: 10.1039/C3PY01306E.
- Simultaneous Polymerization Induced Self-Assembly (PISA) and Guest Molecule Encapsulation, B. Karagoz, C. Boyer, T. P. Davis (2014) Macromolecular Rapid Communication accepted on 17/10/2013