Dendronized Gold Nanoparticles
(a) as Nanotheranostics in cancer chemotherapy…
The goal of this project is to use gold nanoparticles (AuNPs) to create theranostic systems that simultaneously carry and target two (or more) different and synergistic therapeutic agents to tumors while monitoring the therapeutic response in real-time using clinical imaging (MRI, X-ray CT, optical imaging). This approach has the advantage of increasing treatment efficiency while decreasing chemotherapeutic dose, toxicity from side effects, and drug resistance. The strategy used for the construction of such multifunctional nanoparticles involves the decoration of a gold nanoparticle core with a variety of dendrons displaying the same backbone structure but functionalized differently at the end of the branches (Figure 1). For this project, the Daniel’s lab prepares dendrons with a polypropylene imine (PPI) backbone, which has shown promise for lysosomal escape through proton sponge effect. These PPI dendrons are being modified at their termini with targeting moieties, imaging tags and different therapeutic agents, all of which are chosen based upon the type of cancer that is to be targeted. However a common imaging ability will be provided by the utilization of gadolinium complexes as magnetic resonance imaging (MRI) contrast agents, and an example of drugs being incorporated is cisplatin. The dendrons will be functionalized with each of these specific functions and they will be gathered around one gold nanoparticle in order to impart multi-functionality to the nanovector. At the moment, the two cancers being targeted are pancreatic cancer and castration-resistant prostate cancer, since they are extremely aggressive and poorly responsive to conventional chemotherapy, but this theranostic platform is designed to be easily tailored for other cancers as well.
(b) for Mild hyperthermia study to enhance delivery of therapeutic nanocarriers in tumors…
The objective of this ongoing project is to explore the potential to increase the accumulation of gold nanoparticles (AuNPs) in a mouse model of human prostate cancer by elevating the temperature by a few degrees Celsius, either in the tumor alone or in the whole body.
The Daniel lab has developed targeted AuNPs by functionalization of dendronized AuNPs with Fab fragments (Figure 2a). In collaboration, the Zhu lab (UMBC Mechanical Engineering) has demonstrated the feasibility of using microCT to visualize and analyze the AuNP distribution in tumors. Also, measurements of interstitial pressure in tumors illustrated a decrease in interstitial pressure after 1 hour whole body heating to 40°C and an enhanced AuNP delivery to PC3 tumors due to 1 hour whole body heating (Figure 2c).
(c) for Cancer immunotherapy…
In collaboration with the Szeto lab (UMBC Chemical Engineering), we are investigating the immune response to AuNP for potential use in cancer immunotherapy. We have first investigated the immune response of AuNP-dendron-Fab in comparison to the AuNP-G3CO2H and AuNP-G3NH2 via a flow based multiplex bead assay (LuminexTM assay). We have observed that the AuNPs did exhibit a dose and time dependent immune response. It was noted that all the AuNPs studied (with different coating: positively charged, negatively charged, or with Fab) were non-immunogenic at all concentrations in the short duration (4 hour study). However, in the 24 hour study, we noted that the positively charged AuNPs elicited over 10-fold (versus control) immune response at 16 nM AuNP concentration and minimal response for 1nM AuNP concentration. The immune response generated from the negatively charged AuNPs also showed a similar trend. However, the immune response from the 16 nM concentration was 4-5 fold of the control group. These studies indicate that the immune responses elicited by AuNPs are concentration-, surface charge- and time-dependent. More studies are ongoing.
Controlled Assembly of Inorganic Nanoparticles for the Formation of new Hybrid Nanomaterials
The goal of this project is to couple metal nanoparticles to semiconductor nanoparticles to modify the properties of the individual component particles. The coupling of nanoparticles has been used to enhance scattering, fluorescence, and absorption, leading to applications in sensing, photocatalysis, and light harvesting. However, the exact properties that emerge are highly dependent on the precise arrangement and number of the coupled nanoparticles, and creating uniform, discrete assemblies remains a challenge. In particular, the coupling of plasmonic and excitonic nanoparticles has untapped potential if strong coupling between their respective plasmons and excitons can be reliably achieved. Novel properties, for example Fano interference and Rabi splitting, are expected to arise when these particles are strongly coupled (Figure 3, left). But coupling strength is especially dependent on the precise position of the component particles. Nevertheless, a system composed of a single emitter quantum dot strongly coupled to plasmonic nanoparticles would have widespread applications in photonics, optics, and information processing, making such a system desirable.
To this end, the Daniel’s lab is investigating the assembly and optical properties of gold nanoparticles-CdSe/CdS quantum dots conjugates, in collaboration with the Pelton lab (UMBC, Physics). The Daniel lab has linked excitonic nanoparticles (CdSe/CdS quantum dots) to gold nanoparticles through covalent bonds (Figure 3, right). Strong plasmon-exciton coupling was achieved between a single CdSe/CdS quantum dot and the gap plasmon formed between a gold nanosphere and a silver film, providing the first definitive evidence of strong coupling between a single emitter and a gap plasmon. This study revealed that the yield of strongly coupled particles was limited by the geometry of nanospheres. To address this, a method was developed to sharpen gold nanorods post-synthesis by etching them with cysteamine. The sharpened tips of these nanorods provide the local geometry that was observed to be necessary to obtain strong coupling. The Daniel lab has also recently started investigating the use of gold nanobipyramids for the linking of a single quantum dot at its tip.
The work described here demonstrates the wide-ranging applications of inorganic nanoparticle assemblies, from bio-detection to photonics, and represents a major step towards the development of usable materials using strongly coupled plasmonic and excitonic nanoparticles.
