Targeted cancer therapy mediated by chemotherapeutic agent-incorporated nanoparticles (NPs) has yet to be translated successfully into clinical usage. To achieve cancer targeting, NPs must possess specific characteristics allowing for evasion of non-specific phagocytosis by hepatic and spleenic reticuloendothelial cells so that NPs can preferentially localize in solid tumor tissues. Bypassing this systemic barrier is challenging and has yet to be realized in cancer drug delivery. Most current NPs injected systemically, with or without surface conjugated targeting ligands, accumulate within non-target organs especially in the liver or spleen. Numerous studies suggested that the size and the surface properties of NPs can have direct correlation with their biodistribution in vivo. But because of the difficulty of controlling particles sizes precisely, the correlation of NP size with in vivo NP biodistribution has yet to be established. NP formulation challenges still exist for controlling NP sizes and surface characteristics. Polymeric NPs currently in numerous preclinical and clinical studies are formulated via nanoprecipitation (co-precipitation of hydrophobic drugs and polymers) or self- assembly processes (e.g., micellation or vesiclation). However, these processes usually lead to NPs with heterogeneous particle sizes. NPs with controlled sizes can be prepared using top-down, template-directed nanofabrication techniques. However, preparing NPs in large quantity is not practical using this top-down strategy, especially when attempting to prepare NPs in kilogram scale under GLP/GMP for human clinical studies. It still remains elusive whether the scalability issue can be addressed for the top-down approach. It is of great importance and urgent needs for new system/strategy that allows preparation of NPs with precisely controlled sizes so that they can be used to study size-biodistribution correlation and potentially to deliver chemotherapeutics in a cancer-specific manner. In this R21 proposed study, we aim to develop monodisperse silica NPs with controlled size and study their biodistribution with and without conjugated targeting ligand.
We aim to gain substantial information with regard to the correlation of the size/targeting ligand density with NP biodistribution profiles. We also aim to develop camptothecin-containing, monodisperse, fast-degrading silica NPs with the size and surface property optimized based on information collected from the previous study and then test these NPs in tumor-bearing mice for their capability of targeting cancer.
The size and surface property of nanoparticles have dramatic effect on their in vivo biodistribution and capability of cancer targeting. However, the correlation of particle size and surface property with its in vivo biodistribution and cancer targeting still remains elusive. In this R21 proposed studies, we aim to develop silica NPs with discrete, close to mono-disperse sizes and controlled density of the surface-bound targeting ligand to study their biodistribution profiles and cancer targeting capability, and then use the information collected to develop camptothecin-containing, fast-degrading silica nanoparticles for in vivo cancer targeting.
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