Formulation of Diblock Polymeric Nanoparticles through Nanoprecipitation Technique

Nanotechnology is a relatively new branch of science that involves harnessing the unique properties of particles that are nanometers in scale (nanoparticles). Nanoparticles can be engineered in a precise fashion where their size, composition and surface chemistry can be carefully controlled. This enables unprecedented freedom to modify some of the fundamental properties of their cargo, such as solubility, diffusivity, biodistribution, release characteristics and immunogenicity. Since their inception, nanoparticles have been utilized in many areas of science and medicine, including drug delivery, imaging, and cell biology1-4. However, it has not been fully utilized outside of "nanotechnology laboratories" due to perceived technical barrier. In this article, we describe a simple method to synthesize a polymer based nanoparticle platform that has a wide range of potential applications

Effect of drug release kinetics on nanoparticle therapeutic efficacy and toxicity

Nanoparticles’ drug release kinetics can directly affect their therapeutic efficacy and toxicity

Folate-Targeted Polymeric Nanoparticle Formulation of Docetaxel Is an Effective Molecularly Targeted Radiosensitizer with Efficacy Dependent on the Timing of Radiotherapy

Nanoparticle (NP) chemotherapeutics hold great potential as radiosensitizers. Their unique properties, such as preferential accumulation in tumors and their ability to target tumors through molecular targeting ligands, are ideally suited for radiosensitization. We aimed to develop a molecularly targeted nanoparticle formulation of docetaxel (Dtxl) and evaluate its property as a radiosensitizer. Using a biodegradable and biocompatible lipid-polymer NP platform and folate as a molecular targeting ligand, we engineered a folate-targeted nanoparticle (FT-NP) formulation of Dtxl. These NPs have sizes of 72±4 nm and surface charges of −42±8 mV. Using folate receptor over-expressing KB cells and folate receptor low HTB-43 cells, we showed folate-mediated intracellular uptake of NPs. In vitro radiosensitization studies initially showed FT-NP is less effective than Dtxl as a radiosensitizer. However, the radiosensitization efficacy is dependent on the timing of radiotherapy. In vitro radiosensitization conducted with irradiation given at the optimal time (24 hours) showed FT-NP Dtxl is as effective as Dtxl. When FT-NP Dtxl is compared to Dtxl and non-targeted nanoparticle (NT-NP) Dtxl in vivo, FT-NP was found to be significantly more effective than Dtxl or NT-NP Dtxl as a radiosensitizer. We also confirmed that radiosensitization is dependent on timing of irradiation in vivo. In summary, FT-NP Dtxl is an effective radiosensitizer in folate-receptor over-expressing tumor cells. Time of irradiation is critical in achieving maximal efficacy with this nanoparticle platform. To the best of our knowledge, our report is the first to demonstrate the potential of molecularly targeted NPs as a promising new class of radiosensitizers

Effect of drug release kinetics on nanoparticle therapeutic efficacy and toxicity

The effects of nanoparticle (NP) properties, such as size, shape and surface charge, on their efficacy and toxicity have been studied extensively. However, the effect of controlled drug release on NP efficacy and toxicity has not been thoroughly evaluated in vivo. Our study aims to fill this knowledge gap. A key challenge in characterizing the relationship between drug release and therapeutic ratio is to fabricate NPs that differ only in their drug release profile but are otherwise identical. To overcome this challenge, we developed crosslinkable lipid shell (CLS) NPs, where the drug release kinetics can be modulated without changing any other NP property. Using CLS NPs with wortmannin and docetaxel as model drugs, we determined the relationship between the release and therapeutic efficacy and toxicity of the drugs. We have determined that drug release kinetics can affect the therapeutic efficacy of NP docetaxel and NP wortmannin in vitro and in vivo. Our study also demonstrates that a decrease in drug release kinetics can result in a decrease in the hepatotoxicity of CLS NP wortmannin. Using two model drugs, the current findings provide the first direct evidence that NP drug release profile is a critical factor in determining the NP therapeutics’ efficacy and toxicity in vivo