Incorporation of CdSe/ZnS semiconductor quantum dots (QDs) into viral particles provides a new paradigm for the design of intracellular microscopic probes and vectors. Several strategies for the incorporation of QDs into viral capsids were explored; those functionalized with poly(ethylene glycol) (PEG) can be self-assembled into viral particles with minimal release of photoreaction products and enhanced stability against prolonged irradiation.
Therapeutic drug delivery across the blood-brain barrier (BBB) is not only inefficient, but also nonspecific to brain stroma. These are major limitations in the effective treatment of brain cancer. Transferrin peptide (Tfpep) targeted gold nanoparticles (Tfpep-Au NPs) loaded with the photodynamic pro-drug, Pc 4, have been designed and compared with untargeted Au NPs for delivery of the photosensitizer to brain cancer cell lines. In vitro studies of human glioma cancer lines (LN229 and U87) overexpressing the transferrin receptor (TfR) show a significant increase in cellular uptake for targeted conjugates as compared to un-targeted particles. Pc 4 delivered from Tfpep-Au NPs clusters within vesicles after targeting with the Tfpep. Pc 4 continues to accumulate over a 4 hour period. Our work suggests that TfR-targeted Au NPs may have important therapeutic implications for delivering brain tumor therapies and/or providing a platform for noninvasive imaging.
Gadolinium (Gd) contrast agents are predominantly used for T1 MR imaging. However, the high toxicity of Gd3+ and potential side effects including nephrogenic systemic fibrosis have led to the search for alternative T1 contrast agents. Since manganese (Mn) has paramagnetic properties with five unpaired electrons that permit high spin number, long electronic relaxation times, and labile water exchange, we evaluated Mn as a T1 magnetic resonance imaging (MRI) contrast agent for lung imaging. Here we report on the design and synthesis of multifunctional lipid-micellar nanoparticles (LMNs) containing Mn oxide (M-LMNs) for MRI that can also be used for DNA and drug delivery. Oleic acid-coated MnO nanoparticles were encapsulated in micelles composed of polyethylene glycol (PEG-2000), phosphatidylethanolamine (PE), DC-cholesterol, and dioleoyl-phosphatidylethanolamine (DOPE). The particles are taken up in vitro by human embryonic kidney (HEK293), Lewis lung carcinoma (LLC1), and A549 cells and are devoid of cytotoxicity. When administered to mice intranasally, they preferentially accumulate in the lungs. In vitro phantom and ex vivo lung MRI results confirmed that M-LMNs are able to enhance T1 MRI contrast. M-LMNs loaded with plasmid DNA and/or doxorubicin are efficiently taken up by HEK293 cells in vitro and by target cells in vivo. Taken together, these results demonstrate that M-LMNs are capable of simultaneously providing MRI contrast and DNA and/or drug delivery to target cells in the lung and therefore may prove useful as a lung theranostic, especially for lung cancers.
Targeting gold nanoparticles (AuNPs) with two or more receptor binding peptides has been proposed to address intratumoral heterogeneity of glioblastomas that overexpress multiple cell surface receptors to ultimately improve therapeutic efficacy. AuNPs conjugated with peptides against both the epidermal growth factor and transferrin receptors and loaded with the photosensitizer phthalocyanine 4 (Pc 4) have been designed and compared with monotargeted AuNPs for in vitro and in vivo studies. The (EGFpep+Tfpep)-AuNPs-Pc 4 with a particle size of ~41 nm improved both specificity and worked synergistically to decrease time of maximal accumulation in human glioma cells that overexpressed two cell surface receptors as compared to cells that overexpressed only one. Enhanced cellular association and increased cytotoxicity were achieved. In vivo studies show notable accumulation of these agents in the brain tumor regions.
In this study, we developed a stable, nontoxic novel micelle nanoparticle to attenuate responses of endothelial cell (EC) inflammation when subjected to oxidative stress, such as observed in organ transplantation. Targeted Rapamycin Micelles (TRaM) were synthesized using PEG-PE-amine and N-palmitoyl homocysteine (PHC) with further tailoring of the micelle using targeting peptides (cRGD) and labeling with far-red fluorescent dye for tracking during cellular uptake studies. Our results revealed that the TRaM was approximately 10 nm in diameter and underwent successful internalization in Human Umbilical Vein EC (HUVEC) lines. Uptake efficiency of TRaM nanoparticles was improved with the addition of a targeting moiety. In addition, our TRaM therapy was able to downregulate both mouse cardiac endothelial cell (MCEC) and HUVEC production and release of the pro-inflammatory cytokines, IL-6 and IL-8 in normal oxygen tension and hypoxic conditions. We were also able to demonstrate a dose-dependent uptake of TRaM therapy into biologic tissues ex vivo. Taken together, these data demonstrate the feasibility of targeted drug delivery in transplantation, which has the potential for conferring local immunosuppressive effects without systemic consequences while also dampening endothelial cell injury responses.
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