Differential proteomics analysis of the surface heterogeneity of dextran iron oxide nanoparticles and the implications for their in vivo clearance

In order to understand the role of plasma proteins in the rapid liver clearance of dextran-coated superparamagnetic iron oxide (SPIO) in vivo, we analyzed the full repertoire of SPIO-binding blood proteins using novel two-dimensional differential mass spectrometry approach. The identified proteins showed specificity for surface domains of the nanoparticles: mannan-binding lectins bound to the dextran coating, histidine-rich glycoprotein and kininogen bound to the iron oxide part, and the complement lectin and contact clotting factors were secondary binders. Nanoparticle clearance studies in knockout mice suggested that these proteins, as well as several previously identified opsonins, do not play a significant role in the SPIO clearance. However, both the dextran coat and the iron oxide core remained accessible to specific probes after incubation of SPIO in plasma, suggesting that the nanoparticle surface could be available for recognition by macrophages, regardless of protein coating. These data provide guidance to rational design of bioinert, long-circulating nanoparticles.National Cancer Institute (U.S.) (Grant CA119335)National Cancer Institute (U.S.) (Grant CA124427

Hyperpolarized Long-T1 Silicon Nanoparticles for Magnetic Resonance Imaging

Silicon nanoparticles are experimentally investigated as a potential hyperpolarized, targetable MRI imaging agent. Nuclear T_1 times at room temperature for a variety of Si nanoparticles are found to be remarkably long (10^2 to 10^4 s) - roughly consistent with predictions of a core-shell diffusion model - allowing them to be transported, administered and imaged on practical time scales without significant loss of polarization. We also report surface functionalization of Si nanoparticles, comparable to approaches used in other biologically targeted nanoparticle systems.Comment: supporting material here: http://marcuslab.harvard.edu/Aptekar_hyper1_sup.pd

New FTY720-docetaxel nanoparticle therapy overcomes FTY720-induced lymphopenia and inhibits metastatic breast tumour growth

Purpose: Combining molecular therapies with chemotherapy may offer an improved clinical outcome for chemoresistant tumours. Sphingosine-1-phosphate (S1P) receptor antagonist and sphingosine kinase 1 (SK1) inhibitor FTY720 (FTY) has promising anticancer properties, however, it causes systemic lymphopenia which impairs its use in cancer patients. In this study, we developed a nanoparticle (NP) combining docetaxel (DTX) and FTY for enhanced anticancer effect, targeted tumour delivery and reduced systemic toxicity. Methods: Docetaxel, FTY and glucosamine were covalently conjugated to poly(lactic-co-glycolic acid) (PLGA). NPs were characterised by dynamic light scattering and electron microscopy. The cellular uptake, cytotoxicity and in vivo antitumor efficacy of CNPs were evaluated. Results: We show for the first time that in triple negative breast cancer cells FTY provides chemosensitisation to DTX, allowing a four-fold reduction in the effective dose. We have encapsulated both drugs in PLGA complex NPs (CNPs), with narrow size distribution of ~ 100 nm and excellent cancer cell uptake providing sequential, sustained release of FTY and DTX. In triple negative breast cancer cells and mouse breast cancer models, CNPs had similar efficacy to systemic free therapies, but allowed an effective drug dose reduction. Application of CNPs has significantly reversed chemotherapy side effects such as weight loss, liver toxicity and, most notably, lymphopenia. Conclusions: We show for the first time the DTX chemosensitising effects of FTY in triple negative breast cancer. We further demonstrate that encapsulation of free drugs in CNPs can improve targeting, provide low off-target toxicity and most importantly reduce FTY-induced lymphopenia, offering potential therapeutic use of FTY in clinical cancer treatment

Enhanced immunocompatibility and hemocompatibility of nanomedicines across multiple species using complement pathway inhibitors

The activation of complement by nanomedicines triggers immune uptake and proinflammatory responses. Complement pathway inhibitors could offer strategies to address these challenges. Here, we assess the efficacy of inhibitors with various nanoparticles, including dextran superparamagnetic iron oxide nanoworms, polyethylene glycol (PEG) liposomal drugs, and mRNA lipid nanoparticles. In human sera, inhibitors of the alternative pathway iptacopan and danicopan exhibit variable efficacies, ranging from high nanomolar to incomplete inhibition. However, both iptacopan and danicopan display poor efficacy with PEGylated liposomal doxorubicin. Sutimlimab, an inhibitor of the classical pathway, demonstrates poor efficacy with PEGylated liposomal doxorubicin, even in sera with anti-PEG antibodies. Iptacopan displays donor-dependent inhibition of the uptake of nanoparticles in human blood. Bolus coadministration of iptacopan with nanoworms in mice, rats, and dogs inhibits C3 opsonization and uptake by granulocytes. Iptacopan also alleviates nanoparticle-induced lethargy in rats and severe hypotension in dogs. These data suggest that complement inhibitors can enhance the immunocompatibility and hemocompatibility of nanomedicines in a donor-dependent manner

Phase I Clinical Trial of Systemically Administered TUSC2(FUS1)-Nanoparticles Mediating Functional Gene Transfer in Humans

Background: Tumor suppressor gene TUSC2/FUS1 (TUSC2) is frequently inactivated early in lung cancer development. TUSC2 mediates apoptosis in cancer cells but not normal cells by upregulation of the intrinsic apoptotic pathway. No drug strategies currently exist targeting loss-of–function genetic abnormalities. We report the first in-human systemic gene therapy clinical trial of tumor suppressor gene TUSC2. Methods: Patients with recurrent and/or metastatic lung cancer previously treated with platinum-based chemotherapy were treated with escalating doses of intravenous N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTAP):cholesterol nanoparticles encapsulating a TUSC2 expression plasmid (DOTAP:chol-TUSC2) every 3 weeks. Results: Thirty-one patients were treated at 6 dose levels (range 0.01 to 0.09 milligrams per kilogram). The MTD was determined to be 0.06 mg/kg. Five patients achieved stable disease (2.6–10.8 months, including 2 minor responses). One patient had a metabolic response on positron emission tomography (PET) imaging. RT-PCR analysis detected TUSC2 plasmid expression in 7 of 8 post-treatment tumor specimens but not in pretreatment specimens and peripheral blood lymphocyte controls. Proximity ligation assay, performed on paired biopsies from 3 patients, demonstrated low background TUSC2 protein staining in pretreatment tissues compared with intense (10–25 fold increase) TUSC2 protein staining in posttreatment tissues. RT-PCR gene expression profiling analysis of apoptotic pathway genes in two patients with high posttreatmen

Alteração vocal auto-referida em professores: prevalência e fatores associados

OBJETIVO: Estimar a prevalência de alteração vocal auto-referida em professores e identificar fatores associados. MÉTODOS: Estudo transversal com amostra de 393 professores do ensino fundamental de Florianópolis, SC, por meio de questionário autoaplicado em 2009. Foi realizada análise multivariável de regressão de Poisson estimando-se as razões de prevalência e intervalos de 95% de confiança. RESULTADOS: A prevalência de alteração vocal foi de 47,6% (IC95% 42,6;52,5). Após o ajuste, permaneceram associados à maior prevalência de alteração vocal ser do sexo feminino e a presença de rinite/sinusite e faringite. CONCLUSÕES: Foi observada elevada prevalência de alteração vocal auto-referida entre os professores estudados.OBJETIVO: Estimar la prevalencia de alteración vocal auto-referida en profesores e identificar factores asociados. MÉTODOS: Estudio transversal con muestra de 393 profesores de enseñanza fundamental de Florianópolis, Sur de Brasil, por medio de cuestionario auto-aplicado en 2009. Se realizó análisis multivariable de regresión de Poisson, estimándose las tasas de prevalencia e intervalos de 95% de confianza. RESULTADOS: La prevalencia de alteración vocal fue de 47,6% (IC95% 42,6;52,5). Posterior al ajuste, permanecieron asociados a la mayor prevalencia de alteración vocal ser del sexo femenino y la presencia de rinitis/sinusitis y faringitis. CONCLUSIONES: Se observó elevada prevalencia de alteración vocal auto-referida entre los profesores estudiados.OBJECTIVE: To estimate the prevalence of self-reported voice problems and to identify associated factors. METHODS: A cross-sectional study was carried out in a sample of 393 public elementary and middle school teachers in Florianópolis, Southern Brazil, in 2009. A self-administered questionnaire was used. A multivariable Poisson regression model was performed to estimate prevalence ratios and their related 95% confidence intervals. RESULTS: The prevalence of voice problems was 47.6% (95%CI 42.6;52.5). In the final adjusted analysis the following variables remained associated with a higher prevalence of voice problems: being female and the presence of rhinitis/sinusitis and pharyngitis. CONCLUSIONS: A high prevalence of self-reported voice problems was found among the teachers studied

Modulating Pharmacokinetics, Tumor Uptake and Biodistribution by Engineered Nanoparticles

Inorganic nanoparticles provide promising tools for biomedical applications including detection, diagnosis and therapy. While surface properties such as charge are expected to play an important role in their in vivo behavior, very little is known how the surface chemistry of nanoparticles influences their pharmacokinetics, tumor uptake, and biodistribution.Using a family of structurally homologous nanoparticles we have investigated how pharmacological properties including tumor uptake and biodistribution are influenced by surface charge using neutral (TEGOH), zwitterionic (Tzwit), negative (TCOOH) and positive (TTMA) nanoparticles. Nanoparticles were injected into mice (normal and athymic) either in the tail vein or into the peritoneum.Neutral and zwitterionic nanoparticles demonstrated longer circulation time via both i.p. and i.v. administration, whereas negatively and positively charged nanoparticles possessed relatively short half-lives. These pharmacological characteristics were reflected on the tumor uptake and biodistribution of the respective nanoparticles, with enhanced tumor uptake by neutral and zwitterionic nanoparticles via passive targeting