Browsing by Author "Ferrari, Mauro"

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    A quantitative approach to discover predictors of biodistribution for drug delivery vectors in cancer.
    (2019-04-19) Nizzero, Sara; Nordlander, Peter; Ferrari, Mauro; Pimpinelli, Alberto
    Systemic aspects of cancer simultaneously offer the biggest clinical challenge and the most promising therapeutic niche in the treatment of solid tumors. In fact, treatment often fails in late stages due to the presence of metastasis, a migratory phenotype of cancer invasion. Metastases consist in cancer spread to distant organs which often presents characteristic high levels of heterogeneity and acquired resistance to treatments. Multi-stage injectable delivery vectors have proven powerful in exploiting systemic transport properties connected to physiological parameters to enhance tumor accumulation and directly improve therapeutic efficacy. The theoretical framework in which these concepts first developed is now known by the term transport oncophysics: the study of mass transport phenomena relevant to oncology with a physics-based approach. For injectable inorganic delivery vectors, the major innovation relies on the capability to tailor their organ distribution (biodistribution) upon injection. This capability comes from the controllable design of such systems, which present a discoidal shape with sizes in the micrometer range. While these systems have shown disruptive results in the treatment of triple negative breast cancer metastasis, there is still a lack of fundamental understanding on how patient-specific physiological parameters affect their biodistribution. However, it is well known that patient physiology is often dysregulated in cancer patients. These alterations can be caused by a multitude of reasons: cancer itself, the presence of concurring diseases or conditions, and previous treatment. This patient heterogeneity poses an additional challenge in therapeutic translation of injectable delivery systems. In this work, significant clinically relevant physiological parameters are screened, systematically altered, and quantitatively characterized as transport barriers for systemic delivery. Systematic in vivo biodistribution studies are conducted to address changes in biodistribution resulting from controlled alteration of specific physiological parameters. Uptake kinetic is characterized through time-resolved analysis, and investigated to inform on synergistic relationships among different parameters. A computational approach is then developed to identify a pharmacokinetic (PK) model able to predict the system behavior, and used to investigate the importance of several parameters, and functional relationships. This combined in vivo / in silico approach enables the quantitative description of mechanistic rules that determine the biodistribution of systemically injected delivery vectors. The framework that emerges from this study opens the way to a new paradigm for personalized adaptive therapy, where quantitative measurements, systematic analysis, and mathematical modeling can be combined to investigate and characterize functional relationships between quantitatively characterized physiological parameters and clinically relevant measurables for injectable inorganic delivery vectors.
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    Enhanced MRI relaxivity of Gd3+-based contrast agents geometrically confined within porous nanoconstructs
    (Wiley, 2012) Sethi, Richa; Ananta, Jeyarama S.; Karmonik, Christof; Zhong, Meng; Fung, Steve H.; Liu, Xuewu; Li, King; Ferrari, Mauro; Wilson, Lon J.; Decuzzi, Paolo; Smalley Institute for Nanoscale Science and Technology; Center for Biological and Environmental Nanotechnology
    Gadolinium chelates, which are currently approved for clinical MRI use, provide relaxivities well below their theoretical limit, and they also lack tissue specificity. Recently, the geometrical confinement of Gd3+-based contrast agents (CAs) within porous structures has been proposed as a novel, alternative strategy to improve relaxivity without chemical modification of the CA. Here, we have characterized and optimized the performance of MRI nanoconstructs obtained by loading [Gd(DTPA)(H2O)]2− (Magnevist®) into the pores of injectable mesoporous silicon particles. Nanoconstructs with three different pore sizes were studied, and at 60 MHz, they exhibited longitudinal relaxivities of ~24 m m−1 s−1 for 5–10 nm pores and ~10 m m−1 s−1 for 30 – 40 nm pores. No enhancement in relaxivity was observed for larger pores sizes. Using an outer-sphere compound, [GdTTHA]3−, and mathematical modeling, it was demonstrated that the relaxivity enhancement is due to the increase in rotational correlation times (CA adsorbed on the pore walls) and diffusion correlation times (reduced mobility of the water molecules), as the pore sizes decreases. It was also observed that extensive CA adsorption on the outer surface of the silicon particles negates the advantages offered by nanoscale confinement. Upon incubation with HeLa cells, the nanoconstructs did not demonstrate significant cytotoxicity for up to 3 days post incubation, at different particle/cell ratios. In addition, the nanoconstructs showed complete degradation after 24 h of continuous agitation in phosphate-buffered saline. These data support and confirm the hypothesis that the geometrical confinement of Gd3+-chelate compounds into porous structures offers MRI nanoconstructs with enhanced relaxivity (up to 6 times for [Gd(DTPA)(H2O)]2−, and 4 times for [GdTTHA]3−) and, potentially, improved stability, reduced toxicity and tissue specificity.
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    Geometrical confinement of Gd(DOTA) molecules within mesoporous silicon nanoconstructs for MR imaging of cancer
    (Elsevier, 2014) Gizzatov, Ayrat; Stigliano, Cinzia; Ananta, Jeyerama S.; Sethi, Richa; Xu, Rong; Guven, Adem; Ramirez, Maricela; Shen, Haifa; Sood, Anil; Ferrari, Mauro; Wilson, Lon J.; Liu, Xuewu; Decuzzi, Paolo; Smalley Institute for Nanoscale Science and Technology
    Porous silicon has been used for the delivery of therapeutic and imaging agents in several biomedical applications. Here, mesoporous silicon nanoconstructs (SiMPs) with a discoidal shape and a sub-micrometer size (1,000 × 400 nm) have been conjugated with gadolinium-tetraazacyclododecane tetraacetic acid Gd(DOTA) molecules and proposed as contrast agents for Magnetic Resonance Imaging. The surface of the SiMPs with different porosities – small pore (SP: ~ 5 nm) and huge pore (HP: ~ 40 nm) – and of bulk, non-porous silica beads (1,000 nm in diameter) have been modified with covalently attached (3-aminopropyl)triethoxysilane (APTES) groups, conjugated with DOTA molecules, and reacted with an aqueous solution of GdCl3. The resulting Gd(DOTA) molecules confined within the small pores of the Gd-SiMPs achieve longitudinal relaxivities r1 of ~ 17 (mM·s)−1, which is 4 times greater than for free Gd(DOTA). This enhancement is ascribed to the confinement and stable chelation of Gd(DOTA) molecules within the SiMP mesoporous matrix. The resulting nanoconstructs possess no cytotoxicity and accumulate in ovarian tumors up to 2% of the injected dose per gram tissue, upon tail vein injection. All together this data suggests that Gd-SiMPs could be efficiently used for MR vascular imaging in cancer and other diseases.
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    Hierarchically Structured Magnetic Nanoconstructs with Enhanced Relaxivity and Cooperative Tumor Accumulation
    (Wiley, 2014) Gizzatov, Ayrat; Key, Jaehong; Aryal, Santosh; Ananta, Jeyarama; Cervadoro, Antonio; Palange, Anna Lisa; Fasano, Matteo; Stigliano, Cinzia; Zhong, Meng; Di Mascolo, Daniele; Guven, Adem; Chiavazzo, Eliodoro; Asinari, Pietro; Liu, Xuewu; Ferrari, Mauro; Wilson, Lon J.; Decuzzi, Paolo; R.E. Smalley Institute for Nanoscale Science and Technology
    Iron oxide nanoparticles are formidable multifunctional systems capable of contrast enhancement in magnetic resonance imaging, guidance under remote fields, heat generation, and biodegradation. Yet, this potential is underutilized in that each function manifests at different nanoparticle sizes. Here, sub-micrometer discoidal magnetic nanoconstructs are realized by confining 5 nm ultra-small super-paramagnetic iron oxide nanoparticles (USPIOs) within two different mesoporous structures, made out of silicon and polymers. These nanoconstructs exhibit transversal relaxivities up to ≈10 times (r 2 ≈ 835 mm −1 s−1) higher than conventional USPIOs and, under external magnetic fields, collectively cooperate to amplify tumor accumulation. The boost in r 2 relaxivity arises from the formation of mesoscopic USPIO clusters within the porous matrix, inducing a local reduction in water molecule mobility as demonstrated via molecular dynamics simulations. The cooperative accumulation under static magnetic field derives from the large amount of iron that can be loaded per nanoconstuct (up to ≈65 fg) and the consequential generation of significant inter-particle magnetic dipole interactions. In tumor bearing mice, the silicon-based nanoconstructs provide MRI contrast enhancement at much smaller doses of iron (≈0.5 mg of Fe kg−1 animal) as compared to current practice.