Purpose: The multikinase inhibitor sorafenib displays antitumor activity in preclinical models of osteosarcoma. However, in sorafenib-treated patients with metastatic-relapsed osteosarcoma, disease stabilization and tumor shrinkage were short-lived and drug resistance occurred.

In recent decades ultrasound-guided delivery of drugs loaded on nanocarriers has been the focus of increasing attention to improve therapeutic treatments. Ultrasound has often been used in combination with microbubbles, micron-sized spherical gas-filled structures stabilized by a shell, to amplify the biophysical effects of the ultrasonic field. Nanometer size bubbles are defined nanobubbles. They were designed to obtain more efficient drug delivery systems. Indeed, their small sizes allow extravasation from blood vessels into surrounding tissues and ultrasound-targeted site-specific release with minimal invasiveness. Additionally, nanobubbles might be endowed with improved stability and longer residence time in systemic circulation. This review will describe the physico-chemical properties of nanobubbles, the formulation parameters and the drug loading approaches, besides potential applications as a therapeutic tool.

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Ag nanoparticles synthesized on porous silicon samples were studied and applied as substrates for surface‐enhanced Raman scattering (SERS). The metallic nanostructures prepared by immersion plating were characterized by UV–Vis reflectance spectroscopy and scanning electron microscopy. SERS activity of the substrates was tested using Cyanine dye 1,3,3,1′,3′,3′‐esamethyl‐5,5′‐dimethoxyindodicarbocyanine iodide (Cy5‐OCH3) as a probe molecule. The Raman spectra obtained for different excitation wavelengths indicate amplifications ascribed to plasmonic resonances with an enhancement factor up to 107. CGIYRLRS peptides were chemisorbed on the Ag nanoparticles with the plasmonic resonance tuned at the excitation energy. Such oligopeptides were used as baits for a specific polyclonal antibody. The overall Raman enhancement allowed to evidence a good selectivity to the target analyte as required by most of the SERS applications on biological assays. Copyright © 2011 John Wiley & Sons, Ltd.

When citing, please refer to the published version. MMP-9 and increases TIMP-1 without affecting TIMP-2 secretion, whereas in human 60 keratinocytes it reduces MMP-2, MMP-9, and TIMP-2, without affecting TIMP-1 release. 61Provided that the phenotype of the cellular environment is better understood, chronic wounds 62 might be targeted by new oxygenating compounds such as chitosan-or dextran-shelled and 63 2H,3H-decafluoropentane-cored oxygen-loaded nanodroplets (OLNs). Here, we investigated 64 the effects of hypoxia and dextran-shelled OLNs on the pro-angiogenic phenotype and 65 behavior of human dermal microvascular endothelium (HMEC-1 cell line), another cell 66 population playing key roles during wound healing. Normoxic HMEC-1 constitutively 67 released MMP-2, TIMP-1 and TIMP-2 proteins, but not MMP-9. Hypoxia enhanced MMP-2 68 and reduced TIMP-1 secretion, without affecting TIMP-2 levels, and compromised cell 69 ability to migrate and invade the extracellular matrix. When taken up by HMEC-1, nontoxic 70OLNs abrogated the effects of hypoxia, restoring normoxic MMP/TIMP levels and 71 promoting cell migration, matrix invasion, and formation of microvessels. These effects were 72 specifically dependent on time-sustained oxygen diffusion from OLN core, since they were 73 not achieved by oxygen-free nanodroplets or oxygen-saturated solution. Collectively, these 74 data provide new information on the effects of hypoxia on dermal endothelium and support 75 the hypothesis that OLNs might be used as effective adjuvant tools to promote chronic wound 76 healing processes. 77 78Keywords: oxygen; nanodroplet; matrix metalloproteinase (MMP); tissue inhibitor of 79 metalloproteinase (TIMP); human microvascular endothelial cell (HMEC); skin. 80 5 Introduction 81 82After injury, skin integrity must be restored promptly to reestablish the homeostatic 83 mechanisms, minimize fluid loss, and prevent infection [Greaves et al., 2013]. This is 84 achieved through wound healing, a complex biological process where multiple pathways are 85 simultaneously activated to induce tissue repair and regeneration. Traditionally, acute wound 86 healing is defined as a complex multi-step and multi-cellular process, distinguished in four 87 phases involving different cell types: i) hemostasis, involving platelets; ii) inflammation, 88 involving neutrophils, monocytes, and macrophages; iii) proliferation, involving 89 keratinocytes, endothelial cells, and fibroblasts; and iv) matrix remodeling, involving 90 keratinocytes, myofibroblasts, and endothelial cells. [Diegelmann et al., 2004]. In particular, 91 during the third and fourth phases, the endothelium plays a pivotal role, since wound 92 microvasculature is rebuilt through angiogenesis to restore the supply of oxygen, blood 93 constituents and nutrients to the regenerating tissue, helping to promote fibroplasia and 94 prevent sustained tissue hypoxia [Eming et al., 2014]. Notably, oxygen represents a key 95 regulator of normal wound healing since it is required for collagen deposition, 96 epith...

Molecular targeting of drug delivery nanocarriers is expected to improve their therapeutic index while decreasing their toxicity. Here we report the identification and characterization of novel peptide ligands specific for cells present in high-risk neuroblastoma (NB), a childhood tumor mostly refractory to current therapies. To isolate such targeting moieties, we performed combined in vitro/ex-vivo phage display screenings on NB cell lines and on tumors derived from orthotopic mouse models of human NB. By designing proper subtractive protocols, we identified phage clones specific either for the primary tumor, its metastases, or for their respective stromal components. Globally, we isolated 121 phage-displayed NB-binding peptides: 26 bound the primary tumor, 15 the metastatic mass, 57 and 23 their respective microenvironments. Of these, five phage clones were further validated for their specific binding ex-vivo to biopsies from stage IV NB patients and to NB tumors derived from mice. All five clones also targeted tumor cells and vasculature in vivo when injected into NB-bearing mice. Coupling of the corresponding targeting peptides with doxorubicin-loaded liposomes led to a significant inhibition in tumor volume and enhanced survival in preclinical NB models, thereby paving the way to their clinical development.

Homing of colorectal cancer (CRC) cells to the liver is a non-random process driven by a crosstalk between tumour cells and components of the host tissue. Here we report the isolation of a liver metastasis-specific peptide ligand (CGIYRLRSC) that binds a complex of E-cadherin and α6 integrin on the surface of CRC cells. We identify angiopoietin-like 6 protein as a peptide-mimicked natural ligand enriched in hepatic blood vessels of CRC patients. We demonstrate that an interaction between hepatic angiopoietin-like 6 and tumoural α6 integrin/E-cadherin drives liver homing and colonization by CRC cells, and that CGIYRLRSC inhibits liver metastasis through interference with this ligand/receptor system. Our results indicate a mechanism for metastasis whereby a soluble factor accumulated in normal vessels functions as a specific ligand for circulating cancer cells. Consistently, we show that high amounts of coexpressed α6 integrin and E-cadherin in primary tumours represent a poor prognostic factor for patients with advanced CRC.

Background L-DOPA is an amino acid precursor to the neurotransmitter dopamine that is