Article

An orally delivered small-molecule formulation with antiangiogenic and anticancer activity

Vascular Biology Program and Department of Surgery, Children's Hospital Boston, Harvard Medical School, 1 Blackfan Circle, St. Karp Research Building, Boston, Massachusetts 02215, USA.
Nature Biotechnology (Impact Factor: 39.08). 08/2008; 26(7):799-807. DOI: 10.1038/nbt1415
Source: PubMed

ABSTRACT Targeting angiogenesis, the formation of blood vessels, is an important modality for cancer therapy. TNP-470, a fumagillin analog, is among the most potent and broad-spectrum angiogenesis inhibitors. However, a major clinical limitation is its poor oral availability and short half-life, necessitating frequent, continuous parenteral administration. We have addressed these issues and report an oral formulation of TNP-470, named Lodamin. TNP-470 was conjugated to monomethoxy-polyethylene glycol-polylactic acid to form nanopolymeric micelles. This conjugate can be absorbed by the intestine and selectively accumulates in tumors. Lodamin significantly inhibits tumor growth, without causing neurological impairment in tumor-bearing mice. Using the oral route of administration, it first reaches the liver, making it especially efficient in preventing the development of liver metastasis in mice. We show that Lodamin is an oral nontoxic antiangiogenic drug that can be chronically administered for cancer therapy or metastasis prevention.

Download full-text

Full-text

Available from: Avner Adini, Jul 28, 2015
0 Followers
 · 
126 Views
  • Source
    • "Corneal Micropocket Assay. The corneal micropocket assay was performed as previously detailed (Benny et al., 2008). In brief, pellets containing 80 ng carrier-free recombinant human bFGF or 160 ng VEGF (R&D Systems, Minneapolis, MN) were implanted into micropockets that were created in the cornea of anesthetized mice. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Obtustatin and Viperistatin, members of the disintegrin protein family, served as lead compounds or the synthesis of linear and cyclic peptides containing the KTS binding motif. The most active inear peptide, a Viperistatin analog, indicated the importance of Cys19 and Cys29, as well as the presence of Arg at position 24 for their biological activity, and was used as the basic sequence for the synthesis of cyclic peptides. Vimocin (Compound 6) and Vidapin (Compound 10), showed a high potency (IC50 0.17 nM) and intermediate efficacy (20% and 40%) in inhibition of adhesion of α1/α2 integrin overexpressor cells to respective collagens. Vimocin was more active in inhibition of the wound healing (53%) and corneal micropocket (17%) vascularization, while Vidapin was more potent in inhibition of migration in Matrigel tube formation assay (90%). Both compounds similarly inhibited proliferation (50-90%) of endothelial cells, and angiogenesis induced by VEGF (80%) and glioma (55%) in the chorioallantoic membrane assay. These peptides were not toxic to endothelial cell cultures and caused no acute toxicity upon iv injection in mice, and were stable for 10-30 hours in human serum. The in vitro and in vivo potency of the peptides are consistent with conformational ensembles and 'bio-active' space shared by Obtustatin and Viperistatin. These findings suggest that Vimocin and Vidapin can serve as a dual α1β1/α2β1 integrin antagonists in anti-angiogenesis and cancer therapy.
    Journal of Pharmacology and Experimental Therapeutics 06/2014; 350(3). DOI:10.1124/jpet.114.214643 · 3.86 Impact Factor
  • Source
    • "nanoparticle colloidal properties (size, charge and PEG density) over interaction with A␤ 1–42 peptide (Fig. 1). To achieve this goal, we have selected poly(ethylene glycol)-block-polylactide (PEG-b- PLA) copolymer nanoparticles, which represent a widely employed class of nanocarriers for biomedical purposes (Benny et al., 2008). The colloidal features of the nanoparticles were modulated by playing with the nature of the surfactant, whereas the density of PEG chains displayed at the nanoparticle surface was finely tuned by using various PEG-b-PLA/PLA blend ratios during nanoparticle preparation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the extracellular deposition of amyloid-β peptides (Aβ). During the past few years, promising approaches based on nanotechnologies have emerged to alter Aβ aggregation and its related toxicity. This study aims to investigate the influence of the nanoparticle colloidal properties over the interaction with Aβ peptide 1-42 (Aβ(1-42)). Using capillary electrophoresis with laser-induced fluorescence detection, it was shown that biodegradable poly(ethylene glycol)-block-polylactide (PEG-b-PLA) nanoparticles were able to interact with Aβ(1-42) peptide leading to its uptake in rather short time periods. In addition, we highlighted the crucial role of the nanocarrier colloidal properties on the uptake kinetics. Whereas nanoparticles stabilized by sodium cholate (lower size and higher negative surface charge) gave optimum uptake kinetics, nanoparticles stabilized with others surfactants presented lower interactions. In contrast, PEG density seemed to have no influence on the interaction when sodium cholate was used for the preparation. This study intends to give new insights into Aβ(1-42) peptide interaction with nanoparticulate systems by helping to determine suitable nanoparticle characteristics regarding forthcoming therapeutic strategies against AD.
    Journal of Biotechnology 07/2011; 156(4):338-40. DOI:10.1016/j.jbiotec.2011.07.020 · 2.88 Impact Factor
  • Source
    • "It contains special moieties that expedite cellular uptake, including tumor-specific antibodies or other homing devices that promote receptor-mediated endocytosis and a transport vehicle that releases drug intracellularly, and contains antisense oligonucleotides (AON) that target specific tumor mRNA sequences. Polycephin has (1) a disulfide bond cleavable by intracellular glutathione, (2) a pH-sensitive hydrazone bond, (3) a tetrapeptide cleaved by lysosomal cathepsin B, whose activity is elevated in tumors, (4) an intrinsic release function from endosomes (Kabanov et al., 2005; Benny et al., 2008), and (5) PEG for polymer stabilization and protection (Sukhishvili et al. 2000; Bae and Urban, 2006). In addition, it can be readily detected in biological fluids (blood, urine, and spinal fluid) and tissues if a radioactive tracer or fluorescent dye is conjugated to its PMLA scaffold. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Nanotechnology is the design and assembly of submicroscopic devices called nanoparticles, which are 1-100 nm in diameter. Nanomedicine is the application of nanotechnology for the diagnosis and treatment of human disease. Disease-specific receptors on the surface of cells provide useful targets for nanoparticles. Because nanoparticles can be engineered from components that (1) recognize disease at the cellular level, (2) are visible on imaging studies, and (3) deliver therapeutic compounds, nanotechnology is well suited for the diagnosis and treatment of a variety of diseases. Nanotechnology will enable earlier detection and treatment of diseases that are best treated in their initial stages, such as cancer. Advances in nanotechnology will also spur the discovery of new methods for delivery of therapeutic compounds, including genes and proteins, to diseased tissue. A myriad of nanostructured drugs with effective site-targeting can be developed by combining a diverse selection of targeting, diagnostic, and therapeutic components. Incorporating immune target specificity with nanostructures introduces a new type of treatment modality, nano-immunochemotherapy, for patients with cancer. In this review, we will discuss the development and potential applications of nanoscale platforms in medical diagnosis and treatment. To impact the care of patients with neurological diseases, advances in nanotechnology will require accelerated translation to the fields of brain mapping, CNS imaging, and nanoneurosurgery. Advances in nanoplatform, nano-imaging, and nano-drug delivery will drive the future development of nanomedicine, personalized medicine, and targeted therapy. We believe that the formation of a science, technology, medicine law-healthcare policy (STML) hub/center, which encourages collaboration among universities, medical centers, US government, industry, patient advocacy groups, charitable foundations, and philanthropists, could significantly facilitate such advancements and contribute to the translation of nanotechnology across medical disciplines.
    NeuroImage 02/2010; 54 Suppl 1:S106-24. DOI:10.1016/j.neuroimage.2010.01.105 · 6.36 Impact Factor
Show more