12 research outputs found
Selective Alpha-Particle Mediated Depletion of Tumor Vasculature with Vascular Normalization
BACKGROUND: Abnormal regulation of angiogenesis in tumors results in the formation of vessels that are necessary for tumor growth, but compromised in structure and function. Abnormal tumor vasculature impairs oxygen and drug delivery and results in radiotherapy and chemotherapy resistance, respectively. Alpha particles are extraordinarily potent, short-ranged radiations with geometry uniquely suitable for selectively killing neovasculature. METHODOLOGY AND PRINCIPAL FINDINGS: Actinium-225 ((225)Ac)-E4G10, an alpha-emitting antibody construct reactive with the unengaged form of vascular endothelial cadherin, is capable of potent, selective killing of tumor neovascular endothelium and late endothelial progenitors in bone-marrow and blood. No specific normal-tissue uptake of E4G10 was seen by imaging or post-mortem biodistribution studies in mice. In a mouse-model of prostatic carcinoma, (225)Ac-E4G10 treatment resulted in inhibition of tumor growth, lower serum prostate specific antigen level and markedly prolonged survival, which was further enhanced by subsequent administration of paclitaxel. Immunohistochemistry revealed lower vessel density and enhanced tumor cell apoptosis in (225)Ac-E4G10 treated tumors. Additionally, the residual tumor vasculature appeared normalized as evident by enhanced pericyte coverage following (225)Ac-E4G10 therapy. However, no toxicity was observed in vascularized normal organs following (225)Ac-E4G10 therapy. CONCLUSIONS: The data suggest that alpha-particle immunotherapy to neovasculature, alone or in combination with sequential chemotherapy, is an effective approach to cancer therapy
PET Imaging of Soluble Yttrium-86-Labeled Carbon Nanotubes in Mice
The potential medical applications of nanomaterials are shaping the landscape of the nanobiotechnology field and driving it forward. A key factor in determining the suitability of these nanomaterials must be how they interface with biological systems. Single walled carbon nanotubes (CNT) are being investigated as platforms for the delivery of biological, radiological, and chemical payloads to target tissues. CNT are mechanically robust graphene cylinders comprised of sp(2)-bonded carbon atoms and possessing highly regular structures with defined periodicity. CNT exhibit unique mechanochemical properties that can be exploited for the development of novel drug delivery platforms. In order to evaluate the potential usefulness of this CNT scaffold, we undertook an imaging study to determine the tissue biodistribution and pharmacokinetics of prototypical DOTA-functionalized CNT labeled with yttrium-86 and indium-111 ((86)Y-CNT and (111)In-CNT, respectively) in a mouse model.The (86)Y-CNT construct was synthesized from amine-functionalized, water-soluble CNT by covalently attaching multiple copies of DOTA chelates and then radiolabeling with the positron-emitting metal-ion, yttrium-86. A gamma-emitting (111)In-CNT construct was similarly prepared and purified. The constructs were characterized spectroscopically, microscopically, and chromatographically. The whole-body distribution and clearance of yttrium-86 was characterized at 3 and 24 hours post-injection using positron emission tomography (PET). The yttrium-86 cleared the blood within 3 hours and distributed predominantly to the kidneys, liver, spleen and bone. Although the activity that accumulated in the kidney cleared with time, the whole-body clearance was slow. Differential uptake in these target tissues was observed following intravenous or intraperitoneal injection.The whole-body PET images indicated that the major sites of accumulation of activity resulting from the administration of (86)Y-CNT were the kidney, liver, spleen, and to a much less extent the bone. Blood clearance was rapid and could be beneficial in the use of short-lived radionuclides in diagnostic applications
Enhanced Retention of the Ξ±-Particle-Emitting Daughters of Actinium-225 by Liposome Carriers
Fused PET and CT images at 3 hours post-injection of <sup>86</sup>Y-CNT, compound 4, showing a transverse (z-direction, images a and d), a coronal (y-direction, images b and e), and a sagittal (x-direction, images c and f) slice of one representative animal from group I (i.v., a, b and c) and one from group II (i.p., d, e and f).
<p>Fused PET and CT images at 3 hours post-injection of <sup>86</sup>Y-CNT, compound 4, showing a transverse (z-direction, images a and d), a coronal (y-direction, images b and e), and a sagittal (x-direction, images c and f) slice of one representative animal from group I (i.v., a, b and c) and one from group II (i.p., d, e and f).</p
Plot of the blood clearance of <sup>111</sup>In-CNT, compound 5, following i.v. injection (<i>n</i>β=β3 per group).
<p>Plot of the blood clearance of <sup>111</sup>In-CNT, compound 5, following i.v. injection (<i>n</i>β=β3 per group).</p
Synthetic scheme to prepare <sup>86</sup>Y-CNT.
<p>Synthetic scheme to prepare <sup>86</sup>Y-CNT.</p
Raman spectra measured with a 488 nm laser.
<p>(a) acid-oxidized and purified CNT, compound 1; (b) sidewall amine-functionalized CNT, compound 2; (c) DOTA-functionalized CNT, compound 3. The spectra for 1 and 2 are plotted on the left axis (0-120,000), and 3 on the right axis (0β450,000).</p
Microscopic images of 3 provide data to evaluate the (a) size distribution of 22 individual DOTA-CNT obtained from (b) a representative TEM image of solubilized 3 (scale barβ=β100 nm); (c) AFM image of the height (scale barβ=β0β60 nm) and (d) TEM image (scale barβ=β100 nm) of representative DOTA-CNT bundles.
<p>Microscopic images of 3 provide data to evaluate the (a) size distribution of 22 individual DOTA-CNT obtained from (b) a representative TEM image of solubilized 3 (scale barβ=β100 nm); (c) AFM image of the height (scale barβ=β0β60 nm) and (d) TEM image (scale barβ=β100 nm) of representative DOTA-CNT bundles.</p
Gel permeation HPLC chromatograph of compound 3 (0.020 mg) dissolved in DMF on a stationary phase of PLgel MIXED-A column with DMF mobile phase at 1 mL/min at ambient temperature.
<p>(a) Chromatograph is shown with absorbance at 330 nm. (b) The UV-VIS absorbance spectrum of the peak at 11.7 min.</p