Preparation of Heat-Denatured Macroaggregated Albumin for Biomedical Applications Using a Microfluidics Platform

Abstract

Albumin is widely used in pharmaceutical applications to alter the pharmacokinetic profile, improve efficacy, or decrease the toxicity of active compounds. Various drug delivery systems using albumin have been reported, including microparticles. Macroaggregated albumin (MAA) is one of the more common forms of albumin microparticles, which is predominately used for lung perfusion imaging when labeled with radionuclide technetium-99m (99mTc). These microparticles are formed by heat-denaturing albumin in a bulk solution, making it very challenging to control the size and dispersity of the preparations (coefficient of variation, CV, ∼50%). In this work, we developed an integrated microfluidics platform to create more tunable and precise MAA particles, the so-called microfluidic-MAA (M2A2). The microfluidic chips, prepared using off-stoichiometry thiol-ene chemistry, consist of a flow-focusing region followed by an extended and water-heated curing channel (85 °C). M2A2 particles with diameters between 70 and 300 μm with CVs between 10 and 20% were reliably prepared by adjusting the flow rates of the dispersed and continuous phases. To demonstrate the pharmaceutical utility of M2A2, particles were labeled with indium-111 (111In) and their distribution was assessed in healthy mice using nuclear imaging. 111In-M2A2 behaved similarly to 99mTc-MAA, with lung uptake predominately observed early on followed by clearance over time by the reticuloendothelial and renal systems. Our microfluidic chip represents an elegant and controllable method to prepare albumin microparticles for biomedical applications.

Biodistribution of Native and Nanoformulated Innate Defense Regulator Peptide 1002

“…Following an IV bolus, 67 Ga-NOTA-IDR-1002 was rapidly cleared at the 2.2 mg/kg dose level, which is in line with our previous work with radiolabeled IDR-1018 as well as the broader HDP literature. − Acute respiratory toxicity and enhanced lung uptake were observed upon IV dose escalation of 67 Ga-NOTA-IDR-1002 in a similar manner as with IDR-1018 . Although the exact reasons for IDR-1002 toxicity was not explored further here, it may be due to lytic disruption of the blood/air exchange surfaces or embolic effects due to the peptide precipitating in the blood. ,− Both IDR-1002 and IDR-1018 displayed toxicity at relatively lower doses compared to other IDR peptides given intravenously, such as HH-2 (8 mg/kg in mice), IDR-1 (100 mg/kg in mice) and IMX942 (8 mg/kg in man) . The reason for these differences is poorly understood and warrants further investigation.…”

“…SPECT/CT imaging was conducted and analyzed as previously described , using a MILabs VECTor platform outfitted with an extra-ultrahigh sensitivity mouse pinhole collimator (MILabs; Houten, The Netherlands). , Acquisition times and details are provided in Supplemental Table 2. SPECT data was reconstructed using U-SPECT Rec2.5li software (MILabs) on the gallium-67 photopeak of 96 ± 20 keV and SkyScan NRecon software (Micro Photonics Inc.) for the CT file.…”

“…An ex vivo biodistribution following the final SPECT/CT acquisition was performed as previously described by our group. , After euthanizing the animals via heart puncture and cervical dislocation, selected organs and tissues were removed, weighed, and measured using a Cobra II 5010 gamma counter (Packard Instruments) within a 140–290 keV energy window. After decay correcting the data to the time of injection, a calibration factor was applied to convert the data from units of CPM to MBq.…”

“…SPECT/CT imaging was conducted and analyzed as previously described 31,65 using a MILabs VECTor platform outfitted with an extra-ultrahigh sensitivity mouse pinhole collimator (MILabs; Houten, The Netherlands). 66,67 Acquisition times and details are provided in Supplemental Table 2.…”

Agglomerated serum albumin adsorbed protocatechuic acid coated superparamagnetic iron oxide nanoparticles as a theranostic agent

“…Albumin is a plasma protein found in lymph, saliva, cerebrospinal cord, and interstitial fluid, involved in the transport and dissolution of endogenous compounds, thereby regulating the osmotic pressure of the blood [48,49]. Albumin is well-known for its ability to specifically target tumour regions due to enhanced permeability and retention (EPR) effect as well as albumin receptor binding, which is a unique advantage as the carrier for tumour-targeted drug delivery [50].…”