CRLX101 (formerly IT-101)–A Novel Nanopharmaceutical of Camptothecin in Clinical Development

CRLX101 (formerly IT-101) is a first-in-class nanopharmaceutical, currently in Phase 2a development, which has been developed by covalently conjugating camptothecin (CPT) to a linear, cyclodextrin-polyethylene glycol (CD-PEG) co-polymer that self-assembles into nanoparticles. As a nanometer-scale drug carrier system, the cyclodextrin polymeric nanoparticle technology, referred to as “CDP”, has unique design features and capabilities. Specifically, CRLX101 preclinical and clinical data confirm that CDP can address not only solubility, formulation, toxicity, and pharmacokinetic challenges associated with administration of CPT, but more importantly, can impart unique biological properties that enhance CPT pharmacodynamics and efficacy

Preclinical to clinical development of the novel camptothecin nanopharmaceutical CRLX101

AbstractCamptothecin (CPT) is a potent broad-spectrum anticancer agent that acts through inhibition of topoisomerase 1. Clinical development of CPT was unsuccessful due to poor drug solubility, insufficient in vivo stability of the active form, and toxicity. In order to address these issues, a polymeric nanoparticle comprised of cyclodextrin-poly(ethylene glycol) copolymer (CDP) conjugated to CPT (CRLX101) has been developed and Phase 2 clinical studies are ongoing. Camptothecin is conjugated to the polymer in its active form at 10–12wt.% loading. CRLX101 self-assembles in solution into nanoparticles with an apparent solubility increase of >1000-fold as compared to the parent drug camptothecin. Preclinical studies exhibited CRLX101 pharmacokinetics superior to the parent drug. Drug concentration in tumor relative to plasma and other major organs is consistent with the enhanced permeation and retention (EPR) anticipated from a nanoparticle. Significant anti-tumor activity was observed that is superior when compared to irinotecan across a broad range of xenograft models. Pharmacokinetic data are consistent with the prolonged half-life and increased AUC. The CRLX101 preclinical and clinical data confirm that CDP can address not only solubility, formulation, toxicity, and pharmacokinetic challenges associated with administration of CPT, but more importantly, can impart unique biological properties, that enhance pharmacodynamics and efficacy of camptothecin

SIMS : Self Sovereign Identity Management System with Preserving Privacy in Blockchain

Blockchain, which is a useful tool for providing data integrity, has emerged as an alternative to centralized servers. Concentrating on the integrity of the blockchain, many applications have been developed. Specifically, a blockchain can be utilized in proving the user\u27s identity using its strong integrity. However, since all data in the blockchain is publicly available, it can cause privacy problems if the user\u27s identity is stored in the blockchain unencrypted. Although the encryption of the private information can diminish privacy problems in the blockchain, it is difficult to transparently utilize encrypted user information in the blockchain. To provide integrity and privacy of user information simultaneously in the blockchain, we propose a SIMS (Self-Sovereign Identity Management System) framework based on a zk-SNARK (zero-knowledge Succinct Non-interactive ARgument of Knowledge). In our proposed SIMS, the user information is employed in a privacy-preserving way due to the zero-knowledge property of the zk-SNARK. We construct a SIMS scheme and prove its security. We describe applications of SIMS and demonstrate its practicality through efficient implementations

Correlating preclinical animal studies and human clinical trials of a multifunctional, polymeric nanoparticle

Nanoparticles are currently being investigated in a number of human clinical trials. As information on how nanoparticles function in humans is difficult to obtain, animal studies that can be correlative to human behavior are needed to provide guidance for human clinical trials. Here, we report correlative studies on animals and humans for CRLX101, a 20- to 30-nm-diameter, multifunctional, polymeric nanoparticle containing camptothecin (CPT). CRLX101 is currently in phase 2 clinical trials, and human data from several of the clinical investigations are compared with results from multispecies animal studies. The pharmacokinetics of polymer-conjugated CPT (indicative of the CRLX101 nanoparticles) in mice, rats, dogs, and humans reveal that the area under the curve scales linearly with milligrams of CPT per square meter for all species. Plasma concentrations of unconjugated CPT released from CRLX101 in animals and humans are consistent with each other after accounting for differences in serum albumin binding of CPT. Urinary excretion of polymer-conjugated CPT occurs primarily within the initial 24 h after dosing in animals and humans. The urinary excretion dynamics of polymer-conjugated and unconjugated CPT appear similar between animals and humans. CRLX101 accumulates into solid tumors and releases CPT over a period of several days to give inhibition of its target in animal xenograft models of cancer and in the tumors of humans. Taken in total, the evidence provided from animal models on the CRLX101 mechanism of action suggests that the behavior of CRLX101 in animals is translatable to humans

The JCMT BISTRO Survey: Revealing the diverse magnetic field morphologies in Taurus dense cores with sensitive sub-millimeter polarimetry

© 2021. The Author(s). Published by the American Astronomical Society. This is an open access article distributed under the Creative Commons Attribution License, to view a copy of the license, see: https://creativecommons.org/licenses/by/4.0/We have obtained sensitive dust continuum polarization observations at 850 $\mu$m in the B213 region of Taurus using POL-2 on SCUBA-2 at the James Clerk Maxwell Telescope (JCMT), as part of the BISTRO (B-fields in STar-forming Region Observations) survey. These observations allow us to probe magnetic field (B-field) at high spatial resolution ($\sim$2000 au or $\sim$0.01 pc at 140 pc) in two protostellar cores (K04166 and K04169) and one prestellar core (Miz-8b) that lie within the B213 filament. Using the Davis-Chandrasekhar-Fermi method, we estimate the B-field strengths in K04166, K04169, and Miz-8b to be 38$\pm$14 $\mu$G, 44$\pm$16 $\mu$G, and 12$\pm$5 $\mu$G, respectively. These cores show distinct mean B-field orientations. B-field in K04166 is well ordered and aligned parallel to the orientations of the core minor axis, outflows, core rotation axis, and large-scale uniform B-field, in accordance with magnetically regulated star formation via ambipolar diffusion taking place in K04166. B-field in K04169 is found to be ordered but oriented nearly perpendicular to the core minor axis and large-scale B-field, and not well-correlated with other axes. In contrast, Miz-8b exhibits disordered B-field which show no preferred alignment with the core minor axis or large-scale field. We found that only one core, K04166, retains a memory of the large-scale uniform B-field. The other two cores, K04169 and Miz-8b, are decoupled from the large-scale field. Such a complex B-field configuration could be caused by gas inflow onto the filament, even in the presence of a substantial magnetic flux.Peer reviewe

The JCMT BISTRO Survey: A Spiral Magnetic Field in a Hub-filament Structure, Monoceros R2

We present and analyze observations of polarized dust emission at 850 μm toward the central 1 7 1 pc hub-filament structure of Monoceros R2 (Mon R2). The data are obtained with SCUBA-2/POL-2 on the James Clerk Maxwell Telescope (JCMT) as part of the B-fields in Star-forming Region Observations survey. The orientations of the magnetic field follow the spiral structure of Mon R2, which are well described by an axisymmetric magnetic field model. We estimate the turbulent component of the magnetic field using the angle difference between our observations and the best-fit model of the underlying large-scale mean magnetic field. This estimate is used to calculate the magnetic field strength using the Davis–Chandrasekhar–Fermi method, for which we also obtain the distribution of volume density and velocity dispersion using a column density map derived from Herschel data and the C18O (J = 3 - 2) data taken with HARP on the JCMT, respectively. We make maps of magnetic field strengths and mass-to-flux ratios, finding that magnetic field strengths vary from 0.02 to 3.64 mG with a mean value of 1.0 \ub1 0.06 mG, and the mean critical mass-to-flux ratio is 0.47 \ub1 0.02. Additionally, the mean Alfv\ue9n Mach number is 0.35 \ub1 0.01. This suggests that, in Mon R2, the magnetic fields provide resistance against large-scale gravitational collapse, and the magnetic pressure exceeds the turbulent pressure. We also investigate the properties of each filament in Mon R2. Most of the filaments are aligned along the magnetic field direction and are magnetically subcritical

The JCMT BISTRO Survey: Studying the Complex Magnetic Field of L43

We present observations of polarized dust emission at 850 μm from the L43 molecular cloud, which sits in the Ophiuchus cloud complex. The data were taken using SCUBA-2/POL-2 on the James Clerk Maxwell Telescope as a part of the BISTRO large program. L43 is a dense (NH 10 22 2 ~ –1023 cm−2) complex molecular cloud with a submillimeter-bright starless core and two protostellar sources. There appears to be an evolutionary gradient along the isolated filament that L43 is embedded within, with the most evolved source closest to the Sco OB2 association. One of the protostars drives a CO outflow that has created a cavity to the southeast. We see a magnetic field that appears to be aligned with the cavity walls of the outflow, suggesting interaction with the outflow. We also find a magnetic field strength of up to ∼160 ± 30 μG in the main starless core and up to ∼90 ± 40 μG in the more diffuse, extended region. These field strengths give magnetically super- and subcritical values, respectively, and both are found to be roughly trans-Alfvénic. We also present a new method of data reduction for these denser but fainter objects like starless cores

Filamentary Network and Magnetic Field Structures Revealed with BISTRO in the High-mass Star-forming Region NGC 2264: Global Properties and Local Magnetogravitational Configurations

We report 850 μm continuum polarization observations toward the filamentary high-mass star-forming region NGC 2264, taken as part of the B-fields In STar forming Regions Observations large program on the James Clerk Maxwell Telescope. These data reveal a well-structured nonuniform magnetic field in the NGC 2264C and 2264D regions with a prevailing orientation around 30° from north to east. Field strength estimates and a virial analysis of the major clumps indicate that NGC 2264C is globally dominated by gravity, while in 2264D, magnetic, gravitational, and kinetic energies are roughly balanced. We present an analysis scheme that utilizes the locally resolved magnetic field structures, together with the locally measured gravitational vector field and the extracted filamentary network. From this, we infer statistical trends showing that this network consists of two main groups of filaments oriented approximately perpendicular to one another. Additionally, gravity shows one dominating converging direction that is roughly perpendicular to one of the filament orientations, which is suggestive of mass accretion along this direction. Beyond these statistical trends, we identify two types of filaments. The type I filament is perpendicular to the magnetic field with local gravity transitioning from parallel to perpendicular to the magnetic field from the outside to the filament ridge. The type II filament is parallel to the magnetic field and local gravity. We interpret these two types of filaments as originating from the competition between radial collapsing, driven by filament self-gravity, and longitudinal collapsing, driven by the region's global gravity