3 research outputs found
Comparative Physiology of Mice and Rats: Radiometric Measurement of Vascular Parameters in Rodent Tissues
A solid understanding of physiology is beneficial in optimizing
drug delivery and in the development of clinically predictive models
of drug disposition kinetics. Although an abundance of data exists
in the literature, it is often confounded by the use of various experimental
methods and a lack of consensus in values from different sources.
To help address this deficiency, we sought to directly compare three
important vascular parameters at the tissue level using the same experimental
approach in both mice and rats. Interstitial volume, vascular volume,
and blood flow were radiometrically measured in selected harvested
tissues of both species by extracellular marker infusion, red blood
cell labeling, and rubidium chloride bolus distribution, respectively.
The latter two parameters were further compared by whole-body autoradiographic
imaging. An overall good interspecies agreement was observed for interstitial
volume and blood flow on a weight-normalized basis in most tissues.
In contrast, the measured vascular volumes of most rat tissues were
higher than for mouse. Mice and rats, the two most commonly utilized
rodent species in translational drug development, should not be considered
as interchangeable in terms of vascular volume per gram of tissue.
This will be particularly critical in biodistribution studies of drugs,
as the amount of drug in the residual blood of tissues is often not
negligible, especially for biologic drugs (e.g., antibodies) having
long circulation half-lives. Physiologically based models of drug
pharmacokinetics and/or pharmacodynamics also rely on accurate knowledge
of biological parameters in tissues. For tissue parameters with poor
interspecies agreement, the significance and possible drivers are
discussed
Enhanced Tumor Retention of a Radiohalogen Label for Site-Specific Modification of Antibodies
A known limitation of iodine radionuclides
for labeling and biological tracking of receptor targeted proteins
is the tendency of iodotyrosine to rapidly diffuse from cells following
endocytosis and lysosomal degradation. In contrast, radiometal–chelate
complexes such as indium-111–1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic
acid (In-111-DOTA) accumulate within target cells due to the residualizing
properties of the polar, charged metal-chelate-amino acid adduct.
Iodine radionuclides boast a diversity of nuclear properties and chemical
means for incorporation, prompting efforts to covalently link radioiodine
with residualizing molecules. Herein, we describe the Ugi-assisted
synthesis of [I-125]ÂHIP-DOTA, a 4-hydroxy-3-iodophenyl (HIP) derivative
of DOTA, and demonstration of its residualizing properties in a murine
xenograft model. Overall, this study displays the power of multicomponent
synthesis to yield a versatile radioactive probe for antibodies across
multiple therapeutic areas with potential applications in both preclinical
biodistribution studies and clinical radioimmunotherapies
Exploration of Pyrrolobenzodiazepine (PBD)-Dimers Containing Disulfide-Based Prodrugs as Payloads for Antibody–Drug Conjugates
A number
of cytotoxic pyrrolobenzodiazepine (PBD) monomers containing
various disulfide-based prodrugs were evaluated for their ability
to undergo activation (disulfide cleavage) <i>in vitro</i> in the presence of either glutathione (GSH) or cysteine (Cys). A
good correlation was observed between <i>in vitro</i> GSH
stability and <i>in vitro</i> cytotoxicity toward tumor
cell lines. The prodrug-containing compounds were typically more potent
against cells with relatively high intracellular GSH levels (e.g.,
KPL-4 cells). Several antibody–drug conjugates (ADCs) were
subsequently constructed from PBD dimers that incorporated selected
disulfide-based prodrugs. Such HER2 conjugates exhibited potent antiproliferation
activity against KPL-4 cells <i>in vitro</i> in an antigen-dependent
manner. However, the disulfide prodrugs contained in the majority
of such entities were surprisingly unstable toward whole blood from
various species. One HER2-targeting conjugate that contained a thiophenol-derived
disulfide prodrug was an exception to this stability trend. It exhibited
potent activity in a KPL-4 <i>in vivo</i> efficacy model
that was approximately three-fold weaker than that displayed by the
corresponding parent ADC. The same prodrug-containing conjugate demonstrated
a three-fold improvement in mouse tolerability properties <i>in vivo</i> relative to the parent ADC, which did not contain
the prodrug