Synthesis and Biodistribution of ²¹¹At-Labeled, Biotinylated, and Charge-Modified Poly-l-lysine:  Evaluation for Use as an Effector Molecule in Pretargeted Intraperitoneal Tumor Therapy

Abstract

Poly-L-lysine (7, 21, and 204 kDa) has been evaluated as an effector carrier for use in pretargeted intraperitoneal tumor therapy. For the synthesis, the epsilon-amino groups on the poly-L-lysine were modified in three steps utilizing conjugate biotinylation with biotin amidocaproate N-hydroxysuccinimide ester (BANHS), conjugate radiolabeling with (211)At using the intermediate reagent N-succinimidyl 3-(trimethylstannyl)benzoate (m-MeATE), and charge modification using succinic anhydride, resulting in an increase in the molecular weight of approximately 80% of the final product. The labeling of the m-MeATE reagent and subsequent conjugation of the polymer were highly efficient with overall radiochemical yields in the range of 60-70%. The in vitro avidin binding ability of the modified polymer was almost complete (90-95%), as determined by binding to avidin beads using a convenient filter tube assay. Following intraperitoneal (ip) injection in athymic mice, the 13 kDa polymer product was cleared mainly via the kidneys with fast kinetics (biological half-live T(b) approximately 2 h) and with low whole-body retention. The clearance of the 38 kDa polymer was distributed between kidneys and liver, and the 363 kDa polymer was mainly sequestered by the liver with a T(b) of 8 h. Increased tissue uptake in the thyroid, lungs, stomach, and spleen following the distribution of the large effector molecules (38 and 363 kDa) suggests that degradation of the polymers by the liver may release some of the label as free astatine/astatide.

Tuning the Unidirectional Electron Transfer at Interfaces with Multilayered Redox‐active Supramolecular Bionanoassemblies

“…[32][33][34][35][36][37] In our case, the platform to build-up the supramolecular assemblies was constructed by initially chemisorbing a binary mixed SAM on Au surfaces in order to create a biotinylated surface (Fig. 1, step 1).…”

Biotinylated and Chelated Poly-L-Lysine as Effector for Pretargeting in Cancer Therapy and Imaging

“…Thus, the optimum amount of chelator bound to the effector molecule must be evaluated in vivo (as well as the optimum amount of the other groups incorporated in the effector molecule). 211 Lindegren et al [12 At [12,18,23]. The study by ] showed a decreasing kidney dose when increasing the size of the effector from 13 kDa to 386 kDa.…”

“…211 At)-labelling, [12,18] except for that chelators were attached to the polylysine instead of astatine-binding residues. Poly-L-lysine of high purity (98.5%) and well defined size of 30 or 50 lysine residues (Caslo ApS, Lyngby, Denmark) was dissolved to a concentration of 2 mg/ml in 0.2 M carbonate buffer, pH ~8.5, which had been filtered through Chelex 100 resin (Bio-Rad Laboratories, Hercules, CA, USA).…”

“…Since not only molecular size, but also charge influences the renal handling [11], the ability to vary charge also provides opportunities to optimize the biodistribution. Polylysine has formerly been used as a multicarrier in pretargeting as well as in other contexts in the field of targeted radionuclide therapy [12][13][14][15].…”

Pretargeted Radioimmunotherapy for Hematologic and Other Malignancies

“…5 The latter forms stable complexes with yttrium-90 ( 90 Y) 59 and is widely used as an effector in PRIT. However, alternative b-or a-emitting radionuclides can be used, as DOTA forms highly stable complexes with other isotopes such as 64 Cu, 67 Ga, 149 Pm, 166 62,63 In the second approach, biotin-conjugated antibody is used to target the tumor. Antibody biotinylation is easily accomplished; importantly, addition of a few molecules of biotin (molecular weight: 244 Da) does not alter immunoreactivity, plasma kinetics, or rates of antibody permeation and diffusion and only minimally increases the molecular weight of the targeting vehicle.…”