PET imaging with copper‐64 as a tool for real‐timein vivoinvestigations of the necessity for cross‐linking of polymeric micelles in nanomedicine

Abstract

Polymeric micelles in nanomedicine are often cross-linked to prevent disintegration in vivo. This typically requires clinically problematic chemicals or laborious procedures. In addition, cross-linking may interfere with advanced release strategies. Despite this, it is often not investigated whether cross-linking is necessary for efficient drug delivery. We used positron emission tomography (PET) imaging with Cu to demonstrate general methodology for real-time in vivo investigations of micelle stability. Triblock copolymers with 4-methylcoumarin cores of ABC-type (PEG-PHEMA-PCMA) were functionalized in the handle region (PHEMA) with CB-TE2A chelators. Polymeric micelles were formed by dialysis and one half was core cross-linked (CL) by UV light and the other half was not (nonCL). Both CL and nonCL were radiolabeled with Cu and compared in vivo in tumor-bearing mice, with free Cu as control. Accumulation in relevant organs was quantified by region of interest analysis on PET images and ex vivo counting. It was observed that CL and nonCL showed limited differences in biodistribution from each other, whereas both differed markedly from control (free Cu). This demonstrated that 4-methylcoumarin core micelles may form micelles that are stable in circulation even without cross-linking. The methodology presented here where individual unimers are radiolabeled is applicable to a wide range of polymeric micelle types.

Preclinical evaluation of cationic DOTA-triarginine-lipid conjugates for theranostic liquid brachytherapy

“…Only 2.4 ± 0.7 %ID/tumor and 1.4 ± 0.4 %ID/tumor was found in the tumor at 6 hours and 24 hours respectively, underscoring the rapid wash-out. Free 64 CuCl 2 is known to accumulate in solid tumors after systemic administration [19,20]. Here however, we observed an initial tumor clearance with significantly lower activity at the 12 minute time point compared to 2 minutes after injection (p = 0.004), and the retention of free 64 Cu was only 45 ± 5% ID/tumor at 12 minutes.…”

Remote-loading of liposomes with manganese-52 and in vivo evaluation of the stabilities of 52Mn-DOTA and 64Cu-DOTA using radiolabelled liposomes and PET imaging

“…In order to rely on results from such surface-labeling (figure 1), the stabilities of the employed chelates must be ascertained. Suboptimal stability will result in the release or transchelation of free radiometal with biodistributions that differ from the investigated tracer [19,20]. Indeed, the stability of radiometalchelator complexes placed on the surface of nanoparticles, on antibodies, peptides or small molecules, is paramount for conducting precise quantitative studies.…”

“…Pancreas was included since free 52 Mn has been reported to accumulate strongly in this organ [14], while free 64 Cu is known to accumulate in liver [20,41].…”

Current outlook on radionuclide delivery systems: from design consideration to translation into clinics

“…Later, Jensen with co-workers developed triblock PEG‐pHEMA‐PCMA micelle modified with macrocyclic chelator 2,2′‐(1,4,8,11‐tetraazabicyclo[6.6.2]hexadecane‐4,11‐diyl)diacetic acid (CB‐TE2A) using pre-labeling approach for complexation with radioisotope 64 Cu. The conjugation of CB‐TE2A chelator was performed to the primary alcohols of the pHEMA block through 4‐dimethylaminopyridine–catalyzed 1‐ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide coupling in dimethylformamide (DMF) [172].…”

“…The acidic TME can trigger degradation of MnO 2 and thus decomposition of nanoparticles into individual 131 I-HSA with sub-10 nm sizes and greatly improves intratumoral diffusion[134] 111 InDendrimersChelation (SCN-Bz-DTPA)SPECT, optical imagingKobayashi et al synthesized nanoprobes with multimodal and multicolor potential, which employed a polyamidoamine dendrimer platform linked to both radionuclides and optical probes, permitting dual-modality scintigraphic and five-color near-infrared optical lymphatic imaging using a multiple-excitation spectrally resolved fluorescence imaging technique[155] 125 IPolymeric-based NPsIodination via aromatic electrophilic substitutionPET, SPECTTang et al produced polymeric NPs using Flash NanoPrecipitation and radiolabeled them with 125 I at high radiochemical yields (> 90%). The nanocarriers demonstrated extended circulation half-lives and gradual RES clearance[175] 64 CuPolymeric micellesChelation (CB‐TE2A)PETJensen et al investigated the novel triblock PEG‐pHEMA‐PCMA micelle modified with macrocyclic chelator and difference of in vivo biodistribution of cross-linked an non cross-linked micelles using PET[172]…”