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

Abstract

Liquid brachytherapy is an emerging technology for internal radiation therapy where liquids containing radionuclides are administered directly into solid tumors. These technologies are less invasive than conventional brachytherapy, and can potentially improve the dose coverage and homogeneity of the radioactivity distribution within the tumor. For this purpose, we have developed a novel cationic micelle system for delivery of a range of radionuclides. The system is applicable for emitters of alpha, beta or photon radiation, and enables dose-mapping via theranostic nuclear imaging. Methods: The cationic micelles were developed as linear surfactants comprising the chelator DOTA, a triarginine sequence and a palmitoyl or stearoyl fatty acid chain. The critical micelle concentration of the surfactants was determined, and the micelles were radiolabelled with 64 Cu or 177 Lu in high radiochemical purity (>95%). The tumor retention and biodistribution of the 64 Cu-radiolabeled surfactants, administered as micelles or formulated in liposomes, were investigated in vivo by PET/CT in a tumor bearing mouse model. Results: The interaction of the micelles with anionic lipid membranes was demonstrated to be favourable, using a liposome partition assay. In vivo, the surfactants formulated both as cationic micelles and liposomes displayed the best intratumoral retention, with micelles providing more homogeneous activity distribution. Conclusion: A cationic, surfactant-based drug delivery system was developed and demonstrated promise as a vehicle for liquid brachytherapy when formulated as micelles or in liposomes. The system enables accurate dosimetry due to the flexible radiochemistry of DOTA.

Noninvasive Imaging of Cancer Immunotherapy

“…Of note, and in line with the advancement of noninvasive imaging approaches, significant advances are being made in the realm of multifunctional “nanotheranostics” to develop new imaging and therapeutic approaches. Recent nanotheranostic therapeutic advancements include the development of a new liquid brachytherapy approach via novel cationic micelle and liposome formulations 175 , and the use of cross-linked iron oxide nanoparticles conjugated to azademethylcolchicine (CLIOT-ICT) as a method to eradicate a subpopulation of quiescent glioblastoma initiating cells 176 . Another recent theranostic advancement is the analysis of cancer cells by ultrasensitive dark-field imaging using gold nanoparticle bouquets 177 .…”

DNA Nanostructures and DNA‐Functionalized Nanoparticles for Cancer Theranostics

“…[ 8 ] Theranostics combines diagnostics with therapeutics, enabling cancer to be diagnosed and treated on an individual, personalized level, and allowing the therapeutic efficacy to be monitored noninvasively and in real time. [ 9 ] Such platforms utilize contrast agents which can be tracked in vivo using at least one imaging modality, e.g., magnetic resonance imaging (MRI), [ 10 ] positron emission tomography (PET), [ 11 ] computed tomography (CT), [ 12 ] surface‐enhanced Raman scattering (SERS), [ 13 ] or fluorescence. [ 14 ] A therapeutic module such as chemotherapeutics, [ 15 ] immunotherapies, [ 16 ] or photosensitive molecules [ 17 ] is also incorporated.…”

“…[ 26 ] In the last decade, a better understanding of tumor biology and synthesis of versatile nanomaterials such as polymers and polymer gels, lipids, inorganic NPs, and biomacromolecular scaffolds has aided the development of novel theranostic platforms for cancer. [ 11,14,21b,27 ] The development of such materials is very diverse and extensively reviewed elsewhere. [ 28 ]…”

Production of high specific activity rhenium-186 for radiotherapeutic applications and reformulation of a novel liquid brachytherapy agent

“…Brachytherapy, which is another form of radiation therapy involving the implantation of sealed radioactive sources into tumors, may benefit from the decay characteristics of 90 Y, but a limitation of conventional brachytherapy is the patient's discomfort from intratumoral placement of multiple sources. [78,79]. BetaBrach TM , contrarily, is a novel approach to brachytherapy, formulated as a liquid suspension of 90 Y-labeled yttrium hydroxycarbonate microparticles [80].…”

“…BetaBrach TM , contrarily, is a novel approach to brachytherapy, formulated as a liquid suspension of 90 Y-labeled yttrium hydroxycarbonate microparticles [80]. The liquid brachytherapy approach allows for implantation with a syringe for a less invasive administration [79]. The current synthetic procedure for BetaBrach TM generates the microparticles by heating a solution of urea, nocarrier added (NCA) [ 90 Y]YCl 3 , and non-radioactive YCl 3 [80].…”