PVA-Microbubbles as a Radioembolization Platform: Formulation and the In Vitro Proof of Concept

Abstract

This proof-of-concept study lays the foundations for the development of a delivery strategy for radioactive lanthanides, such as Yttrium-90, against recurrent glioblastoma. Our appealing hypothesis is that by taking advantage of the combination of biocompatible polyvinyl alcohol (PVA) microbubbles (MBs) and endovascular radiopharmaceutical infusion, a minimally invasive selective radioembolization can be achieved, which can lead to personalized treatments limiting off-target toxicities for the normal brain. The results show the successful formulation strategy that turns the ultrasound contrast PVA-shelled microbubbles into a microdevice, exhibiting good loading efficiency of Yttrium cargo by complexation with a bifunctional chelator. The selective targeting of Yttrium-loaded MBs on the glioblastoma-associated tumor endothelial cells can be unlocked by the biorecognition between the overexpressed αVβ3 integrin and the ligand Cyclo(Arg-Gly-Asp-D-Phe-Lys) at the PVA microbubble surface. Hence, we show the suitability of PVA MBs as selective Y-microdevices for in situ injection via the smallest (i.e., 1.2F) neurointerventional microcatheter available on the market and the accumulation of PVA MBs on the HUVEC cell line model of integrin overexpression, thereby providing ~6 × 10−15 moles of Y90 per HUVEC cell. We further discuss the potential impact of using such versatile PVA MBs as a new therapeutic chance for treating glioblastoma multiforme recurrence.

Endovascular Applications for the Management of High-Grade Gliomas in the Modern Era

“…These carriers should have a high loading capacity for radiotherapeutic agent, be compatible with endovascular techniques and microcatheters, and have the ability to selectively accumulate in the tumor [75]. One approach is ultrasonic microbubbles with polyvinyl alcohol (PVA) shells to load yttrium into a substrate capable of being delivered by a microcatheter as an endovascular radiopharmaceutical infusion [76]. Achieving selective targeting of yttrium-loaded microbubbles (MBs) on glioblastoma-associated tumor endothelial cells may be attainable through biorecognition mechanisms.…”

“…Achieving selective targeting of yttrium-loaded microbubbles (MBs) on glioblastoma-associated tumor endothelial cells may be attainable through biorecognition mechanisms. Specifically, the overexpressed αVβ3 integrin can interact with the ligand Cyclo(Arg-Gly-Asp-D-Phe-Lys) present on the PVA microbubble surface, facilitating precise delivery to the tumor site [76]. The main limitation of radiopharmaceuticals includes limited BBB penetration properties of conjugated ligands, heterogeneous antigen expression limiting target-mediated therapy, and translatability from preclinical models [69].…”

“…One unique advantage of endovascular drug delivery is the option to go beyond medication delivery and offer endovascular embolization as well. Targeted radioembolization may be a potential pre-operative adjuvant therapy to help reduce microscopic seeding and decrease local recurrence [76]. Intra-operative photodynamic exposure to a tumor premedicated with 5-ALA may induce a thermally mediated and immunologically mediate tumor ablation [102,103].…”

Enhancing Targeted Therapy in Breast Cancer by Ultrasound-Responsive Nanocarriers

“…With this system, they obtained 24 h of controlled release of dexamethasone acetate, normally poorly soluble. Very recent work by Da Ross et al illustrates a growing scope for surface functionalized PVA microbubbles with a system such as the previously described RGD/integrin binding system, increasing their scope to radioembolization with a yttrium payload to treat glioblastoma multiforme [ 133 ].…”

Ultrasound-Stimulated PVA Microbubbles as a Green and Handy Tool for the Cleaning of Cellulose-Based Materials

“…During the last decade, research has focused on expanding the use of echogenic PVA microbubbles (PVAMBs), i.e., micrometer-sized spheres made of an air core stabilized by a hydrophilic cross-linked PVA shell, from biomedicine (e.g., molecular imaging and targeted therapy) to cultural heritage [30][31][32]. Among the main reasons to use cross-linked polymer shell microbubbles (MBs), there are their robustness, chemical versatility, and biocompatibility.…”