Extravasation of biodegradable microspheres in the rat brain

Abstract

Drug development for neurological diseases is greatly impeded by the presence of the blood-brain barrier (BBB). We and others previously reported on extravasation of micrometer-sized particles from the cerebral microcirculation – across the BBB – into the brain tissue over the course of several weeks. This mechanism could potentially be used for sustained parenchymal drug delivery after extravasation of biodegradable microspheres. As a first step toward this goal, we set out to evaluate the extravasation potential in the rat brain of three classes of biodegradable microspheres with drug-carrying potential, having a median diameter of 13 µm (80% within 8–18 µm) and polyethylene glycol concentrations of 0%, 24% and 36%. Extravasation, capillary recanalization and tissue damage were determined in a rat cerebral microembolization model at day 14 after microsphere injection. Microspheres of all three classes had the potential to extravasate from the vessel into the brain parenchyma, with microspheres without polyethylene glycol extravasating the fastest. Microembolization with biodegradable microspheres led to impaired local capillary perfusion, which was substantially restored after bead extravasation. We did not observe overt tissue damage after microembolization with any microsphere: we found very limited BBB disruption (IgG extravasation), no microgliosis (Iba1 staining) and no large neuronal infarctions (NeuN staining). In conclusion, biodegradable microspheres with different polymer compositions can extravasate into the brain parenchyma while causing minimal tissue damage.

Keywords:

• Microsphere extravasation
• angiophagy
• drug delivery
• blood-brain barrier
• biodegradable polymer

Conclusions

In conclusion, we show here that biodegradable microspheres composed of different multiblock copolymers have the potential to extravasate from the cerebral microcirculation into the brain parenchyma. The use of sufficiently small microspheres limited tissue damage due to microembolization. The observed differences in extravasation capacity between the three microsphere compositions warrant further optimization toward the use of such microspheres as a possible drug delivery platform for the sustained release of small molecules, proteins and antibodies to the brain in future studies.

Author’s contributions

AEvdW, ENTPB, PLH and EvB conceived and designed the experiments; AEvdW and TG performed the surgeries; AEvdW acquired the experimental data, analyzed the data. AE and EvB wrote the manuscript, RS and JZ were involved in the design and manufacturing of the biodegradable microspheres; all authors contributed to editing of the manuscript. All authors read and approved the final version of the manuscript.

Disclosure statement

RS and JZ are employed by InnoCore Pharmaceuticals, Groningen, The Netherlands. The SynBiosys® multi-block copolymer platform is patent protected and owned by InnoCore Pharmaceuticals.

Additional information

Funding

This work was supported by Amsterdam Neuroscience (project number NDIS-2019-03). TG was funded by the European Union’s Horizon 2020 research and innovation program under grant agreement No 777072 (INSIST). The funding bodies had no role in the design of the study and collection, analysis and interpretation of data, nor in writing of the manuscript.