Sonosensitive capsules for brain thrombolysis increase ischemic damage in a stroke model.

BACKGROUND: Ischemic stroke is the most common cerebrovascular disease and is caused by interruption of blood supply to the brain. To date, recombinant tissue plasminogen activator (rtPA) has been the main pharmacological treatment in the acute phase. However, this treatment has some drawbacks, such as a short half-life, low reperfusion rate, risk of hemorrhagic transformations, and neurotoxic effects. To overcome the limitations of rtPA and improve its effectiveness, we recently designed sonosensitive sub-micrometric capsules (SCs) loaded with rtPA with a size of approximately 600 nm, synthesized using the layer-by-layer (LbL) technique, and coated with gelatine for clot targeting. In this study, we evaluated the rtPA release of ultrasound (US)-responsive SCs in healthy mice and the therapeutic effect in a thromboembolic stroke model. RESULTS: In healthy mice, SCs loaded with rtPA 1 mg/kg responded properly to external US exposure, extending the half-life of the drug in the blood stream more than the group treated with free rtPA solution. The gelatine coating also contributed to stabilizing the encapsulation and maintaining the response to US. When the same particles were administered in the stroke model, these SCs appeared to aggregate in the ischemic brain region, probably generating secondary embolisms and limiting the thrombolytic effect of rtPA. Despite the promising results of these thrombolytic particles, at least under the dose and size conditions used in this study, the administration of these capsules represents a risk factor for stroke. CONCLUSIONS: This is the first study to report the aggregation risk of a drug carrier in neurological pathologies such as stroke. Biocompatibility analysis related to the use of nano-and microparticles should be deeply studied to anticipate the limitations and orientate the design of new nanoparticles for translation to humans.

Aqueous Stable Gold Nanostar/ZIF-8 Nanocomposites for Light-Triggered Release of Active Cargo Inside Living Cells.

A plasmonic core-shell gold nanostar/zeolitic-imidazolate-framework-8 (ZIF-8) nanocomposite was developed for the thermoplasmonic-driven release of encapsulated active molecules inside living cells. The nanocomposites were loaded, as a proof of concept, with bisbenzimide molecules as functional cargo and wrapped with an amphiphilic polymer that prevents ZIF-8 degradation and bisbenzimide leaking in aqueous media or inside living cells. The demonstrated molecule-release mechanism relies on the use of near-IR light coupled to the plasmonic absorption of the core gold nanostars, which creates local temperature gradients and thus, bisbenzimide thermodiffusion. Confocal microscopy and surface-enhanced Raman spectroscopy (SERS) were used to demonstrate bisbenzimide loading/leaking and near-IR-triggered cargo release inside cells, thereby leading to DNA staining.

Aqueous Synthesis of Copper(II)-Imidazolate Nanoparticles.

A green, simple, and efficient room-temperature aqueous synthetic route for the fabrication of novel porous coordination polymer nanoparticles (NPs) composed of Cu2+ and imidazolate was developed. Colloidal stability, morphology changes, and structural and chemical integrity of the developed NPs, in several solvents having different polarity, were investigated. Basic physicochemical properties of selected NPs (i.e., NP1, NP2, and NP3), such as size, optical and magnetic activity, porosity, thermal stability, structure, aging, and catalytic activity, were determined. Data indicate that the addition of the surfactant hexadecyltrimethylammonium bromide (CTAB) and the final solvent determine the size, morphology, and structure of the different NPs.

High-yield halide-assisted synthesis of metal-organic framework UiO-based nanocarriers.

The synthesis of nanosized metal-organic frameworks (NMOFs) is requisite for their application as injectable drug delivery systems (DDSs) and other biorelevant purposes. Herein, we have critically examined the role of different synthetic parameters leading to the production of UiO-66 crystals smaller than 100 nm. Of note, we demonstrate the co-modulator role conferred by halide ions, not only to produce NMOFs with precise morphology and size, but also to significantly improve the reaction yield. The resulting NMOFs are highly crystalline and exhibit sustained colloidal stability in different biologically relevant media. As a proof of concept, these NMOFs were loaded with Rhodamine 6G (R6G), which remained trapped in most common biologically relevant media. When incubated with living mammalian cells, the R6G-loaded NMOFs were efficiently internalized and did not impair cell viability even at relatively high doses.

In vivo ultrasound-activated delivery of recombinant tissue plasminogen activator from the cavity of sub-micrometric capsules.

External stimuli such as light, magnetic fields or ultrasounds allow for controlled drug release from nanocarriers with spatiotemporal resolution. Such tetherless approaches may become a straightforward solution to overcome the specificity problems typically associated with nanomedicines. Most of current nanomedicines suffer of very low specificity in vivo, thus rendering efficient targeted delivery among the most wanted breakthroughs in the fields of nanotechnology and medicine. Here we present a sonosensitive, sub-micrometric layer-by-layer capsule system for ultrasound-controlled delivery of macromolecules in vivo. As a proof of concept, the serine protease recombinant tissue plasminogen activator (rtPA), a thrombolytic drug widely employed for the treatment of acute ischemic stroke and other thromboembolic pathologies, is used as encapsulated active compound. The activity of encapsulated rtPA and its ultrasound-induced delivery from the cavity of the capsules are demonstrated. We show, first, that rtPA encapsulation prevents its endogenous biological inactivation and do not interfere with the thrombolytic activity of the drug. Second, upon ultrasound application, delivery of rtPA promotes breakdown of blood clots in vitro. Finally, the ultrasound-triggered in vivo delivery of rtPA from capsules intravenously administrated in mice is demonstrated.