siRNA delivery targeting to the lung via agglutination-induced accumulation and clearance of cationic tetraamino fullerene

Abstract

The efficient treatment of lung diseases requires lung-selective delivery of agents to the lung. However, lung-selective delivery is difficult because the accumulation of micrometer-sized carriers in the lung often induces inflammation and embolization-related toxicity. Here we demonstrate a lung-selective delivery system of small interfering RNA (siRNA) by controlling the size of carrier vehicle in blood vessels. The carrier is made of tetra(piperazino)fullerene epoxide (TPFE), a water-soluble cationic tetraamino fullerene. TPFE and siRNA form sub-micrometer-sized complexes in buffered solution and these complexes agglutinate further with plasma proteins in the bloodstream to form micrometer-sized particles. The agglutinate rapidly clogs the lung capillaries, releases the siRNA into lung cells to silence expression of target genes, and is then cleared rapidly from the lung after siRNA delivery. We applied our delivery system to an animal model of sepsis, indicating the potential of TPFE-based siRNA delivery for clinical applications.

Bioactive nanocarbon assemblies: Nanoarchitectonics and applications

“…The TPFE-DNA complexes were also utilized for therapeutic applications where TPFE was used to effectively deliver insulin plasmid to mice leading to reduced blood glucose levels. Recently, delivery of siRNA to the lungs of mice was also achieved with TPFE [106]. Although application of fullerene as a scaffold for cell culture has not been well developed so far, science in the solution phase is well developed compared with the other two nanocarbons, graphene and CNTs, and precisely controlled assembly and functions can be obtained.…”

68Ga‐Ca‐phytate particles: A potential lung perfusion agent of synthetic origin prepared in a cold kit format

“…68 Ga‐Ca‐Sn‐phytate as a foreign material is expected to directly bond with opsonins and/or immunoglobulins in blood, in a pre‐requisite antigen‐presentation step before binding to phagocytic cells. It was shown recently that TPFE‐siRNA particles (0.1–1 μm diameter) rapidly agglutinated with opsonins in the circulation to >6 μm diameter, the larger adduct was trapped in the lung capillaries of mice . The opsonins C3b and C4b for example, each contain a thioester group that is reactive to nucleophilic atoms such as N, O and S comprising an antigen.…”

Overcoming Gene-Delivery Hurdles: Physiological Considerations for Nonviral Vectors

“…The chemical structure of vectors can be altered through tuning of electrostatic interactions in order to reduce the risk of aggregation and ineffective delivery [54]. Specifically, vector stability can be increased through the formation of a hydrophilic shield via grafting of polyethylene glycol (PEG) [55, 56].…”