Dataset Information

The Effect of Size and Shape of RNA Nanoparticles on Biodistribution.

ABSTRACT: Drugs with ideal pharmacokinetic profile require long half-life but little organ accumulation. Generally, PK and organ accumulation are contradictory factors: smaller size leads to faster excretion and shorter half-lives and thus a lower tendency to reach targets; larger size leads to longer circulation but stronger organ accumulation that leads to toxicity. Organ accumulation has been reported to be size dependent due in large part to engulfing by macrophages. However, publications on the size effect are inconsistent because of complication by the effect of shape that varies from nanoparticle to nanoparticle. Unique to RNA nanotechnology, size could be tuned without a change in shape, resulting in a true size comparison. Here we investigated size effects using RNA squares of identical shape but varying size and shape effects using RNA triangles, squares, and pentagons of identical size but varying shape. We found that circulation time increased with increasing RNA nanoparticle size from 5-25 nm, which is the common size range of therapeutic RNA nanoparticles. Most particles were cleared from the body within 2 hr after systemic injection. Undetectable organ accumulation was found at any time for 5 nm particles. For 20 nm particles, weak signal was found after 24 hr, while accumulation in tumor was strongest during the entire study.

SUBMITTER: Jasinski DL

PROVIDER: S-EPMC5910665 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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The Effect of Size and Shape of RNA Nanoparticles on Biodistribution.

Jasinski Daniel L DL Li Hui H Guo Peixuan P

Molecular therapy : the journal of the American Society of Gene Therapy 20171222 3

Drugs with ideal pharmacokinetic profile require long half-life but little organ accumulation. Generally, PK and organ accumulation are contradictory factors: smaller size leads to faster excretion and shorter half-lives and thus a lower tendency to reach targets; larger size leads to longer circulation but stronger organ accumulation that leads to toxicity. Organ accumulation has been reported to be size dependent due in large part to engulfing by macrophages. However, publications on the size ...[more]

PMID: 29402549

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Project description:The development of therapeutics for pediatric use has advanced in the last few decades, yet the off-label use of adult medications in pediatrics remains a significant clinical problem. Nano-based medicines are important drug delivery systems that can improve the bioavailability of a range of therapeutics. However, the use of nano-based medicines for application in pediatric populations is challenged by the lack of pharmacokinetic (PK) data in this population. To address this data gap, we investigated the PK of polymer-based nanoparticles in term-equivalent neonatal rats. We used poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) nanoparticles, which are polymer nanoparticles that have been extensively studied in adult populations but less commonly applied in neonates and pediatrics. We quantified the PK parameters and biodistribution of PLGA-PEG nanoparticles in term-equivalent healthy rats and revealed the PK and biodistribution of polymeric nanoparticles in neonatal rats. We further explored the effects of surfactant used to stabilize PLGA-PEG particles on PK and biodistribution. We showed that 4 h post intraperitoneal injection, nanoparticles had the highest accumulation in serum, at 54.0% of the injected dose for particles with Pluronic® F127 (F127) as the stabilizer and at 54.6% of the injected dose for particles with Poloxamer 188 (P80) as the stabilizer. The half-life of the F127-formulated PLGA-PEG particles was 5.9 h, which was significantly longer than the 1.7 h half-life of P80-formulated PLGA-PEG particles. Among all organs, the liver had the highest nanoparticle accumulation. At 24 h after administration, the accumulation of F127-formulated PLGA-PEG particles was at 26.2% of the injected dose, and the accumulation of P80-formulated particles was at 24.1% of the injected dose. Less than 1% of the injected nanoparticles was observed in healthy rat brain for both F127- and P80-formulated particles. These PK data inform the use of polymer nanoparticle applications in the neonate and provide a foundation for the translation of polymer nanoparticles for drug delivery in pediatric populations.

Project description:The incorporation of oleic acid and oleylamine, acting as organic surfactant coatings for a novel solvothermal synthesis procedure, resulted in the formation of monoclinic KLu(WO4)2 nanocrystals. The formation of this crystalline phase was confirmed structurally from X-ray powder diffraction patterns and Raman vibrational modes, and thermally by differential thermal analysis. The transmission electron microscopy images confirm the nanodimensional size (~12 nm and ~16 nm for microwave-assisted and conventional autoclave solvothermal synthesis) of the particles and no agglomeration, contrary to the traditional modified sol-gel Pechini methodology. Upon doping with holmium (III) and thulium (III) lanthanide ions, these nanocrystals can generate simultaneously photoluminescence and heat, acting as nanothermometers and as photothermal agents in the third biological window, i.e., self-assessed photothermal agents, upon excitation with 808 nm near infrared, lying in the first biological window. The emissions of these nanocrystals, regardless of the solvothermal synthetic methodology applied to synthesize them, are located at 1.45 μm, 1.8 μm and 1.96 μm, attributed to the 3H4 → 3F4 and 3F4 → 3H6 electronic transition of Tm3+ and 5I7 → 5I8 electronic transition of Ho3+, respectively. The self-assessing properties of these nanocrystals are studied as a function of their size and shape and compared to the ones prepared by the modified sol-gel Pechini methodology, revealing that the small nanocrystals obtained by the hydrothermal methods have the ability to generate heat more efficiently, but their capacity to sense temperature is not as good as that of the nanoparticles prepared by the modified sol-gel Pechnini method, revealing that the synthesis method influences the performance of these self-assessed photothermal agents. The self-assessing ability of these nanocrystals in the third biological window is proven via an ex-vivo experiment, achieving thermal knowledge and heat generation at a maximum penetration depth of 2 mm.

Dataset Information

The Effect of Size and Shape of RNA Nanoparticles on Biodistribution.

Publications

The Effect of Size and Shape of RNA Nanoparticles on Biodistribution.

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