Particle size modification of curcumin in relation to its pharmacokinetics and tissue distribution profile

The tissue distribution profile of Danshensu, one of the bioactive components in Radix salviae miltiorrhiae, was investigated after oral administration of Radix salviae miltiorrhiae coupled with Radix curcumae in rabbits. Eighteen rabbits were evenly divided into 3 groups. Rabbits of the groups were orally administrated with carboxymethyl cellulose, Radix salviae miltiorrhiae (10.0 g/kg) and Radix salviae miltiorrhiae (10.0 g/kg) coupled with Radix curcumae (5.0 g/kg), respectively. High performance liquid chromatography-electrospray ionic trap mass spectrometry (HPLC-ESI-MSn) was used for the determination of Danshensu in the tissues including heart, liver, kidney and brain. The statistical results demonstrated that the characteristic profiles of Danshensu were c kidney > c heart > c liver > c brain and c kidney > c brain > c liver > c heart after administration of Radix salviae miltiorrhiae and Radix salviae miltiorrhiae coupled with Radix curcumae, respectively, indicating that Radix curcumae could obviously increase the concentration of Danshensu in brain. This result would provide substantial foundation for the harmonizing effect of Shi herb in a Chinese compound prescription.

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Diverse lipid conjugates for functional extra-hepatic siRNA delivery in vivo

10.1101/289439 ◽

2018 ◽

Author(s):

Annabelle Biscans ◽

Andrew Coles ◽

Reka Haraszti ◽

Dimas Echeverria ◽

Matthew Hassler ◽

...

Keyword(s):

Tissue Distribution ◽

Therapeutic Intervention ◽

Chemical Engineering ◽

Adrenal Glands ◽

Sirna Delivery ◽

Distribution Profile ◽

Wide Range ◽

The Impact ◽

Tissue Distribution Profile

AbstractRNAi-based therapeutics show promising clinical data for treatment of liver-associated disorders. However, siRNA delivery into extra-hepatic tissues remains an obstacle, limiting the use of siRNA-based therapies. Here we report on a first example of chemical engineering of lipophilic conjugates to enable extra-hepatic delivery. We synthesized a panel of fifteen lipophilic siRNA and evaluated the impact of their chemical configuration on siRNA tissue distribution profile. Generally, lipophilic conjugates allow siRNA distribution to a wide range of tissues, where the degree of lipophilicity defines the ratio of liver/spleen to kidney distribution. In addition to primary clearance tissues, several conjugates achieve significant siRNA distribution to lung, heart, adrenal glands, fat, muscle. siRNA tissue accumulation leads to productive silencing, shown with two independent targets. siRNA concentrations necessary for productive silencing are tissue and conjugate dependent, varying significantly from 5 to 200 ng/mg. The collection of conjugated siRNA described here enables functional gene modulation in vivo in lung, muscle, fat, heart, adrenal glands opening these tissues for future therapeutic intervention.

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Albumin-Binding PSMA Radioligands: Impact of Minimal Structural Changes on the Tissue Distribution Profile

Molecules ◽

10.3390/molecules25112542 ◽

2020 ◽

Vol 25 (11) ◽

pp. 2542 ◽

Cited By ~ 1

Author(s):

Luisa M. Deberle ◽

Viviane J. Tschan ◽

Francesca Borgna ◽

Fan Sozzi-Guo ◽

Peter Bernhardt ◽

...

Keyword(s):

Protein Binding ◽

Tissue Distribution ◽

Plasma Protein Binding ◽

Plasma Protein ◽

Structural Changes ◽

Albumin Binding ◽

Distribution Profile ◽

Tissue Distribution Profile

The concept of using ibuprofen as an albumin-binding entity was recently demonstrated by the development of [177Lu]Lu-Ibu-PSMA-01. In the present study, we designed a novel ibuprofen-containing radioligand (Ibu-PSMA-02) with subtle structural changes regarding the linker entity in order to investigate a potential impact on the in vitro and in vivo properties. Ibu-PSMA-02 was prepared using solid-phase synthesis techniques and labeled with lutetium-177. [177Lu]Lu-Ibu-PSMA-02 was evaluated in vitro with regard to its plasma protein-binding properties, PSMA affinity and uptake into PSMA-expressing PC-3 PIP tumor cells. The tissue distribution profile of [177Lu]Lu-Ibu-PSMA-02 was assessed in tumor-bearing mice and dose estimations were performed. The in vitro characteristics of [177Lu]Lu-Ibu-PSMA-02 were similar to those previously obtained for [177Lu]Lu-Ibu-PSMA-01 with respect to plasma protein-binding, PSMA affinity and tumor cell uptake. The in vivo studies revealed, however, an unprecedentedly high uptake of [177Lu]Lu-Ibu-PSMA-02 in PC-3 PIP tumors, resulting in an increased absorbed tumor dose of 7.7 Gy/MBq as compared to 5.1 Gy/MBq calculated for [177Lu]Lu-Ibu-PSMA-01. As a consequence of the high tumor accumulation, [177Lu]Lu-Ibu-PSMA-02 showed higher tumor-to-background ratios than [177Lu]Lu-Ibu-PSMA-01. This study exemplified that smallest structural changes in the linker entity of PSMA radioligands may have a significant impact on their pharmacokinetic profiles and, thus, may be applied as a means for ligand design optimization.

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