siRNA-Based Carrier-Free System for Synergistic Chemo/Chemodynamic/RNAi Therapy of Drug-Resistant Tumors

2021 ◽  
Author(s):  
Yifan Jiang ◽  
Yichang Liu ◽  
Min Wang ◽  
Zhi Li ◽  
Lichao Su ◽  
...  
Keyword(s):  
Drug Resistant ◽  
Free System ◽  
Carrier Free ◽  
Rnai Therapy

scholarly journals Trimeric Small Interfering RNAs and Their Cholesterol-Containing Conjugates Exhibit Improved Accumulation in Tumors, but Dramatically Reduced Silencing Activity

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1877
Author(s):  
Ivan V. Chernikov ◽  
Daniil V. Gladkikh ◽  
Ulyana A. Karelina ◽  
Mariya I. Meschaninova ◽  
Alya G. Ven’yaminova ◽  
...  
Keyword(s):  
Target Gene ◽  
Drug Resistant ◽  
Small Interfering Rnas ◽  
Tumor Bearing ◽  
Carrier Free ◽  
Free Mode ◽  
Derivatives Of ◽  
Transfection Agent

Cholesterol derivatives of nuclease-resistant, anti-MDR1 small-interfering RNAs were designed to contain a 2’-OMe-modified 21-bp siRNA and a 63-bp TsiRNA in order to investigate their accumulation and silencing activity in vitro and in vivo. The results showed that increasing the length of the RNA duplex in such a conjugate increases its biological activity when delivered using a transfection agent. However, the efficiency of accumulation in human drug-resistant KB-8-5 cells during delivery in vitro in a carrier-free mode was reduced as well as efficiency of target gene silencing. TsiRNAs demonstrated a similar biodistribution in KB-8-5 xenograft tumor-bearing SCID mice with more efficient accumulation in organs and tumors than cholesterol-conjugated canonical siRNAs; however, this accumulation did not provide a silencing effect. The lack of correlation between the accumulation in the organ and the silencing activity of cholesterol conjugates of siRNAs of different lengths can be attributed to the fact that trimeric Ch-TsiRNA lags mainly in the intercellular space and does not penetrate sufficiently into the cytoplasm of the cell. Increased accumulation in the organs and in the tumor, by itself, shows that using siRNA with increased molecular weight is an effective approach to control biodistribution and delivery to the target organ.

scholarly journals Nanocrystals of Poorly Soluble Drugs: Drug Bioavailability and Physicochemical Stability

Pharmaceutics ◽  
2018 ◽  
Vol 10 (3) ◽  
pp. 134 ◽  
Author(s):  
Maria Gigliobianco ◽  
Cristina Casadidio ◽  
Roberta Censi ◽  
Piera Di Martino
Keyword(s):  
Drug Delivery ◽  
Particle Size ◽  
Colloidal Particles ◽  
Poorly Soluble Drugs ◽  
Drug Bioavailability ◽  
Free System ◽  
Surface Active Agents ◽  
Carrier Free ◽  
Poorly Soluble ◽  
Surface Active

Many approaches have been developed over time to overcome the bioavailability limitations of poorly soluble drugs. With the advances in nanotechnology in recent decades, science and industry have been approaching this issue through the formulation of drugs as nanocrystals, which consist of “pure drugs and a minimum of surface active agents required for stabilization”. They are defined as “carrier-free submicron colloidal drug delivery systems with a mean particle size in the nanometer range, typically between 10–800 nm”. The primary importance of these nanoparticles was the reduction of particle size to nanoscale dimensions, with an increase in the particle surface area in contact with the dissolution medium, and thus in bioavailability. This approach has been proven successful, as demonstrated by the number of such drug products on the market. Nonetheless, despite the definition that indicates nanocrystals as a “carrier-free” system, surface active agents are necessary to prevent colloidal particles aggregation and thus improve stability. In addition, in more recent years, nanocrystal properties and technologies have attracted the interest of researchers as a means to obtain colloidal particles with modified biological properties, and thus their interest is now also addressed to modify the drug delivery and targeting. The present work provides an overview of the achievements in improving the bioavailability of poorly soluble drugs according to their administration route, describes the methods developed to overcome physicochemical and stability-related problems, and in particular reviews different stabilizers and surface agents that are able to modify the drug delivery and targeting.

scholarly journals In Vitro Characterization of the Anti-Hepatitis B Virus Activity and Cross-Resistance Profile of 2′,3′-Dideoxy-3′-Fluoroguanosine

2006 ◽  
Vol 50 (3) ◽  
pp. 955-961 ◽  
Author(s):  
A.-C. Jacquard ◽  
M.-N. Brunelle ◽  
C. Pichoud ◽  
D. Durantel ◽  
S. Carrouée-Durantel ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Antiviral Activity ◽  
Drug Resistant ◽  
Free System ◽  
Hbv Replication ◽  
Duck Hepatitis ◽  
Huh7 Cells ◽  
B Virus

ABSTRACT The fluorinated guanosine analog 2′,3′-dideoxy-3′-fluoroguanosine (FLG) was shown to inhibit wild-type (wt) hepatitis B virus (HBV) replication in a human hepatoma cell line permanently expressing HBV. Experiments performed in the duck model of HBV infection also showed its in vivo antiviral activity. In this study, we investigated the mechanism of inhibition of FLG on HBV replication and its profile of antiviral activity against different HBV or duck hepatitis B virus (DHBV) drug-resistant mutants. We found that FLG-triphosphate inhibits weakly the priming of the reverse transcription compared to adefovir-diphosphate in a cell-free system assay allowing the expression of an enzymatically active DHBV reverse transcriptase. It inhibits more potently wt DHBV minus-strand DNA synthesis compared to lamivudine-triphosphate and shows a similar activity compared to adefovir-diphosphate. FLG-triphosphate was most likely a competitive inhibitor of dGTP incorporation and a DNA chain terminator. In Huh7 cells transiently transfected with different HBV constructs, FLG inhibited similarly the replication of wt, lamivudine-resistant, adefovir-resistant, and lamivudine-plus-adefovir-resistant HBV mutants. These results were consistent with those obtained in the DHBV polymerase assay using the same drug-resistant polymerase mutants. In conclusion, our data provide new insights in the mechanism of action of FLG-triphosphate on HBV replication and demonstrate its inhibitory activity on drug-resistant mutant reverse transcriptases in vitro. Furthermore, our results provide the rationale for further clinical evaluation of FLG in the treatment of drug-resistant virus infection and in the setting of combination therapy to prevent or delay drug resistance.

Carrier‐Free Delivery of Precise Drug–Chemogene Conjugates for Synergistic Treatment of Drug‐Resistant Cancer

2020 ◽  
Vol 59 (41) ◽  
pp. 17944-17950 ◽  
Author(s):  
Lijuan Zhu ◽  
Yuanyuan Guo ◽  
Qiuhui Qian ◽  
Deyue Yan ◽  
Yuehua Li ◽  
...  
Keyword(s):  
Drug Resistant ◽  
Carrier Free

Carrier‐Free Delivery of Precise Drug–Chemogene Conjugates for Synergistic Treatment of Drug‐Resistant Cancer

2020 ◽  
Vol 132 (41) ◽  
pp. 18100-18106
Author(s):  
Lijuan Zhu ◽  
Yuanyuan Guo ◽  
Qiuhui Qian ◽  
Deyue Yan ◽  
Yuehua Li ◽  
...  
Keyword(s):  
Drug Resistant ◽  
Carrier Free
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