Cathepsin B-activatable cyclic antisense oligonucleotides for cell-specific target gene knockdown in vitro and in vivo

Wang, Zhongyu; Fan, Xinli; Mu, Guanqun; Zhao, Xiaoru; Wang, Qin; Wang, Jing; Tang, Xinjing

doi:10.1016/j.omtn.2023.07.022

“…However, this is a common feature widely presented in endo/ lysosomes. [14] On the other hand, several enzymes are differentially expressed in the endo/lysosomal environment of particular cells, e.g., cancer cells, [15,16] offering unique spurs for nanocarrier activation. Notably, the lysosomal cysteine proteases like cathepsin B (CTSB) are active in the endo/lysosomes of cancer cells, [17,18] leading to the clinical application of tumor-targeted CTSB-sensitive prodrugs [19] and antibody-drug conjugates (ADCs).…”

Section: Introductionmentioning

confidence: 99%

Selective Intracellular Delivery of Antibodies in Cancer Cells with Nanocarriers Sensing Endo/Lysosomal Enzymatic Activity

Chen,

Yang,

Mochida

et al. 2024

Angewandte Chemie

0

View full text Add to dashboard Cite

The differential enzymatic activity in the endo/lysosomes of particular cells could trigger targeted endosomal escape functions, enabling selective intracellular protein delivery. However, this strategy may be jeopardized due to protein degradation during endosomal trafficking. Herein, using custom made fluorescent probes to assess the endosomal activity of cathepsin B (CTSB) and protein degradation, we found that certain cancer cells with hyperacidified endosomes grant a spatiotemporal window where CTSB activity surpass protein digestion. This inspired the engineering of antibody‐loaded polymeric nanocarriers having CTSB‐activatable endosomal escape ability. The nanocarriers selectively escaped from the endo/lysosomes in the cells with high endosomal CTSB activity and delivered active antibodies to intracellular targets. This study provides a viable strategy for cell‐specific protein delivery using stimuli‐responsive nanocarriers with controlled endosomal escape.

show abstract

Selective Intracellular Delivery of Antibodies in Cancer Cells with Nanocarriers Sensing Endo/Lysosomal Enzymatic Activity

Chen,

Yang,

Mochida

et al. 2024

Angew Chem Int Ed

4

0

View full text Add to dashboard Cite

The differential enzymatic activity in the endo/lysosomes of particular cells could trigger targeted endosomal escape functions, enabling selective intracellular protein delivery. However, this strategy may be jeopardized due to protein degradation during endosomal trafficking. Herein, using custom made fluorescent probes to assess the endosomal activity of cathepsin B (CTSB) and protein degradation, we found that certain cancer cells with hyperacidified endosomes grant a spatiotemporal window where CTSB activity surpass protein digestion. This inspired the engineering of antibody‐loaded polymeric nanocarriers having CTSB‐activatable endosomal escape ability. The nanocarriers selectively escaped from the endo/lysosomes in the cells with high endosomal CTSB activity and delivered active antibodies to intracellular targets. This study provides a viable strategy for cell‐specific protein delivery using stimuli‐responsive nanocarriers with controlled endosomal escape.

show abstract

Inhibitory Effects on RNA Binding and RNase H Induction Activity of Prodrug-Type Oligodeoxynucleotides Modified with a Galactosylated Self-Immolative Linker Cleavable by β-Galactosidase

Miyaji,

Masaki,

Seio

2024

Bioconjugate Chem.

0

View full text Add to dashboard Cite

Prodrug-type oligonucleotides (prodrug-ONs) are a class of oligonucleotide designed for activation under specific intracellular conditions or external stimuli. Prodrug-ONs can be activated in the target tissues or cells, thereby reducing the risk of adverse effects. In this study, we synthesized prodrug-type oligodeoxynucleotides activated by β-galactosidase, an enzyme that is overexpressed in cancer and senescent cells. These oligodeoxynucleotides (ODNs) contain a modified thymidine conjugated with galactose via a self-immolative linker at the O4-position. UV-melting analysis revealed that the modifications decreased the melting temperature (T m ) compared with that of the unmodified ODN when hybridized with complementary RNA. Furthermore, cleavage of the glycosidic bond by β-galactosidase resulted in the spontaneous removal of the linker from the nucleobase moiety, generating unmodified ODNs. Additionally, the introduction of multiple modified thymidines into ODNs completely inhibited the RNase Hmediated cleavage of complementary RNA. These findings suggest the possibility of developing prodrug-ONs, which are specifically activated in cancer cells or senescent cells with high β-galactosidase expression.

show abstract

Cathepsin B-activatable cyclic antisense oligonucleotides for cell-specific target gene knockdown in vitro and in vivo

Cited by 3 publications

References 44 publications

Selective Intracellular Delivery of Antibodies in Cancer Cells with Nanocarriers Sensing Endo/Lysosomal Enzymatic Activity

Selective Intracellular Delivery of Antibodies in Cancer Cells with Nanocarriers Sensing Endo/Lysosomal Enzymatic Activity

Selective Intracellular Delivery of Antibodies in Cancer Cells with Nanocarriers Sensing Endo/Lysosomal Enzymatic Activity

Inhibitory Effects on RNA Binding and RNase H Induction Activity of Prodrug-Type Oligodeoxynucleotides Modified with a Galactosylated Self-Immolative Linker Cleavable by β-Galactosidase

Contact Info

Product

Resources

About