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Endocrinology and Metabolic Disease

Neoplasms

siRNA

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Disease Domain	Count

Endocrinology and Metabolic Disease	1
Neoplasms	1

Top 5 Drug Type	Count

siRNA	2

Top 5 Target	Count

FGL1(Fibrinogen-like protein 1)	1
DPP-4(Dipeptidyl peptidase IV)	1

Pancreatic cancer (PC) stands for the most intractable malignancy.Gemcitabine (GEM) is one of the few approved first-line treatments for PC patients.The fast clearance, demanded high dosage, and existence of drug resistance have, nevertheless, posed not only a significant limitation to its clin. efficacy but also serious toxicity concerns.KRAS^G12D mutation is identified as a key driver in many PC patients, and its expression level shows a correlation with drug resistance and mortality.Here, we explored KRAS^G12D siRNA-gemcitabine oligonucleotide chimeras (siKRAS-G_n) as a dual prodrug that was designed to specifically silence KRAS^G12D gene and sensitize PC cells to GEM for the synergistic treatment of PC. siKRAS-G_n conjugates with 1, 2, 3, 4, or 5 units of GEM were synthesized and delivered using cRGD-decorated polymersomes.Interestingly, the proapoptotic activity of siKRAS-G_n was shown to highly depend on the number of GEM, in which three GEM units (siKRAS-G₃) were found to be optimal and induced strong apoptosis of PANC-1 cells (apoptosis rate: 64.2%).In contrast, minimal cell apoptosis was discerned for siKRAS, siKRAS-G₁, siKRAS-G₂, and free GEM (9-fold of that in siKRAS-G₃). siKRAS-G₃, while showing similar KRAS mRNA silencing ability to siKRAS, markedly enhanced the downregulation of KRAS protein in vitro and in vivo.Accordingly, siKRAS-G₃ significantly outperformed siKRAS and siScramble-G₃ in both tumor inhibition and survival benefits.The targeted delivery of the siKRAS-gemcitabine prodrug conjugate has emerged as an appealing treatment for pancreatic cancer.

14 Nov 2023·Macromolecules

Efficient Synthesis of N-Methyl Polypeptides by Organic Acid Promoted Controlled Ring-Opening Polymerization of N-Methyl-α-Amino Acids N-Carboxyanhydrides

Author: Zhao, Ning ; Xuan, Sunting ; Yu, Xinyan ; Dong, Yutong ; Zhang, Lifeng ; Wang, Yong ; Zhang, Zhengbiao

01 Sep 2023·Acta Biomaterialia

Targeted nanodelivery of siRNA against KRAS G12D inhibits pancreatic cancer

Article

Author: Huang, Ri ; Zhong, Zhiyuan ; Meng, Fenghua ; Zhang, Peizhuo ; Du, Hong ; Cheng, Liang

Pancreatic cancer (PC) stands as a most deadly malignancy due to few effective treatments in the clinics. KRAS G12D mutation is a major driver for most PC cases, and silencing of KRAS G12D is considered as a potential therapeutic strategy for PC, which is nevertheless crippled by lacking a pragmatic delivery system for siRNA against KRAS G12D (siKRAS). Here, we report that cRGD peptide-modified bioresponsive chimaeric polymersomes (cRGD-BCP) mediate highly efficient siKRAS delivery to PANC-1 tumor, potently silencing KRAS G12D mRNA in tumor cells and effectively suppressing PC tumor growth in mice. cRGD-BCP exhibited remarkable encapsulation of siKRAS (loading content > 14 wt.%, loading efficiency > 90%) to form stable and uniform (ca. 68 nm) nanovesicles (cRGD-BCP-siKRAS). Of note, cRGD density greatly impacted the cellular uptake and silencing efficiency of cRGD-BCP-siKRAS in PANC-1 cells, in which an optimal cRGD density of 15.7 mol.% achieved 3.7- and 3.6-fold enhancement of internalization and gene silencing, respectively, compared with non-targeted BCP-siKRAS. cRGD-BCP-siKRAS was practically intact after 3-week storage at 4°C. Intriguingly, cRGD-BCP-siKRAS markedly enhanced the uptake of siKRAS in PANC-1 tumor, and at a siKRAS dose of 3 mg/kg knocked down 90% KRAS G12D gene, resulting in potent tumor inhibition and extraordinary survival benefits (median survival time: 101 days versus 38 (PBS group) and 59 days (BCP-siKRAS)) with 40% mice achieved complete regression. It appears that cRGD-mediated nanodelivery of siKRAS provides a potential cure for pancreatic cancer. STATEMENT OF SIGNIFICANCE: Small interfering RNA (siRNA) emerges as a specific and powerful biopharmaceuticals against cancers; however, inefficient in vivo delivery impedes its clinical translation. In spite of the fact that KRAS G12D mutation has been identified as a major driver for most pancreatic cancer, its notorious non-druggability renders little success on development of molecular targeted drugs. Pancreatic cancer is deemed as current king-of-cancer. Here, we show that cyclic RGD peptide installed bioresponsive polymersomes are able to efficiently deliver siRNA against KRAS G12D to pancreatic tumor, resulting in 90% gene knock-down and effective tumor inhibition. Strikingly, two out of five mice have been cured. This targeted nanodelivery of siRNA provides a high-efficacy treatment strategy for pancreatic cancer.

100 Deals associated with Suzhou GenePharma Co., Ltd.

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100 Translational Medicine associated with Suzhou GenePharma Co., Ltd.

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Pipeline

Pipeline Snapshot as of 21 Feb 2025

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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