Medicilon Nucleic Acid Drug Preclinical Evaluation Services

 From May 17^th to 19^th, 2024, the founding meeting of the Nucleic Acid Drug Professional Committee of the Chinese Pharmaceutical Association and the Nucleic Acid Drug Innovation Research Seminar were grandly held in Zhongshan City, Guangdong Province.  This event brought together top experts, scholars and entrepreneurs to discuss the latest research results and development trends in the field of nucleic acid drugs, injecting new vitality into the development of the field of nucleic acid drugs.

As a member of the first committee of the newly established Nucleic Acid Drug Professional Committee of the Chinese Pharmaceutical Association, Dr. Chunlin Chen, Founder and CEO of Medicilon, was invited to attend the conference and delivered an important speech.

Dr. Chen introduced in detail Medicilon's unique advantages in nucleic acid drug evaluation platform and collaboration model, and demonstrated Medicilon's deep strength and forward-looking vision in the field of nucleic acid drug research and development to the guests.

Medicilon has comprehensive preclinical research capabilities for nucleic acid drugs

Medicilon has extensive experience in nucleic acid drug research and development and has comprehensive preclinical research capabilities such as strong research capabilities in drug synthesis, modification and delivery systems to ensure drug stability and activity, complete biological analysis and screening technology to quickly screen potential drugs, professional biological sample analysis and collection capabilities to ensure data authenticity and reliability, and rich experience in non-clinical safety research to provide solid protection for drug research and development.

1. Comprehensive nucleic acid drug synthesis and modification capability

Medicilon's nucleic acid drug synthesis services cover nucleotide monomer synthesis/oligonucleotide synthesis/delivery system synthesis and oligonucleotide conjugate synthesis and more.

Additionally, Medicilon possesses various nucleic acid drug modification techniques, which can be categorized into sugar modification, base modification, backbone modification, and delivery system modification, depending on the modification sites.  These modification techniques can precisely target specific parts of nucleic acid drugs for improvement, thereby optimizing drug stability, biocompatibility, and targeting as well as providing strong technical support for the research and application of nucleic acid drugs.

Sugar Modification: >80 monomers

Base Modification

Backbone Modification

2. Rich experience in delivery system research

Medicilon has accumulated rich experience in the field of delivery system development, especially in areas such as nanoparticle carriers (such as LNP) and nucleic acid-conjugated GalNAc carriers.  These advanced delivery technologies ensure the efficient delivery of nucleic acid drugs in vivo.

Synthesis of 1500⁺ lipid nanoparticles

Lipid molecules exhibit immunogenicity in the human body
Unmodified lipids cannot be targeted for delivery

(1) lonizable lipid:

(2) Phospholipid:

(3) Cholesterol series:

Synthesis of 50⁺ N-acetyl galactosamine (GalNAc)

GalNAc shows no immunogenicity, making it safer
GalNAc targets the ASGPR on hepatocytes and can be absorbed through endocytosis

3. Robust biological analysis capabilities

With robust biological analysis capabilities, Medicilon provides in-depth support for target expression analysis, target sequence analysis, off-target effect analysis, and nucleotide sequence design, ensuring the accuracy and effectiveness of nucleic acid drug development.

Target Expression Analysis

Tissue-Specific Expression Analysis

Isomer Analysis

Target Sequence Analysis

Inter-Species Sequence Homology Analysis

Single Nucleotide Polymorphism (SNP) Analysis

Off-Target Effect Analysis

saRNA-Like Transcriptional Activation

Seed Sequence-Mediated Off-Target Effects

Nucleotide Sequence Design

Designing Novel Modified Nucleosides

Designing Sequences with High Knockout Efficiency

4. Biology-based nucleic acid drug screening techniques

Medicilon possesses biology-based nucleic acid drug screening techniques, covering in vitro screening and off-target effect assessment.  Through GaINAc and siRNA structure optimization, we can precisely screen and optimize the efficacy and specificity of nucleic acid drugs, and conduct in-depth research on off-target effects to ensure the precise effect of drugs and ensure their safety and effectiveness.

In Vitro Screening

GaINAc Structure Optimization Assay	SiRNA Structure Optimization Assay
√ GaINAc-ASGPR1 binding assay-SPR,ELISA √ HepG2 cell uptake-confocal √ HepG2 cell binding-FACS √ Primary hepatocyte uptake-qPCR	√ psiCHECK2 luciferase reporter assay √ Hepatocarcinoma cell line transfection-qPCR √ Primary hepatocyte transfection-qPCR √ Primary hepatocyte uptake-qPCR √ Ago2 loading

Off-Target Effects

Hybridization-Dependent Off-Target Effects	Non-Hybridization-Dependent Off-Target Effects
√ psiCHECK2 luciferase reporter assay-seed sequence √ Cytotoxicity of target KO cell lines-CTG √ RNA-seq √ Microarray	√ TLR3/TLR7/TLR8 dependent cytokinerelease assay-PBMCs-ELISA/Luminex √ HEK-Blue-TLR3/TLR7/TLR8 reporter assay √ Complement activation assay √ Primary hepatocyte and kidney cell toxicityassay

5. Advanced biological sample analysis capabilities

When evaluating the delivery efficiency of nucleic acid drugs, the selection of biological analysis methods is an indispensable step.  These methods encompass a variety of approaches, from traditional liquid-phase detection to molecular detection targeting cytokines.  However, each method has its unique sensitivity, specificity, and potential limitations. Among them, LC-MS/MS analysis method is given priority.

Method	Appropriate Analytes	Advantages	Insufficient
qPCR (after amplification)	Unmodified oligonucleotides (chemical modifications may affect analysis), should not be too short, at least 18 nucleotides or longer	High sensitivity, wide detection range, medium to high throughput capacity	Large sample processing workload, low resolution, low accuracy, low precision, limited specificity, susceptible to matrix interference, unable to distinguish between parent compounds and metabolites
Based on hybridization principles but not amplified, such as fluorescence-labeled probes, ligand-labeled probes; antibody binding, ELISA	Modified or unmodified oligonucleotides	High specificity (sequence-dependent), wide detection range, good sensitivity, good accuracy, and reproducibility	Relies on probes, detection labels, or antibodies for reliability, susceptible to matrix interference, unable to distinguish between parent compounds and metabolites
LC-UV/FL, chromatography combined with UV detection (fluorescence detection)	Modified or unmodified oligonucleotides, should not be too short, at least 24 nucleotides or longer	After separation, it shows high specificity, good accuracy and a wide detection range.	Large sample processing workload, low sensitivity, high separation requirements, if using an FL detector, sensitivity depends on the fluorescent probe.
LC-MS/MS, LC-HRAM (TOF, Orbitrap, etc.)	Modified oligonucleotides, nucleotides should not be too long, less than 25	High specificity and sensitivity for modified nucleic acids, wide detection range, high sensitivity, medium to high throughput capacity, high accuracy, and strong reproducibility	The instrument is expensive, sensitivity and specificity are poor for non-modified nucleic acids, and it causes significant damage to the instrument

6. Capable of comprehensive biological sample collection

Medicilon's biological sample collection technology covers ultrasound-guided liver biopsy, surgery-based liver biopsy, intracerebroventricular administration in monkeys, and lumbar puncture for cerebrospinal fluid collection.  The application of these professional techniques provides crucial data and resource support for drug research and development.

Ultrasound-guided liver biopsy: Can be collected every 2-4 weeks, with 10-20 mg collected each time

Muscle biopsy: Can be collected every 2-7 days, with 20-80 mg collected each time

Surgery-based liver biopsy: Can be collected every 2-4 weeks, with 80-100 mg collected each time

Intracerebroventricular administration in monkeys: administering 2 mL over 10 minutes

Collection of cerebrospinal fluid via lumbar puncture: collecting 0.5-1 mL each time

The road to the research and development of nucleic acid drugs is full of challenges, undoubtedly fostering wider collaboration and coordinated innovation within the industry.  In order to further promote the transformation of scientific research achievements, Medicilon relies on the Zhangjiang Academician Workstation for Drug Innovation (GOI) to engage in close collaboration with academicians, professors, and other top researchers.  This collaboration model not only integrates resources from all parties, greatly promoting the efficiency of translating scientific research achievements, but also promotes the deep integration of research and industry.  At the same time, close collaboration with top researchers enables Medicilon to keep pace with the international technological forefront, continuously enhancing its own technical capabilities and innovation.

Continuous exploration and innovation are the eternal pursuits of scientific research, as well as the core driving force and relentless pursuit of Medicilon.  Medicilon will continue to deepen its exploration in cutting-edge research areas such as nucleic acid drugs, daring to break through technological barriers, and actively seeking extensive collaboration with top global research institutions and pharmaceutical companies, to help more groundbreaking drugs enter clinical trials as soon as possible.

Nucleic Acid Drug R&D Platform

Medicilon nucleic acid drug R&D platform provides an integrated and comprehensive solution that covers drug discovery, CMC and preclinical research services. Our integrated solution will help clients and partners to fulfil their research and development mission for cutting-edge and innovative nucleic acid drugs. Our service platforms include nucleic acid drug discovery, screening and preclinical research services of pharmacology, DMPK and toxicity study for both pharmaceutical companies and academic research institutions.

Nucleic Acid Synthesis and Chemical Modifications

Nucleic acid drugs preparation

Pharmacology evaluation

The Pharmacokinetics Research of Nucleic Acid Drugs