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Conjugation Chemistry

Cleavable & Non-Cleavable Linkers for Oligonucleotides

Custom cleavable and non-cleavable oligo linkers for ADC conjugates, nucleic acid therapeutics, diagnostics, and research.

Overview Popular Linkers All Linkers (Master Table) Design & QC Related Services

Overview

Bio-Synthesis offers one of the broadest portfolios of cleavable and non-cleavable linkers for DNA and RNA oligonucleotide modification. These chemistries enable either controlled release (via redox, pH, enzymatic, photolytic, or thermal triggers) or stable, permanent conjugation to support applications in therapeutics, diagnostics, and advanced research.

Cleavable linkers such as disulfides, acid-labile hydrazones, Val-Cit-PAB enzyme linkers, and photo-/thermally sensitive groups are designed for site-specific drug release, intracellular activation, or responsive probe design. Non-cleavable linkers such as PEG spacers, alkyl chains, SMCC/BMPS, triazole “click” linkers, and thioether or amide bonds provide long-term stability, permanent labeling, and solubility tuning.

Our team supports projects from discovery through regulated production, providing expert linker selection guidance, scalable synthesis, and comprehensive QC (HPLC, ESI-MS, SEC/CE, cleavage profiling). Whether you need a triggerable linker for ADC-style oligo conjugates or a stable spacer for probe design, we deliver tailored solutions that balance stability, release kinetics, and biocompatibility.

Controlled Release Stable Spacers ADC-Style Conjugates Photo/Redox/Enzyme Sensitive PEG / Alkyl Linkers GLP / GMP Alignment

Popular Linkers (Quick Reference)

Common choices used across ADC-style oligo conjugates, probes, and capture tools.

Hide Products & Notes
Product Category Cleaved By Typical Applications Code
Mal-PEG4-Val-Cit-PAB-PNA Enzyme-Cleavable Linkers Cathepsin B ADC oligo conjugates [Mal-PEG4-VC-PAB-PNA]
Mc-Val-Cit-PABC-PNP Enzyme-Cleavable Linkers Cathepsin B ADC oligo conjugates [Mc-VC-PABC-PNP]
Mal-PEG1-Val-Cit-PAB-PNP Enzyme-Cleavable Linkers Cathepsin B ADC oligo conjugates [Mal-PEG1-VC-PAB-PNP]
Gly-Phe-Leu-Gly (GFLG) Enzyme-Cleavable Linkers Lysosomal enzymes ADC oligo conjugates [GFLG]
Mal-Amide-PEG4-Val-Cit-PAB-PNP Enzyme-Cleavable Linkers Cathepsin B ADC oligo conjugates [Mal-Amide-PEG4-VC-PAB-PNP]
Thiol-C6 S–S Disulfide Linkers (Reductive Cleavage) Reducing agents (e.g., GSH, DTT) Antibody–oligo conjugates, intracellular release [Thiol-C6-SS]
SPDP Disulfide Linkers (Reductive Cleavage) Intracellular glutathione Antibody–oligo conjugates, intracellular release [SPDP]
Sulfo-LC-SPDP Disulfide Linkers (Reductive Cleavage) Water-soluble SPDP variant Antibody–oligo conjugates, intracellular release [Sulfo-LC-SPDP]
Hydrazone Acid-Labile Linkers Endosomal acidic pH Targeted delivery systems (e.g., ADCs) [Hydrazone]
PC Spacer Photocleavable Linker UV light Solid-phase synthesis, drug release [PC-Spacer]
PC Linker Photocleavable Linker UV light Light-controlled hybridization/release [PC-Linker]
PC-Biotin Photocleavable Linker UV light Affinity capture and light release [PC-Biotin]
PC Amino C6-Modifier Photocleavable Linker UV light Light-controlled C6 oligo modification [PC-Amino-C6]
Azobenzene Photocleavable Linker Light Photo-responsive structural switching [Azobenzene]
NPOM Caged-dT Photocleavable Linker Light Transcription control [NPOM-dT]
DEACM Caged-dG Photocleavable Linker Light Spatial/temporal biological control [DEACM-dG]
4-Thio-dU Photocleavable Linker Light Light-activated release [4-Thio-dU]
2-Aminopurine Photocleavable Linker Light Structural analysis, release assays [2-AP]
6-Thio-dG Photocleavable Linker Light Photocleavable hybridization studies [6-Thio-dG]
2-Thio-dT Photocleavable Linker Light Duplex modification [2-Thio-dT]
3-Cyanovinylcarbazole (CNVK) Photocleavable Linker Light Photo-crosslinking/hybridization [CNVK]
Azobenzene derivatives Thermally Cleavable Linker Heat-sensitive scission Thermally triggered release [Azobenzene-der]
Alkyl Chains (C3, C6, C12) Non-Cleavable Linker Stable hydrocarbon spacers Labeling, structure, flexibility [Alkyl-C3/C6/C12]
PEG Linkers (PEG4, PEG12, PEG24) Non-Cleavable Linker Flexible, hydrophilic spacers Solubility, steric shielding [PEG4/12/24]
SMCC, BMPS Non-Cleavable Linker Maleimide–NHS crosslinkers Protein or peptide–oligo conjugates [SMCC|BMPS]
Click Chemistry Linkers Non-Cleavable Linker Triazole-forming azide–alkyne linkers Bioorthogonal, durable coupling [Click-Azide/Alkyne]
Thioether Bonds Non-Cleavable Linker Thiols + maleimides (covalent) Long-term, stable bioconjugation [Thioether]
Amide Linkers Non-Cleavable Linker Carboxylic acid + amine (EDC/NHS) Versatile, robust linkage [Amide-EDC/NHS]
Technical Notes
  • Placement: Prefer termini (5′/3′) for minimal Tm impact; internal placement benefits from PEG spacing.
  • Orthogonality: Keep NHS/amine, maleimide/thiol, and click (azide/alkyne) steps separated to avoid cross-reactivity.
  • QC: Identity by ESI-MS/MALDI; purity by HPLC; optional SEC or CE for complex constructs.
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Design & QC

Design Tips

  • Trigger match: Pick the cleavable motif to match the biological micro-environment (redox, endosomal pH, lysosomal enzymes, light access).
  • Terminal first: Start at 5′/3′; consider internal only after Tm validation and spacing.
  • Orthogonal plan: Stage NHS/amine → click → maleimide/thiol to avoid cross-reactions.

We can recommend linker + payload geometry and run cleavage profiling in your buffer system.

QC & Documentation

  • Identity by ESI-MS/MALDI; purity by HPLC; optional SEC or CE.
  • Cleavage verification by UV/fluorescence or LC/MS endpoints.
  • CoA with yield (OD/µmol), purity %, linker identity, and conjugation details.

ISO 9001 / ISO 13485 alignment; GLP/GMP-like practices as scoped.

Can’t find the sugar modification you need?

We routinely source or synthesize specialty phosphoramidites and can align to your internal codes or vendor references.

Speak to a Scientist Browse All Modifications

Technology & Applications

Technology

  • Cleavable linkers: Designed to release payloads under specific triggers such as reducing agents (disulfides), acidic pH (hydrazones), enzymatic cleavage (Val-Cit-PAB, GFLG), light (photocleavables), or heat (thermally labile).
  • Non-cleavable linkers: PEG chains, alkyl spacers, SMCC/BMPS, triazole “click” linkers, thioethers, and amides provide permanent, stable connections for long-term labeling and durable conjugates.
  • Engineering approach: We match linker chemistry to your application, ensuring controlled release or stability, appropriate linker length, and minimized steric hindrance.

Our platform supports synthesis directly on solid-phase or via post-synthetic conjugation, with scalable routes and rigorous QC validation.

Applications

  • Therapeutics: ADC-style oligo conjugates, siRNA/ASO drug delivery, controlled release systems.
  • Diagnostics & probes: Light-triggered capture/release, hybridization assays, FRET probes.
  • Structural biology: Photocleavables (e.g., CNVK, 2-thio bases) enable photo-crosslinking and structural mapping.
  • Surface immobilization: Stable non-cleavable PEG or alkyl linkers for biosensor and microarray platforms.
  • Custom builds: Multi-functional linkers combining cleavable and non-cleavable motifs for advanced designs.

We provide guidance to balance stability, release kinetics, and biocompatibility in your project’s design.

FAQ

What is the difference between cleavable and non-cleavable linkers?

Cleavable linkers are designed to break under specific triggers (redox, pH, enzymes, light, heat), enabling controlled release of payloads. Non-cleavable linkers remain intact, providing permanent spacing or stable conjugation.

Which linker should I choose for ADC-style oligo conjugates?

Enzyme-cleavable linkers such as Val-Cit-PAB or GFLG are preferred for ADC-like constructs, as they release payloads inside lysosomes. We also provide disulfide linkers for reductive intracellular environments.

Do non-cleavable linkers affect oligo hybridization?

PEG and alkyl spacers are designed to be neutral. They usually preserve hybridization but provide steric shielding or spacing. We recommend short pilot studies if critical binding motifs are near the conjugation site.

Can I combine cleavable and non-cleavable linkers?

Yes. Complex designs may use both—for example, a non-cleavable PEG spacer for solubility plus a photocleavable group for triggered release. We can help design orthogonal conjugation strategies.

What QC do you provide with linker-modified oligos?

All linker-modified oligos are characterized by ESI-MS or MALDI, HPLC purity, and optional SEC/CE for larger constructs. Cleavable linkers can be validated with functional cleavage assays under trigger conditions.

Can you scale production for therapeutic applications?

Yes. We support scales from discovery research to GLP/GMP-like production, providing ISO 9001 / ISO 13485 aligned processes, validated QC, and documentation for regulatory submissions.

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Tell us about your linker-oligo project

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Greetings Researchers,

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