Čo sa deje, všetci! As a supplier of peptide linkers for ADCs (Antibody-Drug Conjugates), I've been deep in the world of these tiny but mighty molecules. Dnes sa chcem porozprávať o super zaujímavej otázke: Môžu byť peptidové linkery navrhnuté tak, aby reagovali na špecifické fyziologické podmienky v ADC?

First off, let's quickly go over what ADCs are. They're like these smart little weapons in the fight against diseases, especially cancer. An ADC is made up of three main parts: an antibody, a cytotoxic drug, and a linker. The antibody acts like a homing device, targeting specific cells in the body. The drug is the heavy hitter that actually takes out the bad guys. A linker? Well, it's the glue that holds the whole thing together, and it's got a crucial job.

Now, the idea of engineering peptide linkers to respond to specific physiological conditions is pretty mind - blowing. Zamyslite sa nad tým. Our bodies are full of different environments, each with its own set of conditions like pH levels, enzyme concentrations, and redox states. If we can make peptide linkers that react to these specific conditions, we can control when and where the drug gets released from the ADC.

Začnime s pH. Different parts of our body have different pH values. Napríklad extracelulárne prostredie má zvyčajne pH okolo 7,4, zatiaľ čo vnútro endozómov a lyzozómov môže byť kyslejšie, s pH okolo 5 - 6. Mohli by sme navrhnúť peptidové linkery, ktoré sú stabilné pri normálnom extracelulárnom pH, ale rozkladajú sa v kyslejšom prostredí vo vnútri cieľových buniek. This way, the drug is only released once the ADC has been taken up by the cancer cells, reducing the chances of side - effects on healthy cells.

Redox conditions also play a role. The intracellular environment has a different redox state compared to the extracellular space. We can use this difference to our advantage. Niektoré peptidové linkery môžu byť navrhnuté tak, aby sa rozpadli v redukčnom prostredí vo vnútri buniek vďaka prítomnosti molekúl, ako je glutatión.

At our company, we've been working hard on developing such peptide linkers. VezmiteMC-Val-Cit-PAB-PNPnapríklad. This is a peptide linker that's been designed with a specific sequence that can be cleaved by certain enzymes overexpressed in cancer cells. It's pretty cool because it allows for a controlled release of the drug once it reaches the target cells.

. Tento linker nie je navrhnutý len tak, aby reagoval na špecifické enzýmy, ale má aj štruktúru, ktorá môže byť modifikovaná pre lepšiu konjugáciu s protilátkou a liekom. It's a great example of how we're combining different features to create more effective peptide linkers.

A potom je tuDBCO - PEG4 - Kys. Tento linker má jedinečnú štruktúru, vďaka ktorej je užitočný pre chémiu kliknutia, čo je výkonná metóda na pripojenie protilátky a liečiva k linkeru. It also has properties that can be tuned to respond to different physiological conditions.

Despite these challenges, the future looks bright. Som si istý, že s pokrokom v technológii a naším rastúcim chápaním ľudského tela budeme schopní vytvoriť ešte sofistikovanejšie peptidové linkery.

Referencie

• Jain, RK (2001). Delivery of molecular and cellular medicine to solid tumors. Journal of Controlled Release, 74(1 - 3), 7 - 27.
• Ducry, L., & Stump, B. (2010). Antibody - drug conjugates: linking cytotoxic payloads to monoclonal antibodies. Bioconjugate Chemistry, 21(1), 5-13.
• Shen, BQ a kol. (2012). Konjugáty protilátka - liek na terapiu rakoviny. Nature Biotechnology, 30(7), 685 - 694.