The field of drug delivery has advanced greatly over the past several years, and treatment specificity and efficacy are increasingly aimed at, as is the reduction of side effects. A big issue with drug delivery is how to reach targeted therapy – that is, to put drugs at their site of action and not into healthy tissue. One strategy that has become popular is the use of cleavable linkers in drug conjugates. Such linkers are supposed to stay in place during transport through the body, but once inside the body, if specific physiological circumstances are met, the linker breaks off and the drug is released where it is supposed to be. One of the upcoming innovative solutions here is the use of PC Mal-NHS carbonate ester as PC cleavable linkers which has shown to be extremely useful for drug targeting, controlled release, and therapeutic activity.
Figure 1. Bioactive molecules with an amine such as cRGD and NTA-amine can be linked through the NHS moiety and the molecule can be attached to any material with an azide functional group through CuAAC.( Wegner SV, et al.; 2015)
PC Mal-NHS ester is an advanced chemical linker comprising of three functional groups – phosphocholine (PC), maleimide (Mal) and N-hydroxysuccinimide (NHS) group. Each of these functional classes is used for different purposes in drug delivery. The phosphocholine moieties replicate naturally occurring phospholipids and make it biocompatible and more stable in biological systems. The maleimide group allows the conjugation of thiol molecules (eg, proteins, peptides, antibodies) which are often targeting molecules in drug delivery systems. This NHS ester group is especially useful to form permanent covalent bonds with amines, which then allow for the selective binding of the drug molecule to the linker. Last but not least, the carbonate ester linkage between the maleimide and NHS ester moieties is the cleavable component, one that is engineered to break under certain circumstances – the acidic environment of a tumour, say, or the presence of certain enzymes – so that the anchored drug can be selectively released. PC Mal-NHS carbonate ester linkers have several advantages over other linkers, they're biocompatible and stable in the body, one of the big advantages. This phosphocholine group makes the linker highly compatible with biological membranes, and doesn't activate the immune system, which is important to reduce adverse effects and protect the drug delivery system. This is especially true for new therapies for chronic conditions or disorders that are often lifelong in nature (such as cancer or autoimmune diseases). Moreover, the carbonate ester bond is tuned to react with the acidic pH of the tumour microenvironment, which is perfect for selective drug release. Cancers are often lower in pH than surrounding healthy tissue, and so would be ideal targets for pH-controlled drug delivery systems. Thanks to the pH sensitive character of the carbonate ester, these drug conjugates can be designed so that they remain stable in the bloodstream and release the drug only when it reaches the acidic environment of the tumor or other site of target. The other major strength of PC Mal-NHS carbonate ester linkers as a delivery system is versatility. Maleimide and NHS ester groups can be conjugated to many different therapeutic molecules such as small molecule pharmaceuticals, biologics and nucleic acids. Maleimide-functionalized linkers especially are very good for connecting to thiol molecules like antibodies or peptides, commonly used in targeted therapies. That adaptability makes PC Mal-NHS carbonate ester a compelling candidate for drug delivery systems designed for various disease conditions and populations of patients. The linker could, for example, be used in cancer therapy to attach chemotherapy drugs to antibodies against tumor antigens so that the drugs can be targeted only at cancer cells and left in the surrounding healthy tissue. The same could be done in gene therapy, in which the linker might attach nucleic acids or gene-editing materials to ligands for action, so that the therapeutic payload arrives right at the target's site of action, the nucleus of a particular cell type.
This unique combination of attributes makes the PC Mal-NHS carbonate ester linker a candidate for controlled release drug delivery as well. In conventional drug delivery systems, the active agent is released uncontrolled or too soon and has less than optimal therapeutic effects. But with cleavable linkers, like the PC Mal-NHS carbonate ester, the time and place of release of the drug is exactly controlled. This carbonate ester bond is not permeable under normal physiological conditions but can be broken down by the lactic acidity of the tumor microenvironment or by specific enzymes. This keeps the drug safe in circulation and only becomes active once it reaches the target. This controlled release not only maximizes the effectiveness of the drug but reduces the possibility of side effects, as the drug gets released only where it's needed. In addition, it could be possible to tune the linker's responsiveness to pH or enzyme, enabling drug delivery systems even more tailored to the biology at the target site. Aside from controlled release capabilities, PC Mal-NHS carbonate ester linkers are also highly effective in stability and encapsulation of drugs. The problem with building drugs in traditional manner is that it can't really stabilize the drug while it travels in the bloodstream. Many medicines are especially susceptible to degradation or inactivation in the bloodstream and hence lose efficacy and can become toxic. The PC Mal-NHS carbonate ester linker solves this problem, by establishing an inert attachment site for the drug that will not degrade prematurely. This biocompatibility of the phosphocholine component also makes the conjugate stable in the blood stream so that the drug enters the target intact. What's more, the linker's flexibility to bond covalently with a range of molecules allows multiple drugs or payloads to be enclosed in a single package, making the system more therapeutic. Apart from the cancer treatment, PC Mal-NHS carbonate ester linkers can be applied to many other therapeutic applications, such as immunotherapy, gene therapy and even vaccines. The fact that you can get to a precise tissue or cell makes this method very appropriate for treatments for disorders involving distinct cell populations, like autoimmune disease or neurological disorders. The linker might, for instance, be used in immunotherapy to introduce immune-modulatory molecules directly into immune cells to improve their ability to fight tumours or infections. The same is true for gene therapy: the linker could ensure delivery of gene-editing or therapeutic genes to the right cells in a more precise and effective way. PC Mal-NHS carbonate ester linkers could be directed at immune cells in vaccine formulations so that the vaccine ingredients are delivered to the cells that trigger the immune response. This innovation for the delivery of drugs from PC Mal-NHS carbonate ester linkers is applicable to diagnostics, too. Couple imaging agents or fluorescent markers to the delivery system, and scientists can monitor where and how the drug is distributed and localized at any moment. That opens up possibilities for personalized medicine, in which interventions are tailored to the individual's specific reaction to the drug. Furthermore, being able to track the drug release at the site of interest might help us to learn more about the therapeutic effectiveness of the treatment and make better clinical decisions. This therapeutic and diagnostic integration – called theranostics – is a fantastic prospect that could revolutionize how we manage advanced disease.
Alternate Names:
Mal-NHS-Carbonate Ester
Mal-Activated NHS Carbonate Ester
Maleimide-NHS Carbonate Ester
PC Maleimide-NHS Ester
Mal-NHS Ester
Maleimide-NHS Ester (Carbonate)
PC Maleimide Ester
NHS Maleimide Carbonate Ester
References:
1. Wegner SV, et al. Photocleavable linker for the patterning of bioactive molecules. Sci Rep. 2015, 5:18309.
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