Hyaluronate Fluorescein

Hyaluronate fluorescein (HA-F) is a new hybrid compound. It is a blend of the natural polysaccharide hyaluronic acid (HA) with fluorescein. As we know, hyaluronic acid is a key bioactive ingredient that helps hydrate tissue, help move cells, and heal wounds. Because it is so common in human connective tissues including skin, joints and eyes, it could be the ideal candidate for drug delivery. Biocompatibility, biodegradability and innate capacity to bind to target cell receptors are feature of HA that have created great interest in HA conjugates. Fluorescein conjugated with HA has unique properties that make HA-based drug delivery systems effective for therapy and diagnostics. Fluorescein (because it is a strong fluorescent agent) allows for in vivo, non-invasive tracking of HA drug carriers. It's a very useful tool to visualize and follow biodistribution of therapeutic agents in real time, especially during preclinical and clinical studies where the pharmacokinetics and biodistribution of a drug matter. In an age of personalized medicine and precision therapy, HA and fluorescein meet a fundamental drug delivery problem: getting drugs precisely where they're needed in diseased tissue with the least possible systemic exposure and side-effects. With the targeting power of hyaluronic acid combined with the tracking power of fluorescein, HA-F conjugates offer a path for improving the efficiency, safety and effectiveness of drug delivery.

Figure 1. Fluorescence intensity of HA-dye conjugates in native state and in presence of enzyme hyaluronidase. (Wang W, et al.; 2012)

Hyaluronic acid is at the heart of hyaluronate fluorescein. HA is an extracellular matrix (extracellular matrix) glycosaminoglycan (GAG) present in nature and active in numerous cells. It is found in particular in connective tissues, where it is crucial for water, lubrication and signaling by cells. In addition to these physiological roles, hyaluronic acid is now one of the most prominent carriers of drugs, due to its biocompatibility, biodegradability and ability to interact with numerous receptors at the cell surface, including, in particular, CD44. CD44 is a glycoprotein on the cell surface, overrepresented on most cancer cells and inflamed tissue. This overexpression makes CD44 a natural target for drug delivery, because it provides a means of targeting drugs to the site of pathology. Fluorescein can be conjugated to hyaluronic acid to deliver a drug delivery system that not only targets CD44 receptors, but also can be tightly monitored in vivo as it distributes. The combination of these two roles allows HA-F to improve both therapeutic efficacy and safety by targeting drugs to the target of action, and tracking and optimising the delivery of drugs in real time. In cancer treatment, for example, where tumour cells express a high amount of CD44, HA-based drug delivery systems can deliver chemotherapy drugs to the tumours but spare healthy tissues, thus minimising off-target damage. Also, the fluorescence produced by fluorescein can be used to see the amount of drug that has been accumulated in tumours – useful data to measure the efficacy of treatment and to determine dosage recommendations. The most obvious feature of the hyaluronate fluorescein-based drug delivery systems is that they are tracked and monitored in real time through fluorescence imaging. Fluorescein is an obvious fluorescent dye that will make light under certain wavelengths. This is why it is the perfect sensor to follow the distribution and localization of carrier-loaded drugs throughout the body. For HA-F conjugates, fluorescein makes it possible to track the drug carrier's movement through live animals or human tissues through noninvasive imaging (fluorescence microscopy, optical imaging, fluorescence tomography). The biodistribution of HA-F conjugates can be visualized, which is essential information about pharmacokinetics of delivery systems for researchers to determine drug composition and dosing schedule to provide maximum therapeutic benefit. For instance, by monitoring with fluorescence imaging how HA-F conjugates build up over time in the tumor tissue, clinicians and researchers can decide when and how to give chemotherapy. Also, the in-the-moment tracking feature could flag issues like drug failure or accumulation in non-target tissues so that a better therapy can be delivered. This drug delivery is crucial in the age of precision medicine where treatment must be specific to the patient's disease and physiology. The prick-and-tick property of hyaluronate fluorescein doesn't stop with tissue loading, it can also be applied to the controlled and fast delivery of encapsulated therapeutics. This decomposition of hyaluronic acid occurs in very certain circumstances – such as when there is hyaluronidase or in low pH environments, both found in tumor microenvironments or in the tissue where they are inflamed. This makes HA-F a candidate for the design of stimuli-sensitive drug delivery. In these systems, the absorption of the capsulated drug is initiated by the local biochemical context, and this facilitates the more targeted and controlled release of the drug at the target. Fluorescence of fluorescein also helps track and optimise the release profile of capsulated drugs. In fluorescence imaging, researchers can monitor the breakdown of the HA carrier and the ensuing release of the drug, giving us a true picture of the drug's pharmacodynamics at any given moment. When treating cancer, for instance, the acidic state of the tumour microenvironment can lead to the breakdown of HA, pumping the chemotherapeutic agents directly into the tumour and away from healthy tissue. This type of controlled release reduces systemic toxicity and increases the therapeutic index of the drug. Tracking the drug carrier and release of the drug also provides precision to the delivery of drugs that can be used to enhance the results of chemotherapy for cancer and other diseases that require localisation.

Targeted drug delivery augmented by the monitoring in real time offered by hyaluronate fluorescein presents many possibilities for cancer and inflammatory disease treatment. Oncology HA-F conjugates have been tested as ligands for therapeutic small molecules, nucleic acids (RNA or DNA) and protein therapy. CD44 is high on tumour cells, so these conjugates are particularly potent at targeting cancer tissue and bypassing the disadvantages of standard chemotherapy, including lack of drug bioavailability, off-target effects and systemic toxicity. Fluorescence imaging is important for these applications too, since it can help clinicians track the course of the disease and track how well the drug delivery system is working overtime. This visualization and treatment outcome tracking in real time can have profoundly improved treatment of chronic inflammatory diseases. Hyaluronate fluorescein-based drug delivery systems look promising, but there are a few obstacles left before they are well on their way to clinical application. Among them is how to maintain stability of the HA-F conjugates in storage and in vivo circulation. Hyaluronic acid is easily enzymatically broken down by hyaluronidase, making the drug delivery system less stable and effective. they're testing all sorts of ways to increase stability of HA systems, from crosslinking the hyaluronic acid or altering its shape so it can't be destroyed by enzymatic degradation, while still being targeted. The second is a matter of achieving the best release profile for the therapeutics. Although it is possible to engineer HA-F conjugates for specific conditions, such as pH or enzymes, there's still no clear-cut method for controlling when and how much of the drug actually comes out. The systems are still being perfected by scientists so that the drug comes out when it should be and in the correct amount to get the most therapeutic benefit. Even with such obstacles, the applications of hyaluronate fluorescein for delivery are immense. With the continuing growth in nanotechnology, biotechnology and fluorescence imaging, HA-F conjugates will become essential to targeted and personalized medicine of the future as more effective, safer and efficient therapies for all kinds of diseases.

Alternate Names:
Fluorescein-labeled Hyaluronate
Fluorescein-conjugated Hyaluronic Acid
Fluorescein-Hyaluronate Conjugate
Hyaluronate-Fluorescein Complex
Hyaluronic Acid Fluorescein Derivative
Fluorescent Hyaluronate
Hyaluronan-Fluorescein
Fluorescein-Tagged Hyaluronate
F-Hyaluronate

References:
1. Wang W, et al.; Developing fluorescent hyaluronan analogs for hyaluronan studies. Molecules. 2012, 17(2):1520-34.

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