Biological barriers can limit the availability of a therapeutic agent in the target tissue. Drug delivery systems overcome these limitations to transport the correct dose of drug to its target site. The biopolymer chitosan has great potential for the development of innovative drug delivery systems. We present two articles that explore the treatment of cancer and noise-induced hearing loss with chitosan-based drug delivery systems.
The benefits of drug delivery systems are numerous. The desired calculates can be controlled selectively by functionalization of the Trojan Horse. Once the drug delivery system has arrived at its destination, the load should be targeted and preferably unloaded over a longer period of time. One possibility is to modify the system in such a way that a stimulus can trigger this release of the active ingredient. Systems that can be switched off again, even if desired, are further developed.
A novel nanoparticle delivery system for targeted therapy of noise-induced hearing loss.
Kayyali M.N., Wooltorton J.R.A., Ramsey A.J., Lin M., Chao T.N., Tsourkas A., O'Malley B.W., Li D. J Control Release. 2018 Apr 16;279:243-250. doi: 10.1016/j.jconrel.2018.04.028.
Worldwide, noise induced hearing loss is the most prevalent sensory disability due to the aging population and exposure to excessive noise. US researchers developed a minimally-invasive nanohydrogel drug delivery system for directed transport to the inner ear in order to treat noise-induced hearing loss. The greatest challenge in preventing or treating hearing damage is the targeted release of therapeutics, such as antioxidants, drugs or genetic material, directly in the inner ear. Access to the inner ear for therapeutics is restricted, anatomically, as well as by the blood labyrinth barrier and the round window membrane.
The developed drug delivery system consisted of a thermosensitive chitosan 95/1000 (Degree of Deacetylation/Viscosity) glycerol phosphate hydrogel with integrated functionalized nanoparticles. The nanoparticles were functionalized with a peptide which recognizes a protein that is specifically expressed in the outer hair cells (OHCs) of the inner ear. In addition, a fluorescent dye was incorporated into the outer phospholipid layer for detection. The aqueous interior of the particles contained a drug or model molecule. The hydrogel was applied to the inner ear and released the nanoparticles into the cochlea, where they recognize the OHCs and release the drug. The experimental animals were exposed to a blast trauma two days after treatment with the hydrogel.
- Specific transport of molecules and plasmids to the OHCs in vivo (mice)
- Transport of c-Jun N-terminal kinase inhibitors to the OHCs allowed for improved protection against noise-induced hearing loss compared to non-functionalized nanoparticles
Conclusion: Functionalization makes it possible to guide nanoparticles to their site of action in the inner ear. The site-specific delivery of drugs through nanoparticles would allow improved treatment of NIHL with lower drug concentrations.
Stimuli-responsive chitosan-based nanocarriers for cancer therapy.
Fathi M1, Sahandi Zangabad P., Majidi S., Barar J., Erfan-Niya H., Omidi Y. Bioimpacts. 2017;7(4):269-277. doi: 10.15171/bi.2017.32. Epub 2017 Nov 15.
The review deals with the advantages of chitosan-based drug delivery systems, in which the release of the cargo molecules can be specifically triggered by an external stimulus. Recent developments in stimuli-responsive chitosan nanocarriers, such as micelles, nanocomposites or hydrogels, and their applications in cancer therapy and diagnosis have been considered. The release of the cancer drug from the chitosan-based nanocarrier can be triggered by an external stimulus, such as temperature, light, ultrasound or magnetic fields, or an endogenous stimulus, such as pH, glutathione concentration, or certain enzymes. Research is also being done to improve targeting by combining two stimuli. Chitosan offers biocompatibility, biodegradability, antibacterial properties, and a variety of functionalization or modification options, making it ideally suited as nanocarrier.
In the following, some chitosan-based nanocarrier systems, which can be controlled by internal or external stimuli, are presented.
In comparison to healthy tissue, there is an acidic environment around tumors as the altered cancer cells release lactic acid into the extracellular environment. The review quoted a study by Unsoy et al. (1) in which doxorubicin-loaded pH-sensitive chitosan-coated magnetic nanoparticles were taken up by breast cancer cells via endocytosis. The chitosan nanocarriers, which were stable at physiological pH, were degraded in the cancer cells due to the lower pH and slowly release the doxorubicin inside the cell.
Ultrasonic responsive nanocarrier
There is also research about inducing a targeted release of active substance by means of ultrasound. The development of a nanosystem that combines therapy and diagnostics is mentioned. By stimulation with ultrasound at 37 ° C, the active substance predinisolone phosphate and gadolinium, detectable by magnetic resonance tomography, were released in vitro (2). A slow, continuous release within 24 hours was observed.
Temperature responsive nanocarrier
Various chitosan-based nanocarrier systems (hydrogels, micelles, microspheres, etc.) are well suited for creating temperature-dependent release systems. When the critical solution temperature is exceeded, the hydrogen bonds between the polymer molecules are no longer stable, the nanocarrier system shrinks and the active ingredient is released.
A further development of controllable nanocarriers is a dual stimuli-responsive drug delivery system. Combining two or more stimuli allows more accurate control of drug release. Among others, the article mentions, chitosan-o-nitrobenzyl-based nanocarriers that, after stimulation by light and acidic pH, enabled improved drug release in cancer cells (3).
Conclusion: The use of chitosan-based drug delivery systems could realize a long-term bioavailability of cancer drugs in the target tissue. An on-demand release of cancer drugs controlled by external or internal stimuli, would be possible.
(1) Unsoy G, Khodadust R, Yalcin S, Mutlu P, Gunduz U. Synthesis of Doxorubicin loaded magnetic chitosan nanoparticles for pH responsive targeted drug delivery. Eur J Pharm Sci 2014;62:243-50. doi:10.1016/j.ejps.2014.05.021.
(2) Cavalli R, Argenziano M, Vigna E, Giustetto P, Torres E, Aime S, et al. Preparation and in vitro characterization of chitosan nanobubbles as theranostic agents. Colloids Surf B Biointerfaces 2015;129:39-46. doi:10.1016/j.colsurfb.2015.03.023.
(3) Meng L, Huang W, Wang D, Huang X, Zhu X, Yan D. Chitosan-based nanocarriers with pH and light dual response for anticancer drug delivery. Biomacromolecules 2013;14:2601-10. doi:10.1021/ bm400451v