Imagine curing melanoma with only a topical hydrogel. That’s exactly what researchers at Nanjing Tech University are trying to accomplish.
Melanoma, the deadliest skin cancer, originates from pigmented skin cells called melanocytes. While it begins on the skin’s surface, the cancerous cells can quickly grow inward through the dermis and metastasize, spreading through the bloodstream to other parts of the body (Image 1).
Image 1. The stages of melanoma and the advancement of the subdermal tumor.
As a result, this aggressive form of skin cancer is highly lethal if not diagnosed at an early stage — an estimated 9,320 deaths will occur from melanoma in the U.S. this year. Current treatments of melanoma include surgical resection, traditional chemotherapy/radiotherapy, and emerging immunotherapies. However, each of these therapeutic options is high cost, high risk, and require frequent clinic visits. As a result, transdermal administration of melanoma therapies is an attractive alternative. Still, though, challenges remain with transdermal administration in successfully bypassing physiological barriers. This week in lecture, we discussed these various physiological barriers that are necessary to bypass for drug delivery. We learned how the skin is a particularly difficult barrier to overcome for topical treatments.
Image 2. Example of microneedle delivery systems in the skin.
Overcoming these barriers might just be possible with the new hydrogel system in development at Nanjing Tech University. Recently, certain mechanical devices have been demonstrated to improve the transdermal efficacy of drug delivery such as magentophoresis, sonophoresis, and microneedles (Image 2).
Image 3. Nanoparticle delivery systems
However, these mechanical methods require constant application of the delivery method in order to ensure the absorption of the desired therapeutic. As we have learned in class, nanoparticles have become increasingly explored for drug delivery (Image 3). We learned how nanoparticles can be used to overcome barriers like the skin because of their small size.
In short, nanoparticles are particles less than 1 micron in size that can encapsulate materials for targeted delivery. The material that comprises the outside of the nanoparticle is often a polymer (commonly PLGA, PLA, PGA, etc.) or a lipid, and the encapsulated material can range from small molecule drugs to pigments and dyes.
As a result, nanoparticles are leveraged in clinical applications to control and direct the release of therapeutics at specific hard to reach sites in the body. The researchers of this recent study combined the principles of nanoparticle drug delivery with a hydrogel to ensure continuous delivery. With this, they created a paintable hydrogel with embedded transfersomes (phospholipid-based nanoparticles) encapsulating chemotherapeutic drugs for the noninvasive delivery of therapeutics for melanoma.
The transfersomes were created from phospholipids and various surfactants. In lecture, we discussed the potential for liposome-based nanoparticle systems. Similar to liposomes, the transfersomes used in the study are derived from phospholipids, but they have additional modification with surfactants. These surfactants make the transfersomes more deformable for navigating narrow pathways between skin cells. Specifically, the study used surfactants Tween 80 and sodium deoxycholate to increase the fluidity and permeation of the lipid molecules. In addition, the trasnfersomes were coated with R8H3, a cell-penetrating peptide to further improve the penetration of the nanoparticles through the skin and into tumor cells. These surface modifications, as we have reviewed in lecture, increased the specificity and applicability of the created nanoparticles. Finally, Paclitaxel (PTX), a common chemotherapeutic for melanoma that inhibits cell growth by preventing the disassembly of microtubules, was encapsulated in the transfersomes to model the ability for the nanoparticles to deliver a chemotherapeutic drug transdermally.
Image 4. An overview of the development and mechanism of action of the topical treatment.
The researchers didn’t just create chemotherapy-loaded nanoparticles, though. What was most novel in their research was the incorporation of the nanoparticles in an oligopeptide hydrogel. The hydrogel acts as a reservoir for the nanoparticles, keeping them in contact with the skin and controlling their release into the tumor site. Because the hydrogel can be applied directly onto the skin and left until it is fully absorbed, the nanoparticle/gel formulation improves drug delivery over a nanoparticle solution alone. The R8H3 peptide surface modification enables the nanoparticles to progress even further into a tumor once they have entered the epidermis and deliver PTX directly within a cell’s cytoplasm (Image 4).
The researchers then studied the efficacy of the hydrogel-embedded nanoparticles in vivo in combination with the commercially-available paclitaxel therapeutic, Taxol, which is traditionally used to treat melanoma. Mice with melanoma were treated with the nanoparticle/gel solution at the site of the tumor once a day. Across various experimental groups, the results showed that the hydrogel-nanoparticle solution was more effective in treating melanoma. The researchers noted a decrease in the number of tumor cells in mice treated with the hydrogel-based therapy. What was perhaps most promising about their results is that after topical treatment with the hydrogel, there were no pathological changes in the skin tissue of the treated mice. These results indicate that their developed system is a safe way to enhance the treatment of melanoma transdermally.
However, more work needs to be done. The developed nanoparticle/hydrogel system is effective in the study’s animal model, but additional data and testing are necessary before it can be used to treat melanoma in humans. Based on this research, I believe the use of hydrogels in noninvasive nanoparticle drug delivery systems is promising. This research is quite successful in its aims: to develop a minimally invasive and safe topical treatment for melanoma. However, the study only demonstrated efficacy when the nanoparticle/gel system was used in combination with traditional chemotherapy. Further research into this area should seek to verify the use of the system as a standalone treatment for melanoma. In class, we’ve learned about the different generations of nanoparticle therapies. This study fits into the category of second-generation nanoparticles — those that incorporate surface modifications to tune their function. Where the research could go further is in incorporating third-generation techniques. These are capabilities that enable nanoparticles to respond to their environment. For example, the nanoparticles in this study could have additional modifications that enable them to release different materials as they move through the layers of the skin. Such a modification could make therapeutic delivery more effective, especially in advanced stages of melanoma, by only using the topical hydrogel.
Article:
- Jiang, T., Wang, T., Li, T., Ma, Y., Shen, S., He, B., & Mo, R. (2018). Enhanced Transdermal Drug Delivery by Transfersome-Embedded Oligopeptide Hydrogel for Topical Chemotherapy of Melanoma. ACS Nano doi: 10.1021/acsnano.8b03800.
