A Simple, Effective, and Dual-Functional Drug Delivery Platform for Hydrophobic Agents

Many promising drug candidates fail to reach the market mainly due to poor water solubility, low bioavailability, and potential toxicity; additionally, the current drug discovery process is costly and inefficient. Formulation development represents an important strategy to maximize the success of drug discovery by ensuring high solubility and bioavailability and reduced toxicity. While there have been incremental successes in the field, most of the drug carrier materials in lipid-based or polymeric drug delivery systems use inert substances that lack therapeutic effects, and the use of excess carrier materials adds to the cost and poses potential safety issues. A dual-functional carrier system could enhance the therapeutic benefits of the drug while limiting cost and undesirable side effects.

Description

A novel drug formulation based on PEGylated FTS, a synthetic farnesylcysteine mimetic, acts as a potent and particularly non-toxic antagonist of the Ras family proto-oncogenes present in one-third of human cancers. FTS inhibits the growth of Ras-dependent tumors with no significant toxicity; in addition to its antitumor activity in mice and humans, FTS also exhibits anti-inflammatory activity. PEGylation serves to improve the solubility of FTS, which has a hydrophobic nature and limited bioavailability. The PEG-FTS conjugate forms small-sized micelles, a type of delivery system that has gained considerable attention due to micelles’ small size and ability to solubilize water-insoluble anticancer drugs and accumulate specifically at tumor sites. In this new formulation, both the anticancer drug and the PEG-FTS carrier display antitumor activity and can synergize to amplify the effect. Further, the drug-loading capacity and formulaic stability of the PEG-FTS micellar system can be further improved via incorporation of a drug-interaction motif, leading to the creation and development of highly effective therapeutics with minimal toxicity at a low cost in a timely manner.

Applications

• Dual-function drug delivery platform

Advantages

• Improved stability and loading capacity
• Synergistic effects from anticancer properties of both drug and carrier
• Simpler path to development with a lower associated cost

Invention Readiness

In vivo data

IP Status

https://patents.google.com/patent/US9855341B2; https://patents.google.com/patent/US10376591B2

Related Publication(s)

Chen, Y., Xia, R., Huang, Y., Zhao, W., Li, J., Zhang, X., Wang, P., Venkataramanan, R., Fan, J., Xie, W., Ma, X., Lu, B., & Li, S. (2016). An immunostimulatory dual-functional nanocarrier that improves cancer immunochemotherapy. Nature Communications, 7(1). https://doi.org/10.1038/ncomms13443

Sun, J., Chen, Y., Li, K., Huang, Y., Fu, X., Zhang, X., Zhao, W., Wei, Y., Xu, L., Zhang, P., Venkataramanan, R., & Li, S. (2016). A prodrug micellar carrier assembled from polymers with pendant farnesyl thiosalicylic acid moieties for improved delivery of paclitaxel. Acta Biomaterialia, 43, 282–291. https://doi.org/10.1016/j.actbio.2016.07.014

Zhang, P., Li, J., Ghazwani, M., Zhao, W., Huang, Y., Zhang, X., Venkataramanan, R., & Li, S. (2015). Effective co-delivery of doxorubicin and dasatinib using a PEG-Fmoc nanocarrier for combination cancer chemotherapy. Biomaterials, 67, 104–114. https://doi.org/10.1016/j.biomaterials.2015.07.027

Zhang, X., Lu, J., Huang, Y., Zhao, W., Chen, Y., Li, J., Gao, X., Venkataramanan, R., Sun, M., Stolz, D. B., Zhang, L., & Li, S. (2013). PEG-Farnesylthiosalicylate Conjugate as a Nanomicellar Carrier for Delivery of Paclitaxel. Bioconjugate Chemistry, 24(3), 464–472. https://doi.org/10.1021/bc300608h

Zhang, X., Huang, Y., Zhao, W., Liu, H., Marquez, R., Lu, J., Zhang, P., Zhang, Y., Li, J., Gao, X., Venkataramanan, R., Xu, L., & Li, S. (2014). Targeted Delivery of Anticancer Agents via a Dual Function Nanocarrier with an Interfacial Drug-Interactive Motif. Biomacromolecules, 15(11), 4326–4335. https://doi.org/10.1021/bm501339j