Recently, Prof. Gao Zhonggao's group, in the State Key Laboratory of Bioactive Substance and Function of Natural Medicines, have published an original research paper entitled "Hybrid polymeric micelles based on bioactive polypeptides as pH-responsive delivery systems against melanoma" onBiomaterials(the impact factor was 7.604 published in 2013, with the 5-year impact factor of 8.496), an top international journal in the field of biomaterials and pharmaceutics. Now, the article is available online (http://www.sciencedirect.com/science/article/pii/S0142961214005304).
Functional polymers used as pharmaceutical excipients have fueled the advancement of new drug delivery systems. Many new formulations based on the polymers have been approved for medical applications since the 1990s. In these formulations, the functional excipients allow optimal delivery of various active ingredients to improve their therapeutic effects and reduce their side effects. Conversely, that fact inspired the development of new functional excipients with diverse functionality for the optimal delivery of therapeutics.It has been demonstrated that Tat peptides, one of cell penetrating peptides, can readily cross cell membrane and facilitate intracellular delivery of antitumor drugs. Unfortunately, Tat peptides are characterized by non-specific cellular penetration. Moreover, they are highly susceptible to cleavage by proteolytic enzymes. Thus, intracellular delivery of antitumor agents will be compromised by cleavage with proteolytic enzymes in the circulation.
Research in Prof. Gao Zhonggao's group focus on the design, synthesis and characterization of the functional excipients for biomedical applications. To address the problems mentioned above, Gao's group constructed hybrid micelles with the bioactive polymer poly(L-glutamic acid)n-b -poly(D, L-lacticacid)m (PGAn-b-PLAm) to specifically expose Tat peptides to tumor cells for intracellular delivery of Doxorubicin. Gao's group have revealed that PGAn-b-PLAm protect Tat peptides from proteolytic cleavage in the circulation, but under tumor-acidic conditions, PGAn-b -PLAm undergo a conformational transition to expose Tat peptides to cancer cells and improve the cellular internalization of Doxorubicin. Importantly, this transition also contributes to the formation of channels in the shell of the micelles, accelerating the release of Doxorubicin. The micelles have shown targeting and tumor-suppressing ability against malignant melanoma in a tumor-bearing animal model. This approach provides a rational design for targeting delivery systems that carries antitumor drugs into cancer cells. Additionally, this work also explores the connection between conformation of polypeptide-based excipients and their biological functionalities for drug delivery.
