生物药研究的关键问题之一是提高候选活性​大分子的类药性（尤其是生物药剂学特性）。分子生物学、结构生物学、基因工程的飞速发展为蛋白递药研究带来了新技术与方法。对蛋白结构进行合理设计及生物改造正成为药剂学的重要方向。我们提出了蛋白药物的分子结构药剂学研究的新概念，以蛋白毒素天花粉蛋白为研究对象，基于药物输送原则进行蛋白的“结构-输送”理性设计，来改善与类药性密切相关的药动学、药效学、免疫学性质。基于内源白蛋白搭乘式、内含肽介导自剪切的大分子前药输送策略，通过重组技术在天花粉蛋白上引入特定功能域，令其搭乘于血浆白蛋白。白蛋白的结合及掩蔽作用使该给药系统处于灭活“前药型”；同时白蛋白介导肿瘤靶向输送，进入肿瘤细胞后，响应高还原性环境，融合蛋白的内含肽域发生剪切，释放出游离天花粉蛋白。本项目通过分子结构药剂学研究新思路，来改善以天花粉蛋白为例的核糖体失活蛋白的类药性质及其治疗耐​药脑胶质瘤的作用。

A crucial issue for biologics research is how to improve the drug-like properties of active macromolecular candidates, in term of the biopharmaceutics profiles. The significant progress on molecular biology, structure biology, and genetic engineering has provided many new technologies and methods for the research of protein drug delivery. Rational design of protein structure for improved in vivo delivery has become a cutting-edge area in pharmaceutical research. Herein proposed is a conceptual work of molecular structure pharmaceutics of proteins. Trichosanthin, a ribosome-inactivated protein, will be investigated as protein drug candidate. Rational design of "structure-delivery" based on the drug delivery principles will be studied in order to improve the drugability-associated PK, PD, and immunology profiles. A macromolecular prodrug strategy based on albumin-hitchhiking delivery and intein-mediated cleavage will be developed. Some specific functional domains (i.e., albumin-binding domain and intein domain) will be fused to trichosanthin by a recombinant method. The trichosanthin fusion protein will hitchhike onto serum albumin in systemic circulation via the interaction of its fused albumin-binding domain. The binding with albumin and its shielding effect on trichosanthin will render poor accessibility to the active domains of trichosanthin, thus yielding a "prodrug-like" feature. Importantly, albumin can function as targeting motif which binds with the tumor-associated overexpression of albumin receptors such as SPARC, gp60, gp30, and gp18, thus achieving albumin-mediated tumor targeting trichosanthin delivery. Once entering the tumor cells, the highly reducing environment will trigger the intein-mediated cleavage and the consequent release of free trichosanthin for carrying out its antitumor activity. In summary, we aim to overcome the poor drug-like properties of ribosome-inactivated proteins (e.g., trichosanthin) via a research strategy of molecular structure pharmaceutics of proteins, and explore the therapeutic application of the drug delivery system on drug-resistant glioma.