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Yingchong Chen,1 Yuling Liu,2 Jin Xie,1 Qin Zheng,1 Pengfei Yue,1 Liru Chen,3 Pengyi Hu,1 Ming Yang1 1Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, People’s Republic of China; 2Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, People’s Republic of China; 3Beijing Hospital, Beijing 100730, People’s Republic of ChinaCorrespondence: Pengfei Yue; Ming YangKey Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, 1688 Meilingdadao Road, Nanchang 330004, People’s Republic of ChinaTel/ Fax +86 791 8711 8658Email ypfpharm@126.com; yangming_215@163.comPurpose: Nose-to-brain drug delivery is an effective approach for poorly soluble drugs to bypass the blood–brain barrier. A new drug intranasal delivery system, a nanosuspension-based in situ gel, was developed and evaluated to improve the solubility and bioavailability of the drug and to prolong its retention time in the nasal cavity.Materials and Methods: Breviscapine (BRE) was chosen as the model drug. BRE nanosuspensions (BRE-NS) were converted into BRE nanosuspension powders (BRE-NP). A BRE nanosuspension in situ gelling system (BRE-NG) was prepared by mixing BRE-NP and 0.5% gellan gum (m/v). First, the BRE-NP were evaluated in terms of particle size and by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Subsequently, the critical ionic concentration of the gellan gum phase transition, influence of the deacetylated gellan gum (DGG) concentration on the expansion coefficient (S%), water-holding capacity, rheological properties and in vitro release behaviour of the BRE-NG were investigated. The pharmacokinetics and brain distribution of the BRE-NG after intranasal administration were compared with those of the intravenously injected BRE-NP nanosuspensions in rats.Results: The rheology results demonstrated that BRE-NG was a non-Newtonian fluid with good spreadability and bioadhesion performance. Moreover, the absolute bioavailability estimated for BRE-NG after intranasal administration was 57.12%. The drug targeting efficiency (DTE%) of BRE in the cerebrum, cerebellum and olfactory bulb was 4006, 999 and 3290, respectively. The nose-to-brain direct transport percentage (DTP%) of the cerebrum, cerebellum and olfactory bulb was 0.975, 0.950 and 0.970, respectively.Conclusion: It was concluded that the in situ gel significantly increased the drug retention time at the administration site. Therefore, the nanosuspension-based in situ gel could be a convenient and effective intranasal formulation for the administration of BRE.Keywords: nose-to-brain, nanosuspensions, in situ gel, breviscapine, brain distribution

Yuling Liu,1 Yingchong Chen,2 Longfei Lin,1 Hui Li1 1Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 2Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang, People’s Republic of ChinaCorrespondence: Hui LiInstitute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, 16 Nanxiao Street, Dongzhimen, Dongcheng District, Beijing, People’s Republic of ChinaEmail lihuizys@126.comAbstract: Gambogic acid (GA), a kind of dry resin secreted by the Garcinia hanburyi tree, is a natural active ingredient with various biological activities, such as anti-cancer, anti-inflammatory, antioxidant, anti-bacterial effects, etc. An increasing amount of evidence indicates that GA has obvious anti-cancer effects via various molecular mechanisms, including the induction of apoptosis, autophagy, cell cycle arrest and the inhibition of invasion, metastasis, angiogenesis. In order to improve the efficacy in cancer treatment, nanometer drug delivery systems have been employed to load GA and form micelles, nanoparticles, nanofibers, and so on. In this review, we aim to offer a summary of chemical structure and properties, anti-cancer activities, drug delivery systems and combination therapy of GA, which might provide a reference to promote the development and clinical application of GA.Keywords: gambogic acid, anti-cancer activities, drug delivery systems, combination therapy

Hengfeng Liao1,2, Yue Gao1,2, Chunfang Lian1,2, Yun Zhang1,2, Bangyuan Wang1,2, Yanfang Yang1,2, Jun Ye1,2, Yu Feng1,2, Yuling Liu1,2 1State Key Laboratory of Bioactive substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, People’s Republic of China; 2Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, People’s Republic of ChinaCorrespondence: Yuling LiuState Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xiannongtan Street, Beijing 100050, People’s Republic of ChinaTel +86 108 928 5188Fax +86 108 928 5190Email ylliu@imm.ac.cnPurpose: The aims of this study were to prepare a baicalein self-microemulsion with baicalein-phospholipid complex as the intermediate (BAPC-SMEDDS) and to compare its effects with those of conventional baicalein self-microemulsion (CBA-SMEDDS) on baicalein oral absorption and lymphatic transport.Methods: Two SMEDDS were characterized by emulsifying efficiency, droplet size, zeta potential, cloud point, dilution stability, physical stability, and in vitro release and lipolysis. Different formulations of 40mg/kg baicalein were orally administered to Sprague-Dawley rats to investigate their respective bioavailabilities. The chylomicron flow blocking rat model was used to evaluate their lymphatic transport.Results: The droplet sizes of BAPC-SMEDDS and CBA-SMEDDS after 100x dilution were 9.6±0.2nm and 11.3±0.4nm, respectively. In vivo experiments indicated that the relative bioavailability of CBA-SMEDDS and BAPC-SMEDDS was 342.5% and 448.7% compared to that of free baicalein (BA). The AUC0–t and Cmax of BAPC-SMEDDS were 1.31 and 1.87 times higher than those of CBA-SMEDDS, respectively. The lymphatic transport study revealed that 81.2% of orally absorbed BA entered the circulation directly through the portal vein, whereas approximately 18.8% was transported into the blood via lymphatic transport. CBA-SMEDDS and BAPC-SMEDDS increased the lymphatic transport ratio of BA from 18.8% to 56.2% and 70.2%, respectively. Therefore, self-microemulsion not only significantly improves oral bioavailability of baicalein, but also increases the proportion lymphatically transported. This is beneficial to the direct interaction of baicalein with relevant immune cells in the lymphatic system and for proper display of its effects.Conclusion: This study demonstrates the oral absorption and lymphatic transport characteristics of free baicalein and baicalein SMEDDS with different compositions. This is of great significance to studies on lymphatic targeted delivery of natural immunomodulatory compounds.Keywords: SMEDDS, phospholipid complex, baicalein, oral bioavailability, lymphatic transport

Jun Ye,1–3 Yanfang Yang,1,2 Wujun Dong,1,2 Yue Gao,1,2 Yingying Meng,1,2 Hongliang Wang,1,2 Lin Li,1,2 Jing Jin,1 Ming Ji,1 Xuejun Xia,1,2 Xiaoguang Chen,1 Yiqun Jin,3 Yuling Liu1,21State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, People’s Republic of China; 2Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, People’s Republic of China; 3Research and Development Department, Beijing Wehand-bio Pharmaceutical Co. Ltd, Beijing, 102600, People’s Republic of ChinaBackground: Tumor-associated macrophages (TAMs) are critical in tumor progression and metastasis. Selective targeting of TAMs holds great potential to ameliorate the immunosuppressive tumor microenvironment and enhance the efficacy of antitumor therapy. Various liposomes have been developed to target TAMs via cell-specific surface receptors either to deplete or re-educate TAMs. Since immuno-stimulation often initiates with the interaction of nanocarriers with the innate immunity cells such as macrophages, the intrinsic impact of drug-free liposomes on macrophage activation and polarization via cell interaction is one of the most critical issues in nanomedicine for promoting effective immunotherapy.Methods: In this study, conventional bare liposomes, PEGylated liposomes, and mannosylated liposomes were developed and the cytotoxicity, cellular internalization, immunostimulatory activity, targeting efficiency, antitumor efficacy, and mechanism were evaluated in vitro and in vivo.Results: All liposomes displayed an ideal particle size, good biocompatibility, and controlled release behavior. Mannosylated liposomes exhibited superior in vitro cellular internalization and tumor spheroid penetration with the aid of the mannose receptor-mediated TAMs-targeting effects. In particular, mannosylated liposomes promoted the polarization of both M0 and M2 to the M1 phenotype by enhancing the expression ratio of CD86/CD206 in vitro. Of note, mannosylated liposomes could inhibit G422 glioma tumor growth, which may be attributed to the polarization of TAMs, as evidenced by the reduction in expression level of the TAMs surface marker.Conclusion: These results indicate the potential value of mannosylated liposomes in the design of a rational delivery system to enhance the antitumor immune efficacy of immunomodulators by inducing a shift from the M2 to the M1 phenotype.Keywords: liposomes, cancer immunotherapy, tumor-associated macrophages, mannose receptor, drug delivery