（一）科学贡献

1. “药物-材料-水”的分子间相互作用对制剂结构和行为的影响：

作为一个热力学不稳定体系，无定形药物-高分子固体分散体（amorphous solid dispersion, ASD）的物理稳定性是这一制剂的主要风险之一。 我们提出了设计ASD的工作路线图，以降低ASD的稳定性风险。这一思路被业内同行广泛认可。 此外，我们提出“药物-材料-水”的分子间相互作用是决定ASD药学表现的核心影响因素，并且建立了表征“药物-材料-水”三者相互作用的方法学。我们还通过体内外实验明确证明了药物-材料的相互作用对药物制剂的溶出，生物利用度的影响。以上这些工作对难溶药物的制剂设计和优化具备重要应用意义。

2. 针对KRAS突变的癌症细胞的药物递送策略：

KRAS突变被认为很难以进行靶向药物设计。我们提出了一种靶向KRAS突变癌症细胞的药物递送策略。这一策略的提出是基于KRAS突变癌症细胞不同于KRAS野生型正常细胞的生物学特点，即，增强的巨胞饮和低表达的FcRn受体。在药物递送领域内，利用疾病生物学机制，靶向特定基因型细胞的药物递送是一个全新的尝试。

3. 高浓度蛋白的聚集动力学和溶液稳定性机制：

皮下和局部注射蛋白药物，常常需要很高浓度的蛋白溶液制剂。在高浓度下，蛋白分子相互作用变得更为复杂，对蛋白的结构和胶体稳定性都可带来负面影响，并加速不可逆的蛋白聚集，导致药效降低、产品表观质量下降、病人过敏反应而降低用药的安全性。高浓度蛋白溶液的设计和风险评价一般都是以试错方式进行的。我们尝试从物理化学、胶体科学层面探究影响蛋白溶液相分离和聚集的关键因素和动力学过程，为高浓度蛋白制剂设计提供理论依据。

（二）论文发表

      Tian Z, Jiang X, Chen Z, Huang C, Qian F*. Quantifying Protein Shape to Elucidate its influence on Solution Viscosity in High-Concentration Electrolyte Solutions. Mol. Pharmaceutics 2024.

      Huang C, Wang Y, Huang J, Liu H, Chen Z, Jiang Y, Chen Y, Qian F*. A bioengineered anti-VEGF protein with high affinity and high concentration for intravitreal treatment of wet age-related macular degeneration. Bioeng Transl Med. 2023;e10632. doi:10.1002/btm2.10632

Zhu, S., Fan, S., Tang, T., Huang, J., Zhou, H., Huang, C., ... & Qian, F*. (2023). Polymorphic nanobody crystals as long‐acting intravitreal therapy for wet age‐related macular degeneration. Bioengineering & Translational Medicine, e10523.

Dou L, Liu H, Wang K, Liu J, Liu lei, Ye J , Wang R, Deng H, Qian F.*; Albumin binding revitalizes NQO1 bioactivatable drugs as novel therapeutics for pancreatic cancer, Journal of Controlled Release, Volume 349, September 2022, Pages 876-889.

Liu L, Chen L, Wouter M, Peter S, Qian F.*; Water-Resistant Drug–Polymer Interaction Contributes to the Formation of Nano-Species during the Dissolution of Felodipine Amorphous Solid Dispersions, Mol. Pharmaceutics. June 27, 2022, https://doi.org/10.1021/acs.molpharmaceut.2c00250

    Kong W, Liu Z, Sun M, Liu H, Kong C, Ma J, Wang R, Qian F.*; Synergistic Autophagy Blockade and VDR Signaling Activation Enhance Stellate Cell Reprogramming in Pancreatic Ductal Adenocarcinoma, Cancer Letters. 2022 Jul 28;539:215718. doi: 10.1016/j.canlet.2022.215718. Epub 2022 May 5.

    Huang C, Chen C, Franzen L, Anderski J, Qian F *; Spray-Dried Monoclonal Antibody Suspension for High-Concentration and Low-Viscosity Subcutaneous Injection, Mol. Pharmaceutics. April 13, 2022, https://doi.org/10.1021/acs.molpharmaceut.2c00039

   Huiqin Liu,  Qian F.*,  Exploiting macropinocytosis for drug delivery into KRAS mutant cancer. Theranostics. 2022; 12(3): 1321-1332. doi: 10.7150/thno.67889

Fang Yuan, Mengnan Sun, Zhengsheng Liu, Huiqin Liu, Weijian Kong, Rui Wang,  Qian F.*,  Macropinocytic dextran facilitates KRAS-targeted delivery while reducing drug-induced tumor immunity depletion in pancreatic cancer. Theranostics. 2022; 12(3): 1061-1073. doi: 10.7150/thno.65299

   Liu C; Wang C; Wang S; Liu L; Sun C; Qian F*, An Elusive Drug–Drug Cocrystal Prepared Using a Heteroseeding Strategy, Cryst. Growth Des. 2021, 21, 10, 5659–5668, https://doi.org/10.1021/acs.cgd.1c00512

   Liu H; Yu S;  Qian F*, Opportunities and delusions regarding drug delivery targeting pancreatic cancer-associated fibroblasts, Advanced Drug Delivery Reviews, 2021 May;172:37-51. https://doi.org/10.1016/j.addr.2021.02.012

    Mi W; Chen H; Zhu A, Zhang T, Qian F*, Melting point prediction of organic molecules by deciphering the chemical structure into a natural language, Chemical Communications, 2021, 57, 2633 – 2636

    Zhou T,; Qian F.*;  Adenosine Triphosphate-Induced Rapid Liquid–Liquid Phase Separation of a Model IgG1 mAb, Mol. Pharmaceutics. 2021 18 (1), 267-274， DOI: 10.1021/acs.molpharmaceut.0c00905 

    Zhou T; Xu L; Zhang N;, Qian F*,First-order nucleation and subsequent growth promote liquid-liquid phase separation of a model IgG1 mAb, Int. J. Pharm., 588 (2020) 119681

    Wang S,; Liu C,; Chen H.; Zhu A.; Qian F*, Impact of Surfactants on Polymer Maintained Nifedipine Supersaturation in Aqueous Solution, Pharmaceutical Research, volume 37, Article number: 113 (2020)

    Yuan F; Sun M; Liu H; Qian F.*, Albumin-conjugated drug is irresistible by single gene mutation of endocytic system: verification by genome-wide CRISPR-Cas9 loss-of function screens, Journal of Controlled Release,Vol 323, 10 July 2020, Pages 311-320

    Hu C.; Liu Z.; Liu C.; Zhang Y.; Fan H.; Qian F.*; Improvement of Antialveolar Echinococcosis Efficacy of Albendazole by a Novel Nanocrystalline Formulation with Enhanced Oral Bioavailability, ACS Infect. Dis. 2020, 6, 5, 802–810

    Hu C.; Liu Z.; Liu C.; Li J.; Xu L.; Chen C.; Fan H.; Qian F.*; I Enhanced Oral Bioavailability and Anti-Echinococcosis Efficacy of Albendazole Achieved by Optimizing the “Spring” and “Parachute”, Mol. Pharmaceutics. 2019, 16, 12, 4978–4986

    Liu Z.; Zhang L.; Tian Z.; Kong C.; Liu C.; Liu H.; Yuan F.; Kong W.; Qian F.*; Paclitaxel and Itraconazole Co-encapsulated Micelle Prolongs the Survival of Spontaneous LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre Genetically Engineered Mouse Model of Pancreatic Cancer, Advanced Therapeutics. 2019, 1900032, DOI: 10.1002/adtp.201900032

    Chen Y.; Chen H.; Wang S.; Liu C.; Qian F*.; A Single Hydrogen to Fluorine Substitution Reverses the Trend of Surface Composition Enrichment of Sorafenib Amorphous Solid Dispersion upon Moisture Exposure, Pharmaceutical Research, (2019) 36: 105. https://doi.org/10.1007/s11095-019-2632-5

    Kong C; Li Y; Liu Z; Ye J; Wang Z; Zhang L; Kong W.; Liu H.; Liu C.; Pang H.; Hu Z.; Gao J.; and Qian F*, Targeting the Oncogene KRAS Mutant Pancreatic Cancer by Synergistic Blocking of Lysosomal Acidification and Rapid Drug Release, ACS Nano, 2019 Apr 23;13(4):4049-4063.  doi: 10.1021/acsnano.8b08246.

    Chen H.; Zhang X.; Cheng Y.; Qian F*, Preparation of smectic itraconazole nanoparticles with tunable periodic order using microfluidics based anti-solvent precipitation, CrystEngComm, 2019, 21, 2362

    Liu H; Sun M; Liu Z; Kong C; Kong W; Ye J; Gong J; Huang D; Qian F.*, KRAS-enhanced macropinocytosis and reduced FcRn-mediated recycling sensitize pancreatic cancer to albumin-conjugated drugs, Journal of Controlled Release, Vol 296, 28 February 2019, Pages 40-53 

    Liu C; Xu C; Yu J; Pui Y; Chen H; Wang S; Zhu A; Li J; Qian F.*, Impact of a Single Hydrogen Substitution by Fluorine on the Molecular Interaction and Miscibility between Sorafenib and Polymers, Mol. Pharmaceutics, 2019, 16 (1), pp 318–326

    Chen, Y.; Pui, Y.; Chen, H.; Wang, S; Serno, P.; Tonnis, W.; Chen, L.; Qian F.*, Polymer mediated drug supersaturation controlled by drug-polymer interactions persisting in aqueous environment, 19 Nov 2018, Mol. Pharmaceutics, 2019, 16 (1), pp 205–213 

    Zhang L, Liu Z, Kong C, Liu C, Yang K, Chen H, Huang J, Qian F*., Improving Drug Delivery of Micellar Paclitaxel against Non‐Small Cell Lung Cancer by Coloading Itraconazole as a Micelle Stabilizer and a Tumor Vascular Manipulator, Small, 16 November 2018 https://doi.org/10.1002/smll.201802112

    Liu L.; Kong C.; Huo M.; Liu C.; Peng L.; Zhao T.; Wei Y.; Qian F.* Yuan J.*; Schiff base interaction tuned mesoporous organosilica nanoplatforms with pH-responsive degradability for efficient anti-cancer drug delivery in vivo, Chemical Communications, 2018, 54, 9190-9193

   Wang S,; Liu C,; Chen Y.; Zhu A.;Qian F* Aggregation of Hydroxypropyl Methylcellulose Acetate Succinate under Its Dissolving pH and the Impact on Drug Supersaturation, Mol. Pharmaceutics, 2018, 15, 4643−4653

    Pui Y.; Chen Y.; Chen H.; Wang S.; Liu C.; Tonnis W.; Chen L.; Serno P.; Bracht S.; Qian F.*, Maintaining Supersaturation of Nimodipine by PVP with or without the Presence of Sodium Lauryl Sulfate and Sodium Taurocholate, Mol. Pharmaceutics, 2018, 15 (7), pp 2754–2763

    Chen Z., Yang K., Huang C., Zhu A., Yu L., Qian F.* Surface Enrichment and Depletion of the Active Ingredient in Spray Dried Amorphous Solid Dispersions, Pharmaceutical Research (2018) Jan 29;35(2):38.

    Wang S.; Liu C.; Chen Y.; Zhang Z.; Zhub A.;Qian F.*; A high-sensitivity HPLC-ELSD method for HPMC-AS quantification and its application in elucidating the release mechanism of HPMC-AS based amorphous solid dispersions, Euro. J. Pharm. Sci. Vol. 122, 15 September 2018, Pages 303-310

    Chen H, Pui Y, Liu C, Chen Z, Su C, Hageman M, Hussain M, Haskell R, Stefanski K, Foster K, Gudmundsson O, Qian, F*, Moisture-Induced Amorphous Phase Separation of Amorphous Solid Dispersions: Molecular Mechanism, Microstructure, and Its Impact on Dissolution Performance, J Pharm Sci., January 2018, Volume 107, Issue 1, Pages 317–326

   Liu C.; Liu Z.; Chen Y.; Chen Z.; Chen H.; Pui Y.; Qian F.*, Oral bioavailability enhancement of β-lapachone, a poorly soluble fast crystallizer, by cocrystal, amorphous solid dispersion, and crystalline solid dispersion, Euro. J. Pharm. Biopharm, Vol. 124, March 2018, Pages 73-81, https://doi.org/10.1016/j.ejpb.2017.12.016

    Zhang X., Chen H., Qian F.*;  Cheng Y., Preparation of itraconazole nanoparticles by anti-solvent precipitation method using a cascaded microfluidic device and an ultrasonic spray drier, Chemical Engineering Journal, 334 (2018) 2264-2272

    Zhang L, Liu Z, Yang K, Kong C, Liu C, Chen H, Huang J,Qian F*. Tumor Progression of Non-Small Cell Lung Cancer Controlled by Albumin and Micellar Nanoparticles of Itraconazole, a Multitarget Angiogenesis Inhibitor, Mol Pharmaceutics. 2017, 14 (12), pp 4705–4713

    Zhang L, Sun H, Chen Z, Liu Z, Huang N, Qian F.*; Intermolecular Interactions between Coencapsulated Drugs Inhibit Drug Crystallization and Enhance Colloidal Stability of Polymeric Micelles. Mol Pharmaceutics. 2017, 14, 3568−3576 

     Wang S, Zhang X, Wu G, Tian Z, Qian F.*; Optimization of high-concentration endostatin formulation: Harmonization of excipients' contributions on colloidal and conformational stabilities.,  Int J Pharm. 2017 Sep 15;530(1-2):173-186. doi: 10.1016/j.ijpharm.2017.07.057. Epub 2017 Jul 26.

    Wu G, Wang Co-First S, Tian Z, Zhang N, Sheng H, Dai W, Qian F.*, Elucidating the Weak Protein-Protein Interaction Mechanisms behind the Liquid-Liquid Phase Separation of a mAb Solution by Different Types of Additives. Eur J Pharm Biopharm. Vol. 120, November 2017, Pages 1-8.

    Wang, S.; Wu, G.; Zhang, X.; Tian, Z.; Zhang, N.; Hu, T.; Dai.; W.; Qian F*, Stabilizing two IgG1 monoclonal antibodies by surfactants: Balance between aggregation prevention and structure perturbation, Euro. J. Pharm. Biopharm., Volume 114, May 2017, Pages 263–277

    Chen, Z.; Liu, CY.; Zhang, L.; Qian F.*; Dissolution Characteristics of Fast-Crystallizing β-Lapachone within Different Semicrystalline Microstructures of Polyethylene Glycol or Poly(ethylene oxide)–Poly(propylene oxide)–Poly(ethylene oxide) Triblock Copolymer, Cryst. Growth Des., 2016, 16, 5367-5376

    Chen YJ.; Wang S; Wang S.; Liu C.; Su, C.; Hageman, M.; Hussain, M.; Haskell. R.; Stefanski K.; Qian F*.; Sodium Lauryl Sulfate Competitively Interacts with HPMC-AS and Consequently Reduces Oral Bioavailability of Posaconazole/HPMC-AS Amorphous Solid Dispersion, Mol. Pharmaceutics, 2016, 13, 2787-2795

    Chen YJ.; Wang S; Wang S.; Liu C.; Su, C.; Hageman, M.; Hussain, M.; Haskell. R.; Stefanski K.; Qian F*.; Initial Drug Dissolution from Amorphous Solid Dispersions Controlled by Polymer Dissolution and Drug-Polymer Interaction, Pharmaceutical Research, 2016, 33(10), 2445-2458.

    Liu C, Chen Z, ChenYJ.; Lu J’; Li Y.; Wang S.; Wu G.; Qian F* Improving Oral Bioavailability of Sorafenib by Optimizing the “Spring” and “Parachute” Based on Molecular Interaction Mechanisms, Mol. Pharmaceutic,2016, 13 (2), pp 599–608

    Wang S, Zhang N, Hu T, Dai W, Feng X, Zhang X, and Qian F*.; Viscosity-Lowering Effect of Amino Acids and Salts on Highly Concentrated Solutions of Two IgG1 Monoclonal Antibodies, Mol. Pharmaceutics, 2015, 12 (12), pp 4478–4487

    Zhang L, Zhen Chen, Kuan Yang, Chun Liu, Jinming Gao, and Qian F*.; β-Lapachone and Paclitaxel Combination Micelles with Improved Drug Encapsulation and Therapeutic Synergy as Novel Nanotherapeutics for NQO1-Targeted Cancer Therapy, Mol.Pharmaceutics, 2015, 12 (11), pp 3999–4010

    Liu C, Kong C, Wu G, Zhu J, Javid B, Qian F*, Uniform and amorphous rifampicin microspheres obtained by freezing induced LLPS during lyophilization, Int. J. Pharm., Volume 495, Issue 1, 10 November 2015, Pages 500–507

    Wang S, Liu H, Zhang X, Qian F*, Intranasal and oral vaccination with protein-based antigens: advantages, challenges and formulation strategies, Protein & Cell, July 2015, Volume 6, Issue 7, pp 480-503

    Chen, Z.; Liu,ZS.; Qian F.*; Crystallization of Bifonazole and Acetaminophen within the Matrix of Semicrystalline, PEO-PPO-PEO Triblock Copolymers, Mol. Pharmaceutics, 2015 Feb 21;12(2):590-9.

    Chen YJ.; Liu CY.; Chen.Z.; Su, C.; Hageman, M.; Hussain, M.; Haskell. R.; Stefanski K.; Qian F*.; Drug-polymer-water Interaction and its Implication to the Dissolution Performance of Amorphous Solid Dispersions, Mol. Pharmaceutics, 2015 Feb 12;12(2):576-89.

     Qian F.*; Wang, J.; Hartley, R.; Tao, J.; Haddadin, R.; Mathias, N..; Hussain, M. Solution Behavior of PVP-VA and HPMC-AS Based Amorphous Solid Dispersions and Their Bioavailability Implications, Pharmaceutical Research, 2012, Oct 29 (10) 2765-76

    Qian F.*; Huang, J.; Zhu, Q.; Haddadin, R.; Gawel, J.; Garmise, R.; Hussain, M. Is a Distinctive Single Tg a Reliable Indicator for the Homogeneity of Amorphous Solid Dispersion? International Journal of Pharmaceutics, Volume 395, Issues 1-2, 16 August 2010, Pages 232-235

    Qian F.*; Huang, J.; Hussain, M. Drug-polymer solubility and miscibility: stability consideration and practical challenges in amorphous solid dispersion development. Journal of Pharmaceutical Sciences, 2010, 99 (7), 2941-2947

   Qian F.*; Ni, N.; Burton, L.; Wang, F.; Desikan, S.; Hussain, M.; Smith, RL. Sustained Release Subcutaneous Delivery of BMS-686117, a GLP-1 Receptor Agonist, Via Zinc Adduct.  International Journal of Pharmaceutics, Vol. 374, Issues 1-2, 5 June 2009, 46-52

    Qian, F.*; Moench, P.; Mathias, N.; Desikan, S.; Hussain, M.; Smith, RL. Pulmonary Delivery of a GLP-1 Receptor Agonist, BMS-686117.  International Journal of Pharmaceutics, Vol. 366, 2009, 218–220

    Qian F.*; Ni, N.; Chen, JW.; Desikan, S.; Naringrekar, V.; Hussain, M.; Smith, RL. Formation of Zinc Peptide Spherical Microparticles during Lyophilization From tert-Butyl Alcohol/Water Co-solvent System.  Pharmaceutical Research, Vol. 25, No. 12, December 2008 

    Qian F.*; Tao, J..; Desikan, S.; Hussain, M.; Smith, RL. Mechanistic Investigation of Pluronic® Based Nano-crystalline Solid Dispersion.  Pharmaceutical Research, 2007, 24(8):1551-60.