Drug Development, NanoMedicine, Pharmacokinetics
1. Why Most Anticancer Nanomedicines Do Not Enhance Clinical Efficacy and How to Improve It?
Anticancer nanomedicine, which is designed based on tumor EPR effect and long systemic circulation, was an attractive strategy to improve anticancer efficacy and reduce drug's toxicity. Although thousands of anticancer nanomedicines have achieved outstanding efficacy in preclinical animal cancer models, most anticancer nanomedicines failed to show superior clinical efficacy.This low success rate in clinical patients has provoked decades of debate for the current nanomedicine design strategy. Based on extensive studies of current clinical used nanomedicines, we proposed a new anticancer nanomedicine design strategy, which is cancer type specific, cell type specific, drug specific, and nanocarrier specific. The new anticancer nanomedicine design strategy may improve their success in clinical cancer patients and achieve long-term tumor remission. We currently use these new strategies to design anticancer nanomedicines to remodel immune microenvironment in both tumors and lymph nodes for immunotherapy of triple negative breast cancer and pancreatic cancer.
The latest papers or manuscripts
What Went Wrong with Anticancer Nanomedicine Design and How to Make It Right. Sun D, Zhou S, Gao W. ACS Nano. 2020 Oct 27;14(10):12281-12290.
Reappraisal of anticancer nanomedicine design criteria in three types of preclinical cancer models for better clinical translation. Luan X, Yuan H, Song Y, Hu H, Wen B, He M, Zhang H, Li Y, Li F, Shu P, Burnett JP, Truchan N, Palmisano M, Pai MP, Zhou S, Gao W, Sun D. Biomaterials. 2021 Aug;275:120910.
Albumin nanoparticle containing a PI3Kγ inhibitor and paclitaxel in combination with α-PD1 induces tumor remission of breast cancer in mice. Yudong Song, Luke Bugada, Ruiting Li, Hongxiang Hu, Luchen Zhang, Chengyi Li, Hebao Yuan, Krishani Rajanayake, Nathan Truchan, Fei Wen, Wei Gao, and Duxin Sun. Science Translational Medicine, 2022, 14 (643): onlineDOI: 10.1126/scitranslmed.abl3649
2. Why 90% Drug Development Fails and How to Improve It? (PPT Slides, Video Recording)
In the past few decades, 90% clinical drug development failed from phase I-III clinical trials despite implementation of many successful strategies. The continued high failure of clinical drug development raises a question of whether some aspects of drug development have been overlooked? On the one hand, it is challenging to truly confirm the molecular target that is the cause of human disease and drug’s intended target. On the other hand, current drug optimization process may have misled drug candidate selection and impacted the balance clinical dose/efficacy/safety.
We propose a STAR system (structure-tissue exposure/selectivity-activity relationship) to improve the drug optimization, balance clinical dose/efficacy/toxicity, and improve success rate of drug development. STAR classifies drug candidates into four different classes with different development risks based on three aspects: structure-activity relationship (SAR), Structure-tissue selectivity-relationship (STR), and required clinical dose for balancing clinical efficacy/toxicity. We are currently using STAR system to optimize PI3K inhibitors and other immune modulators for cancer immunotherapy, JAK inhibitors for treating inflammatory bowel disease, anti-viral drugs to treat COVID19 severe disease.
Why 90% of Clinical Drug Development Fails and How to Improve It? Duxin Sun, Wei Gao, Hongxiang Hu, Simon Zhou. Acta Pharmaceutic Sinica B, 2022, 12, 3049
Structure-Tissue Exposure/Selectivity Relationship (STR) Correlates with Clinical Efficacy/Safety. Wei Gao, Hongxiang Hu, Lipeng Dai, Miao He, Hebao Yuan, Huixia Zhang, Jinhui Liao, Bo Wen, Yan Li, Maria Palmisano, Mohamed Dit Mady Traore, Simon Zhou, Duxin Sun. Acta Pharmaceutic Sinica B, 2022, 12, 2462
Optimization of The Prodrug Moiety of Remdesivir to Improve Lung Exposure/Selectivity and Enhance Anti-SARS-CoV-2 Activity. Hongxiang Hu , Mohamed Dit Mady Traore, Ruiting Li, Hebao Yuan, Miao He, Bo Wen, Wei Gao, Colleen B Jonsson, Elizabeth A Fitzpatrick, Duxin Sun. J Med Chem, 2022 (accepted)
Gastrointestinal (GI) locally-activating JAK inhibitor for treatment of Ulcerative Colitis. Mohamed Dit Mady Traore, Yingzi Bu, Lu Wang, Zhongwei Liu, Duxin Sun. J Med Chem (under review)
3. Why Most Anticancer Vaccines only Achieved Short-Term Efficacy and How to Improve It?
Current anticancer therapeutic vaccine are designed to activate CD4/CD8 T cell immunity, but only achieved short-term efficacy in most preclinical animal cancer mdoels and clinical patients. In contrast, the activation of B cell immunity in cancer vaccine design has been controversial. Latest clinical studies suggest activation of B cell immunity especially B/CD4 T cell cross-talk is critical for durable anticancer efficacy of immunotherapy. However, most current anticancer vaccines only activate T cell immunity without promotion of B/T cell cross-talk, which may be one of the reasons for their short-term efficacy. We have developed a virus antigen cluster mimicry nanovaccine (VAMVax) to promote B cell mediated antigen presentation and B/CD4 T cross talk for achieving long-term tumor remission in HER2+ breast cancer.
The latest manuscript
Virus Antigen Cluster Mimicry Nanovaccine Promotes B/CD4 T Cell Cross-Talk Achieving Long-Term Tumor Remission. Chengyi Li, Ryan Clauson, Luke F. Bugada, Bing He, Hongwei Chen, Hongxiang Hu, Polina Chuikov, Ke Fang, Brett D. Hill, Syed M. Rizvi, Yudong Song, Kai Sun, Daniel Huynh, Marilia Cascalho, Lana Garmire, Leo Yu Lei, Irina Grigorova, Fei Wen, Wei Gao, Duxin Sun. 2022 (under review)
4. What Are the Differences in Microbiome, Bile Salts, and Drug Release in Human Stomach, Small Intestine and Colon?
During oral drug product development, in vitro and in vivo drug release in human gastrointestinal (GI) tract needs to be optimized. In addition, the bile salts in the GI tract, which are altered under fasting and fed conditions, impact the drug release, disease states and microbiome. Further, microbiome in human GI tract regulates disease conditions and drug treatments. However, it is not clear what are the differences in microbiome, bile salts, and drug release in different regions of human GI tract (stomach, duodenum, jejunum, ileum, and colon), and how do they affect drug product development and disease states.
This project directly measureed profiles of microbiome, bile salts, and drug release in different regions of human GI tract using intubation or wireless sampling capsule. We directly measured the drug release in different regions of human GI tract (stomach, duodenum, jejunum, and ileum) for the immediate-release, modified-release, and locally-acting drug products. In addition, we also compared the profiles of 15 bile salts in different regions of human small intestine after fasting and fed conditions. Finally, we investigated the different microbiome profiles in different regions of human small intestine and colon.
Spatial and Temporal Analysis of the Stomach and Small-Intestinal Microbiota in Fasted Healthy Humans. Seekatz AM, Schnizlein MK, Koenigsknecht MJ, Baker JR, Hasler WL, Bleske BE, Young VB, Sun D. mSphere. 2019 Mar 13;4(2):e00126-19.
In Vivo Dissolution and Systemic Absorption of Immediate Release Ibuprofen in Human Gastrointestinal Tract under Fed and Fasted Conditions. Koenigsknecht MJ, Baker JR, Wen B, Frances A, Zhang H, Yu A, Zhao T, Tsume Y, Pai MP, Bleske BE, Zhang X, Lionberger R, Lee A, Amidon GL, Hasler WL, Sun D. Mol Pharm. 2017 Dec 4;14(12):4295-4304.
Measurement of in vivo Gastrointestinal Release and Dissolution of Three Locally Acting Mesalamine Formulations in Regions of the Human Gastrointestinal Tract. Yu A, Baker JR, Fioritto AF, Wang Y, Luo R, Li S, Wen B, Bly M, Tsume Y, Koenigsknecht MJ, Zhang X, Lionberger R, Amidon GL, Hasler WL, Sun D. Mol Pharm. 2017 Feb 6;14(2):345-358.