Yunfeng Yan
University of Texas Southwestern Medical Center
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Publication
Featured researches published by Yunfeng Yan.
Journal of the American Chemical Society | 2015
Jing Hao; Petra Kos; Kejin Zhou; Jason B. Miller; Lian Xue; Yunfeng Yan; Hu Xiong; Sussana Elkassih; Daniel J. Siegwart
The ability to control chemical functionality is an exciting feature of modern polymer science that enables precise design of drug delivery systems. Ring-opening polymerization of functional monomers has emerged as a versatile method to prepare clinically translatable degradable polyesters.1 A variety of functional groups have been introduced into lactones; however, the direct polymerization of tertiary amine functionalized cyclic esters has remained elusive. We report a strategy that enabled the rapid synthesis of >130 lipocationic polyesters directly from functional monomers without protecting groups. These polymers are highly effective for siRNA delivery at low doses in vitro and in vivo.
Proceedings of the National Academy of Sciences of the United States of America | 2016
Kejin Zhou; Liem H. Nguyen; Jason B. Miller; Yunfeng Yan; Petra Kos; Hu Xiong; Lin Li; Jing Hao; Jonathan T. Minnig; Hao Zhu; Daniel J. Siegwart
Significance Liver cancer is a leading cause of death and a global health problem. Unfortunately, five small-molecule drugs for hepatocellular carcinoma (HCC) recently failed phase III clinical trials partly because late-stage liver dysfunction amplifies drug toxicity. MicroRNAs (miRNAs) present a promising alternative treatment strategy but require development of delivery vehicles that can avoid this cancer-induced dysfunction, which exacerbates toxicity. We overcame this challenge by developing dendrimer nanoparticles that mediate miRNA delivery to late-stage liver tumors with low hepatotoxicity. An aggressive, MYC-driven transgenic liver cancer model was used to examine let-7g tumor suppressor efficacy, resulting in a significant survival benefit. These dendrimer carriers provide high potency in tumors without negatively affecting normal tissues, solving a critical issue in treating aggressive liver cancer. RNA-based cancer therapies are hindered by the lack of delivery vehicles that avoid cancer-induced organ dysfunction, which exacerbates carrier toxicity. We address this issue by reporting modular degradable dendrimers that achieve the required combination of high potency to tumors and low hepatotoxicity to provide a pronounced survival benefit in an aggressive genetic cancer model. More than 1,500 dendrimers were synthesized using sequential, orthogonal reactions where ester degradability was systematically integrated with chemically diversified cores, peripheries, and generations. A lead dendrimer, 5A2-SC8, provided a broad therapeutic window: identified as potent [EC50 < 0.02 mg/kg siRNA against FVII (siFVII)] in dose–response experiments, and well tolerated in separate toxicity studies in chronically ill mice bearing MYC-driven tumors (>75 mg/kg dendrimer repeated dosing). Delivery of let-7g microRNA (miRNA) mimic inhibited tumor growth and dramatically extended survival. Efficacy stemmed from a combination of a small RNA with the dendrimer’s own negligible toxicity, therefore illuminating an underappreciated complication in treating cancer with RNA-based drugs.
Proceedings of the National Academy of Sciences of the United States of America | 2016
Yunfeng Yan; Li Liu; Hu Xiong; Jason B. Miller; Kejin Zhou; Petra Kos; Kenneth Huffman; Sussana Elkassih; John W. Norman; Ryan Carstens; James Kim; John D. Minna; Daniel J. Siegwart
Significance Ideal cancer therapeutics accurately hit tumors and avoid side effects on healthy cells. We used a patient-derived pair of matched cancer/normal cell lines to discover selective nanoparticles that could deliver a cytotoxic siRNA to kill cancer cells and not normal cells. The finding that cells respond differently to the same nanoparticle has profound implications for gene therapy because cell-type specificity of drug carriers in vivo could alter clinical patient outcomes. Our data suggest that selectivity is an underappreciated reality that should be carefully considered when evaluating drug carriers. The combination of both well-defined molecular targets and nanoparticle delivery to targeted cells is likely required to improve cancer drug accuracy in the clinic. Conventional chemotherapeutics nonselectively kill all rapidly dividing cells, which produces numerous side effects. To address this challenge, we report the discovery of functional polyesters that are capable of delivering siRNA drugs selectively to lung cancer cells and not to normal lung cells. Selective polyplex nanoparticles (NPs) were identified by high-throughput library screening on a unique pair of matched cancer/normal cell lines obtained from a single patient. Selective NPs promoted rapid endocytosis into HCC4017 cancer cells, but were arrested at the membrane of HBEC30-KT normal cells during the initial transfection period. When injected into tumor xenografts in mice, cancer-selective NPs were retained in tumors for over 1 wk, whereas nonselective NPs were cleared within hours. This translated to improved siRNA-mediated cancer cell apoptosis and significant suppression of tumor growth. Selective NPs were also able to mediate gene silencing in xenograft and orthotopic tumors via i.v. injection or aerosol inhalation, respectively. Importantly, this work highlights that different cells respond differentially to the same drug carrier, an important factor that should be considered in the design and evaluation of all NP carriers. Because no targeting ligands are required, these functional polyester NPs provide an exciting alternative approach for selective drug delivery to tumor cells that may improve efficacy and reduce adverse side effects of cancer therapies.
Polymer Chemistry | 2014
Yunfeng Yan; Daniel J. Siegwart
Functional polyester chemistry is well suited to improve delivery of biomacromolecular drugs because it enables tuning of degradation profiles and inclusion of key functional groups (e.g. cationic charges for nucleic acid binding). However, current approaches to introduce functionality suffer from inadequate scalability and modularity. We have developed a scalable library of functional polyesters based on the polymerization of trimethylolpropane allyl ether (TPAE) with diacid chlorides (poly(TPAE-co-AC)s). The reactive side chains can be easily modified with various functional thiols (e.g. alkyl-, amino-, and PEG-) and amines to generate a diverse set of materials, thereby tuning the chemistry for potential opportunities in drug delivery. The polymerization occurs readily under mild conditions at room temperature with Mw for poly(TPAE-co-suberoyl chloride) exceeding 42000 g mol−1. In addition, poly(TPAE-co-adipoyl chloride) was polymerized on a 100+ gram scale in 71% final isolated yield. Due to the structural similarity to established non-functional polyesters such as PLGA, these new materials may find broad application as functional polyesters for gene delivery, tissue engineering, and other nanotechnology applications.
Bioconjugate Chemistry | 2016
Hu Xiong; Petra Kos; Yunfeng Yan; Kejin Zhou; Jason B. Miller; Sussana Elkassih; Daniel J. Siegwart
Dysregulated pH has been recognized as a universal tumor microenvironment signature that can delineate tumors from normal tissues. Existing fluorescent probes that activate in response to pH are hindered by either fast clearance (in the case of small molecules) or high liver background emission (in the case of large particles). There remains a need to design water-soluble, long circulating, pH-responsive nanoprobes with high tumor-to-liver contrast. Herein, we report a modular chemical strategy to create acidic pH-sensitive and water-soluble fluorescent probes for high in vivo tumor detection and minimal liver activation. A combination of a modified Knoevenagel reaction and PEGylation yielded a series of NIR BODIPY fluorophores with tunable pKas, high quantum yield, and optimal orbital energies to enable photoinduced electron transfer (PeT) activation in response to pH. After intravenous administration, Probe 5c localized to tumors and provided excellent tumor-to-liver contrast (apparent T/L = 3) because it minimally activates in the liver. This phenomenon was further confirmed by direct ex vivo imaging experiments on harvested organs. Because no targeting ligands were required, we believe that this report introduces a versatile strategy to directly synthesize soluble probes with broad potential utility including fluorescence-based image-guided surgery, cancer diagnosis, and theranostic nanomedicine.
Biomacromolecules | 2017
Yunfeng Yan; Hu Xiong; Xinyi Zhang; Qiang Cheng; Daniel J. Siegwart
Messenger RNA (mRNA) has recently come into focus as an emerging therapeutic class with great potential for protein replacement therapy, cancer immunotherapy, regenerative medicine, vaccines, and gene editing. However, the lack of effective and safe delivery methods impedes the broad application of mRNA-based therapeutics. We report a robust approach to develop efficient polymeric delivery carriers for mRNA. Lead polyesters were identified by in vitro screening of a 480-member combinatorially modified poly(trimethylolpropane allyl ether-co-suberoyl chloride) library for the delivery of luciferase encoding mRNA (Luc mRNA) to IGROV1 cells. The formulation of mRNA polyplex nanoparticles (NPs) with Pluronic F127 decreased the surface charge. Although this improved the stability of mRNA nanoparticles, the delivery potency decreased with increased F127 content. Thus, we determined that NP stabilization with 5% F127 could balance the protective effects and delivery potency. 5% F127 formulated PE4K-A17-0.33C12 mRNA NPs enabled luciferase expression predominantly in the lungs after intravenous injection into mice. The efficient mRNA delivery specifically to lungs by degradable carriers suggests the potential for the treatment of pulmonary diseases.
Chemical Communications | 2016
Kejin Zhou; Petra Kos; Yunfeng Yan; Hu Xiong; Yi Li Min; Karina A. Kinghorn; Jonathan T. Minnig; Jason B. Miller; Daniel J. Siegwart
Tremendous effort has been made to improve stability and delivery efficacy of small RNA therapeutics. However, nearly all current nano-encapsulation carriers utilize the critical balance between only two interacting parameters: RNA-binding electrostatic interactions and nanoparticle-stabilizing hydrophobic interactions. We report the development of intercalation-meditated nucleic acid (IMNA) nanoparticles, which utilize intercalation as a third interaction to enhance small RNA delivery. This toolbox expansion of interaction parameters may inspire the use of additional forces in nanoparticle drug carriers to increase potency and stability.
ACS Applied Materials & Interfaces | 2018
Hu Xiong; Kejin Zhou; Yunfeng Yan; Jason B. Miller; Daniel J. Siegwart
Current photosensitizers (PSs) for photodynamic therapy (PDT) are limited by their low water solubility and tendency to aggregate, low near-infrared (NIR) absorption, and low cancer selectivity. Here, we designed iodinated, water-soluble NIR boron dipyrromethene-based PSs to achieve image-guided and efficient PDT against cancer in vivo that is enhanced by leveraging tumor-specific pH-responsive activation. PEG2k5c-I and PEG2k5c-OMe-I localized to tumors and were activated by acidic pH in the tumor microenvironment to produce 1O2 and fluorescence for efficient PDT and effective cancer detection after intravenous administration. Upon NIR irradiation, these PSs exhibited strong NIR absorption at 660 and 690 nm, stable NIR emission at 692 and 742 nm, and high 1O2 quantum yields of 0.78 and 0.72 in acidic pH. PEG2k5c-I and PEG2k5c-OMe-I killed cancer cells upon irradiation of NIR light and were nontoxic without irradiation. Light-activated PDT treatment of breast cancer tumors in mice resulted in suppression of tumor growth, DNA damage, and necrosis selectively in tumors. This work thus introduces a versatile method to directly synthesize modular pH-responsive water-soluble PSs and provides a versatile strategy for activatable PDT against cancer.
Biomaterials | 2017
Yunfeng Yan; Kejin Zhou; Hu Xiong; Jason B. Miller; Edward A. Motea; David A. Boothman; Li Liu; Daniel J. Siegwart
Advanced Materials | 2017
Hu Xiong; Hao Zuo; Yunfeng Yan; Gino Occhialini; Kejin Zhou; Yihong Wan; Daniel J. Siegwart