| 项目编号: | 1452855
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| 项目名称: | CAREER: Scalable Synthesis of Designed Biosurfactants to Enhance Drug Bioavailability |
| 作者: | Bryan Berger
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| 承担单位: | Lehigh University
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| 批准年: | 2014
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| 开始日期: | 2015-02-01
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| 结束日期: | 2020-01-31
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| 资助金额: | USD399356
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| 资助来源: | US-NSF
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| 项目类别: | Continuing grant
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| 国家: | US
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| 语种: | 英语
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| 特色学科分类: | Engineering - Chemical, Bioengineering, Environmental, and Transport Systems
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| 英文关键词: | drug solubility
; drug
; biosurfactant
; hyd variant
; career proposal
; commercial drug formulation
; side-effect
; drug solubiization
; target drug
; drug bioavailability
; insoluble drug
; fungal biosurfactant
; high-yield synthesis
; effective pre-clinical drug formulation
; drug formulation
; biosurfactant structure
; poor overall drug efficacy
; model hydrophobic drug compound
; ph-hyd
; biosurfactant property
; current drug formulation
; tween
; novel biosurfactant
; s-hyd
; biosurfactant biomanufacturing
; drug release
|
| 英文摘要: | 1452855
Berger, Bryan W.
It is estimated that more than 40% of all currently developed drugs fail in preclinical evaluation due to low drug solubility, which reduces in vivo bioavailability and results in poor overall drug efficacy. In biopharmaceutical manufacturing, low drug solubility is the most common barrier to developing an effective pre-clinical drug formulation. Pre-clinical formulation is critical to the eventual success of a drug, with major financial consequences of poor drug solubility during pre-clinical formulation. Nearly 70-80% of all drugs fail during pre-clinical and phase I clinical development, with an average investment loss of $100-800 million per drug. Additionally, there are major problems with the biocompatibility of synthetic surfactants such as Tween 80 used to improve drug solubility; Tween 80 has been shown to cause severe side-effects such as anaphylaxis in IV chemotherapeutic formulations. Thus, there is a current, unmet need to develop (1) a detailed understanding of how altering surfactant structure influences drug solubiization to prevent poor drug solubility and associated side-effects and (2) a flexible method for high-yield synthesis of novel biosurfactants at a cost competitive with currently used synthetic surfactants such as Tween 80. The goal of this CAREER proposal is to develop a series of biocompatible biosurfactants capable of overcoming the current limitations of commercial drug formulations in terms of cost, scale and targeted delivery. The results of this work will contribute directly to improved drug bioavailability, biocompatibility and efficacy and enable use of designed biosurfactants in a wide range of commercial drug formulations. Additionally, in partnership with Northampton Community College (NCC), the PI will develop a laboratory course for Lehigh and NCC students in biomanufacturing, and organize a 10-week summer internship program for NCC students interested in pursuing post-graduate studies in STEM fields. Ultimately, the biosurfactant structure, function and design studies described in this CAREER proposal will provide a unique, long-term project that has direct application to a wide range of challenges in drug formulation as well as a unique, cross-institutional educational opportunity for Lehigh and NCC students in STEM-related fields.
The PI will utilize an integrated, structure-guided approach to design variants of the protein hydrophobin (HYD), a naturally-occurring, fungal biosurfactant, to improve drug solubility, biocompatibility and targeted delivery. Importantly, a major focus of this work is on development and production of designed biosurfactants at a scale and cost competitive with synthetic surfactants such as Tween 80. The challenges of engineering novel functions into the biosurfactant to improve targeting and drug solubility will be addressed through (1) engineering HYD variants with pH-dependent surface activity (pH-HYD) for targeted drug release, (2) evolving HYD variants for enhanced solubilization (s-HYD) of a given target drug and (3) integrating both pH- and s-HYD into a commercial-scale formulation that maximizes drug solubility and targeting. Using previous structural information regarding HYD, the investigator will design a series of electrostatically-stabilized HYD variants, each of which will enable pH-dependent assembly and disassembly. Similarly, using a high-yield secretion system developed for HYD coupled to high-throughput methods for characterization, the PI will utilize directed evolution to select HYD variants that enhance drug solubility using a series of model hydrophobic drug compounds as benchmarks. Lastly, by integrating both engineered and evolved HYD variants, a novel, hybrid formulation will be identified that can both deliver drug at high solubility and target delivery effectively. Ultimately, this approach will lead to tailored biosurfactant properties precisely to enable formulation of previously insoluble drugs, engineer enhanced targeting mechanisms such as pH (pH-HYD) to reduce side-effects associated with current drug formulations and develop a low-cost, scalable and sustainable route for biosurfactant biomanufacturing that is broadly applicable to a wide range of formulation application. |
| 资源类型: | 项目
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| 标识符: | http://119.78.100.158/handle/2HF3EXSE/95140
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| Appears in Collections: | 影响、适应和脆弱性
气候减缓与适应
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| Recommended Citation: | |
Bryan Berger. CAREER: Scalable Synthesis of Designed Biosurfactants to Enhance Drug Bioavailability. 2014-01-01.
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