Fan Yuan

Overview:

Dr. Yuan's research interests include drug and gene delivery, mechanisms of molecular transport in cells and tissues, and tumor pathophysiology.

Cure of cancer through chemotherapy requires drug molecules to reach all tumor cells at an adequately high concentration. At present, such a requirement cannot be satisfied in most patients. This is because (a) amount of drugs that can be administered into patients is limited by normal tissue tolerance and (b) drug distribution and cellular response to drugs in tumors are heterogeneous. Therefore, cells in regions with drug concentration below the therapeutic level will cause tumor recurrence and they may also develop resistance to future treatment.

The goal of our research is two-fold. One is to improve delivery of therapeutic agents in solid tumors; and the second is to understand mechanisms of drug resistance in tumors caused by intrinsic cellular heterogeneity and physiological barriers. These studies may provide useful information on how to improve clinical treatment of cancer based on currently available drugs or molecular medicines in the future.

Research projects in our lab include quantification of transport parameters, delivery of drugs encapsulated in temperature sensitive liposomes, physical interventions of drugs, electric field-mediated gene delivery, mathematical modeling of drug and gene delivery.

Positions:

Professor of Biomedical Engineering

Biomedical Engineering
Pratt School of Engineering

Professor in Ophthalmology

Ophthalmology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.S. 1983

Peking University (China)

M.S. 1985

Peking University (China)

Ph.D. 1990

City University of New York

Grants:

Pharmacological Sciences Training Program

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Participating Faculty Member
Start Date
End Date

University Training Program in Biomolecular and Tissue Engineering

Administered By
Biomedical Engineering
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

University Training Program in Biomolecular and Tissue Engineering

Administered By
Biomedical Engineering
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

Intravital point-scanning confocal microscope

Administered By
Biomedical Engineering
Awarded By
National Institutes of Health
Role
Major User
Start Date
End Date

Training in Biomolecular and Tissue Engineering

Administered By
Orthopaedics
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

Publications:

Nuclear Envelope As A Physical Barrier In Electrotransfection.

Authors
Cervia, LD; Wang, L; Chang, C; Mao, M; Yuan, F
MLA Citation
Cervia, L. D., et al. “Nuclear Envelope As A Physical Barrier In Electrotransfection.Molecular Biology of the Cell, vol. 28, AMER SOC CELL BIOLOGY, 2017.
URI
https://scholars.duke.edu/individual/pub1307927
Source
wos
Published In
Molecular Biology of the Cell
Volume
28
Published Date

Role of specific endocytic pathways in electrotransfection of cells.

Electrotransfection is a technique utilized for gene delivery in both preclinical and clinical studies. However, its mechanisms are not fully understood. The goal of this study was to investigate specific pathways of endocytosis involved in electrotransfection. In the study, three different human cell lines (HEK293, HCT116, and HT29) were either treated with ice cold medium postelectrotransfection or endocytic inhibitors prior to electrotransfection. The inhibitors were pharmacological agents (chlorpromazine, genistein, and amiloride) or different small interfering RNA (siRNA) molecules that could knockdown expression of clathrin heavy chain (CLTC), caveolin-1, and Rab34, respectively. The reduction in gene expressions was confirmed with western blot analysis at 48-72h post-siRNA treatment. It was observed that treatments with either ice cold medium, chlorpromazine, or genistein resulted in significant reductions in electrotransfection efficiency (eTE) in all three cell lines, compared to the matched controls, but amiloride treatment had insignificant effects on eTE. For cells treated with siRNA, only CLTC knockdown resulted in eTE reduction for all three cell lines. Together, these data demonstrated that the clathrin-mediated endocytosis played an important role in electrotransfection.
MLA Citation
Chang, Chun-Chi, et al. “Role of specific endocytic pathways in electrotransfection of cells.Molecular Therapy. Methods & Clinical Development, vol. 1, Jan. 2014, p. 14058. Epmc, doi:10.1038/mtm.2014.58.
URI
https://scholars.duke.edu/individual/pub1074786
PMID
26052524
Source
epmc
Published In
Molecular Therapy Methods & Clinical Development
Volume
1
Published Date
Start Page
14058
DOI
10.1038/mtm.2014.58

Enhancement of electric field-mediated gene delivery through pretreatment of tumors with a hyperosmotic mannitol solution.

Pulsed electric fields can enhance interstitial transport of plasmid DNA (pDNA) in solid tumors. However, the extent of enhancement is still limited. To this end, the effects of cellular resistance to electric field-mediated gene delivery were investigated. The investigation used two tumor cell lines (4T1 (a murine mammary carcinoma) and B16.F10 (a metastatic subline of B16 murine melanoma)) either in suspensions or implanted in two in vivo models (dorsal skin-fold chamber (DSC) and hind leg). The volume fraction of cells was altered by pretreatment with a hyperosmotic mannitol solution (1 M). It was observed that the pretreatment reduced the volumes of 4T1 and B16.F10 cells, suspended in an agarose gel, by 50 and 46%, respectively, over a 20-min period, but did not cause significant changes ex vivo in volumes of hind-leg tumor tissues grown from the same cells in mice. The mannitol pretreatment in vivo improved electric field-mediated gene delivery in the hind-leg tumor models, in terms of reporter gene expression, but resulted in minimal enhancement in pDNA electrophoresis over a few microns distance in the DSC tumor models. These data demonstrated that hyperosmotic mannitol solution could effectively improve electric field-mediated gene delivery around individual cells in vivo by increasing the extracellular space.
Authors
Henshaw, J; Mossop, B; Yuan, F
MLA Citation
Henshaw, J., et al. “Enhancement of electric field-mediated gene delivery through pretreatment of tumors with a hyperosmotic mannitol solution.Cancer Gene Therapy, vol. 18, no. 1, Jan. 2011, pp. 26–33. Epmc, doi:10.1038/cgt.2010.51.
URI
https://scholars.duke.edu/individual/pub807830
PMID
20847751
Source
epmc
Published In
Cancer Gene Therapy
Volume
18
Published Date
Start Page
26
End Page
33
DOI
10.1038/cgt.2010.51

Transscleral diffusion of ethacrynic acid and sodium fluorescein.

PURPOSE: One of the current limitations in developing novel glaucoma drugs that target the trabecular meshwork (TM) is the induced corneal toxicity from eyedrop formulations. To avoid the corneal toxicity, an alternative approach would be to deliver TM drugs through the sclera. To this end, we quantified ex vivo diffusion coefficient of a potential TM drug, ethacrynic acid (ECA), and investigated mechanisms of ECA transport in the sclera. METHODS: An Ussing-type diffusion apparatus was built to measure the apparent diffusion coefficient of ECA in fresh porcine sclera at 4 degrees C. To understand mechanisms of ECA transport, we quantified the transscleral transport of a fluorescent tracer, sodium fluorescein (NaF), that has a similar molecular weight but is more hydrophilic compared to ECA. Furthermore, we developed a mathematical model to simulate the transport processes and used it to analyze the experimental data. The model was also used to investigate the dependence of diffusion coefficients on volume fraction of viable cells and the binding of NaF and ECA to scleral tissues. RESULTS: The diffusion coefficients of ECA and NaF in the sclera were 48.5+/-15.1 x 10-7 cm(2)/s (n=9) and 5.23+/-1.93 x 10(-7) cm(2)/s (n=8), respectively. Both diffusion coefficients were insensitive to cell shrinkage caused by ECA during the diffusion experiments and cell damage caused by the storage of tissues ex vivo before the experiments. Binding of ECA to scleral tissues could not be detected. The apparent maximum binding capacity and the apparent equilibrium dissociation constant for NaF were 80+/-5 mM and 2.5+/-0.5 mM (n=3), respectively. CONCLUSIONS: These data demonstrated that ECA diffusion was minimally hindered by structures in the sclera, presumably due to the lack of cells and binding sites for ECA in the sclera.
Authors
Lin, C-W; Wang, Y; Challa, P; Epstein, DL; Yuan, F
MLA Citation
Lin, Cheng-Wen, et al. “Transscleral diffusion of ethacrynic acid and sodium fluorescein.Mol Vis, vol. 13, Feb. 2007, pp. 243–51.
URI
https://scholars.duke.edu/individual/pub737603
PMID
17356511
Source
pubmed
Published In
Molecular Vision
Volume
13
Published Date
Start Page
243
End Page
251

Alginate encapsulation is a highly reproducible method for tumor cell implantation in dorsal skinfold chambers.

Authors
Wang, Y; Chen, Q; Yuan, F
MLA Citation
Wang, Yong, et al. “Alginate encapsulation is a highly reproducible method for tumor cell implantation in dorsal skinfold chambers.Biotechniques, vol. 39, no. 6, Dec. 2005, pp. 834–39. Epmc, doi:10.2144/000112082.
URI
https://scholars.duke.edu/individual/pub711216
PMID
16382900
Source
epmc
Published In
Biotechniques
Volume
39
Published Date
Start Page
834
End Page
839
DOI
10.2144/000112082