Research SummaryMy group has focused on improving delivery of drugs into solid tumors. We have extensively investigated ways using polymers, proteins, and nanocarriers to overcome barriers that impede drug distribution into solid tumors including: improving carrier circulation half-life, optimizing drug release, enhancing extravasation, disrupting interstitial tumor matrix, and improving convective fluid movements within a tumor. Although we have made progress to deliver drugs into solid tumors, the barriers still stand.
My lab uses macrophages to transport therapeutic agents into defined inflammatory lesions, such as solid tumors, or into fungal or tuberculosis lesions. Our approach is to manufacture macrophage precursor cells that can be rapidly expanded, differentiated into macrophages, and engineered to deliver therapeutic agents throughout the tumor matrix or nidus of infection. To translate this idea into a useful medicine requires a more detailed knowledge of how to create a transplantable macrophage that can be quickly generated in high numbers, as well as how to modify the macrophage with nanocarriers or genetic manipulations so it can deliver therapeutics in a controllable and predictable manner. We are encouraged that the macrophage approaches devised in our research might not only be used to treat cancer but also to treat a variety of other disorders including traumatic tissue injury and chronic inflammation.
John Hopkins University, Baltimore, MD, A.B., 1965, Liberal Arts
University of Maryland, College Park, MD, M.S., 1971, Microbiology
SUNY/Buffalo, Buffalo, NY, Ph.D., 1976, Biochemistry
Captain, U.S. Army; Director, Clinical Chemistry, Walson Army Hospital
NIH postdoctoral fellow, Dr. D. Papahadjopoulos, RPMI, Buffalo
Cancer Research Scientist, Roswell Park Cancer Institute, Buffalo
Assistant Professor of Physiology, Tufts Medical School
Assistant Professor of Pharmacy & Pharmaceutical Chemistry, University of California
Associate Professor of Pharmacy & Pharmaceutical Chemistry, University of California
Professor of Biopharmaceutics & Pharmaceutical Chemistry, University of California
- Sparrer HE, Santoso A, Szoka FC Jr., Weissman JS. Evidence for the prion hypothesis: Induction of the yeast [PSI+] factor by in vitro- converted sup35 protein. Science 2000;289:595-599.
- Guo X, Szoka, FC Jr.. Steric stabilization of fusogenic liposomes by a low-pH sensitive PEG-diortho ester-lipid conjugate. Bioconj. Chem. 2001;12(2):291-300.
- Supattapone S, Wille H, Uyechi L, Safar J, Tremblay P, Szoka FC Jr., Cohen F, Prusiner S, Scott M. Branched polymines cure prion-infected neuroblastoma cells. J. of Virology 2001;75(7):3453-3461.
- Eliaz RE, Szoka FC Jr. Liposome encapsulated doxorubicin targeted to CD44: A strategy to kill CD44 overexpressing tumor cells. Cancer Research 2001;61:2592-2601.
- Sperinde JJ, Choi SJ, Szoka FC Jr. Phage display selection of an oligopeptide DNase II inhibitor that enhances gene delivery. J. Gene Med. 2001;3:101-108.
- Uyechi LS, Thurston G, Gagne L, Szoka FC Jr. Mechanism of lipoplex gene delivery in mouse lung: binding and internalization of fluorescent lipid and DNA components. Gene Therapy 2001;8:828-836.
- Padilla De Jesus OL, Ihre HR, Gagne L, Frechet JMJ, Szoka FC Jr. Polyester dendritic systems for drug delivery applications: in vitro and in vivo evaluation. Bioconj. Chem. 2002;13:453-461.
- Eliaz RE, Szoka FC Jr. Robust and prolonged gene expression from injectable polymeric implants. Gene Therapy 2002;9:1230-1237.
- Bronich TK, Ouyang M, Kabanov VA, Eisenberg A, Szoka FC Jr., Kabanov AV. Synthesis of vesicles on polymer template. J. Am. Chem. Soc. 2002;124:11872-11873.
- Guo X, MacKay JA, Szoka FC Jr., Mechanism of pH-triggered collapse of phosphatidylethanolamine liposomes stabilized by an ortho ester polyethyleneglycol lipid. Biophys. J. 2003;84:1784-1795.
- Choi JS, MacKay JA, Szoka FC Jr. Low-pH-sensitive PEG-stabilized plasmid-lipid nanoparticles: preparation and characterization. Bioconjug. Chem. 2003;14(2):420-429.
- Guo X, Szoka FC Jr. Chemical approaches to triggerable lipid vesicles for drug and gene delivery. Accts of Chem. Res. 2003;36:335-341.
- Sonawane ND, Szoka FC Jr., Verkman AS. Chloride accumulation and swelling in endosomes enhances DNA transfer by polyamine-DNA polyplexes. J. Biol. Chem. 2003;278:44826-44831.
- Eliaz RE, Nir S, Marty C, Szoka FC Jr. Determination and modeling of kinetics of cancer cell killing by doxorubicin and doxorubicin encapsulated in targeted liposomes. Cancer Res. 2004;64:711-718.
- Eliaz RE, Nir S, Szoka FC Jr. Interactions of hyaluronan-targeted liposomes with cultured cells: modeling of binding and endocytosis. Methods Enzymol 2004;387:16.
- Guo X, Huang Z, Szoka FC Jr. Improved preparation of PEG-diortho ester-diacyl glycerol conjugates. Methods Enzymol 2004;387:147-152.
- Tang M, Li W, Szoka FC Jr., Toroid Formation in charge neutralized flexible or semiflexible biopolymers: potential pathway for assembly of DNA Carriers. J. Gene Medicine 2004.
- Li W, Huang Z, MacKay JA, Grube S, Szoka FC Jr. Low J PH-sensitive poly(ethylene glycol) (PEG)-stabilized plasmid nanolipoparticles: Effects of PEG chain length, lipid composition and assembly conditions on gene delivery. Gene Med. 2005;7:67-79.
- Huang Z, Li W, MacKay JA, and Szoka FC. Thiocholesterol-based lipids for ordered assembly of bioresponsive gene carriers. Jr. Mol Ther. 2005;11:409-417.
- Mackay JA, Deen DF, Szoka FC Jr.; Distribution in brain of liposomes after convection enhanced delivery; modulation by particle charge, particle diameter, and presence of steric coating. Brain Res. 2005;1035:139-153.
- Lee CC, Yoshida M, Frechet JM, Dy EE, Szoka FC Jr. In vitro and vivo evaluation of hydrophilic dendronized linear polymers. Bioconjug Chem. 2005;16(3):535-41.
- Gillies ER, Dy E, Frechet JM, Szoka FC. Biological evaluation of polyester dendrimer: poly(ethylene oxide) "bow-tie" hybrids with tunable molecular weight and architecture. Mol Pharm. 2005;2(2):129-138.
- Lee CC, MacKay JA, Frechet JM, Szoka FC. Designing dendrimers for biological applications.Nat Biotechnol. 2005 23(12):1517-26.
- Huynh GH, Deen DF, Szoka FC Jr. Barriers to carrier mediated drug and gene delivery to brain tumors. J Control Release. 2006 110(2):236-59.
- Huang Z, Guo X, Li W, Mackay JA, Szoka FC Jr. Acid-triggered transformation of diortho ester phosphocholine liposome. J Am Chem Soc. 2006;128(1):60-1.
- Ruhela D, Riviere K, Szoka FC Jr. Efficient synthesis of an aldehyde functionalized hyaluronic acid and its application in the preparation of hyaluronan-lipid conjugates. Bioconjug Chem. 2006; 17(5):1360-3.
- Lee CC, Cramer AT, Szoka FC Jr, Frechet JM. An intramolecular cyclization reaction is responsible for the in vivo inefficacy and apparent pH insensitive hydrolysis kinetics of hydrazone carboxylate derivatives of doxorubicin. Bioconjug Chem. 2006; 17(5):1364-8.
- Huang Z, Park JI, Watson DS, Hwang P, Szoka FC Jr. Facile Synthesis of Multivalent Nitrilotriacetic Acid (NTA) and NTA Conjugates for Analytical and Drug Delivery Applications. Bioconjug Chem. 2006; 17(6):1592-1600.
- Lee CC, Gillies ER, Fox ME, Guillaudeu SJ, Frechet JM, Dy EE, Szoka FC. A single dose of doxorubicin-functionalized bow-tie dendrimer cures mice bearing C-26 colon carcinomas. Proc Natl Acad Sci U S A. 2006; 103(45):16649-54. Epub 2006 Oct 30.