PMID- 24723985 OWN - NLM STAT- MEDLINE DCOM- 20150123 LR - 20211203 IS - 1838-7640 (Electronic) IS - 1838-7640 (Linking) VI - 4 IP - 6 DP - 2014 TI - A novel tumor targeting drug carrier for optical imaging and therapy. PG - 642-59 LID - 10.7150/thno.8527 [doi] AB - Human serum albumin (HSA), a naturally abundant protein in blood plasma and tissue fluids, has an extraordinary ligand-binding capacity and is advocated as a drug carrier to facilitate drug delivery. To render it tumor targeting specificity, we generated a recombinant HSA fused with the amino-terminal fragment (ATF) of urokinase, allowing the fusion protein to bind to urokinase receptor (uPAR), which is shown to have a high expression level in many tumors, but not in normal tissues. To test the efficacy of this bifunctional protein (ATF-HSA), a hydrophobic photosensitizer (mono-substituted beta-carboxy phthalocyanine zinc, CPZ) was chosen as a cytotoxic agent. A dilution-incubation-purification (DIP) strategy was developed to load the ATF-HSA with this CPZ, forming a 1:1 molecular complex (ATF-HSA:CPZ). We demonstrated that CPZ was indeed embedded inside ATF-HSA at the fatty acid binding site 1 (FA1) of HSA, giving a hydrodynamic radius of 7.5 nm, close to HSA's (6.5 nm). ATF-HSA:CPZ showed high stability and remarkable optical and photophysical properties in aqueous solution. In addition, the molecular complex ATF-HSA:CPZ can bind to recombinant uPAR in vitro and uPAR on tumor cell surfaces, and was efficient in photodynamic killing of tumor cells. The tumor-killing potency of this molecular complex was further demonstrated in a tumor-bearing mouse model at a dose of 0.080 mumol / kg, or 0.050 mg CPZ / kg of mouse body weight. Using fluorescent molecular tomography (FMT), ATF-HSA:CPZ was shown to accumulate specifically in tumors, and importantly, such tumor retention was higher than that of HSA:CPZ. Together, these results indicate that ATF-HSA:CPZ is not only an efficient tumor-specific cytotoxic agent, but also an useful tumor-specific imaging probe. This bifunctional protein ATF-HSA can also be used as a drug carrier for other types of cytotoxic or imaging agents to render them specificity for uPAR-expressing tumors. FAU - Li, Rui AU - Li R AD - 1. State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, 350002, China; ; 4. University of Chinese Academy of Sciences, Beijing, 100049, China. FAU - Zheng, Ke AU - Zheng K AD - 3. College of Chemistry and Chemical Engineering, Fuzhou University, Fuzhou, Fujian, 350002, China; FAU - Hu, Ping AU - Hu P AD - 1. State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, 350002, China; FAU - Chen, Zhuo AU - Chen Z AD - 1. State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, 350002, China; ; 4. University of Chinese Academy of Sciences, Beijing, 100049, China. FAU - Zhou, Shanyong AU - Zhou S AD - 1. State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, 350002, China; FAU - Chen, Jincan AU - Chen J AD - 1. State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, 350002, China; FAU - Yuan, Cai AU - Yuan C AD - 1. State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, 350002, China; FAU - Chen, Song AU - Chen S AD - 1. State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, 350002, China; ; 4. University of Chinese Academy of Sciences, Beijing, 100049, China. FAU - Zheng, Wei AU - Zheng W AD - 2. Key Laboratory of Optoelectronic Materials Chemistry and Physics, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, 350002, China; FAU - Ma, En AU - Ma E AD - 2. Key Laboratory of Optoelectronic Materials Chemistry and Physics, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, 350002, China; FAU - Zhang, Fengling AU - Zhang F AD - 3. College of Chemistry and Chemical Engineering, Fuzhou University, Fuzhou, Fujian, 350002, China; FAU - Xue, Jinping AU - Xue J AD - 3. College of Chemistry and Chemical Engineering, Fuzhou University, Fuzhou, Fujian, 350002, China; FAU - Chen, Xueyuan AU - Chen X AD - 2. Key Laboratory of Optoelectronic Materials Chemistry and Physics, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, 350002, China; ; 4. University of Chinese Academy of Sciences, Beijing, 100049, China. FAU - Huang, Mingdong AU - Huang M AD - 1. State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, 350002, China; ; 4. University of Chinese Academy of Sciences, Beijing, 100049, China. LA - eng PT - Journal Article DEP - 20140324 PL - Australia TA - Theranostics JT - Theranostics JID - 101552395 RN - 0 (Antineoplastic Agents) RN - 0 (Drug Carriers) RN - 0 (Indoles) RN - 0 (Isoindoles) RN - 0 (Organometallic Compounds) RN - 0 (Photosensitizing Agents) RN - 0 (Recombinant Proteins) RN - 0 (Serum Albumin) RN - 0 (Zinc Compounds) RN - 14320-04-8 (Zn(II)-phthalocyanine) RN - EC 3.4.21.73 (Urokinase-Type Plasminogen Activator) SB - IM MH - Animals MH - Antineoplastic Agents/chemistry/pharmacokinetics/therapeutic use MH - Cell Line, Tumor MH - Drug Carriers/*chemistry/pharmacokinetics/therapeutic use MH - Humans MH - Indoles/chemistry MH - Isoindoles MH - Male MH - Mice MH - Neoplasms, Experimental/diagnosis/*drug therapy MH - Organometallic Compounds/chemistry MH - *Photochemotherapy MH - Photosensitizing Agents/chemistry/pharmacokinetics/therapeutic use MH - Recombinant Proteins/chemistry/genetics MH - Serum Albumin/chemistry/genetics MH - *Tomography, Optical MH - Urokinase-Type Plasminogen Activator/chemistry/genetics MH - Zinc Compounds PMC - PMC3982134 OTO - NOTNLM OT - amino-terminal fragment of urokinase OT - fluorescent molecular tomography. OT - human serum albumin OT - phthalocyanine zinc OT - tumor targeting OT - urokinase receptor COIS- Competing Interests: The authors have declared that no competing interest exists. EDAT- 2014/04/12 06:00 MHDA- 2015/01/24 06:00 PMCR- 2014/01/01 CRDT- 2014/04/12 06:00 PHST- 2014/01/08 00:00 [received] PHST- 2014/03/05 00:00 [accepted] PHST- 2014/04/12 06:00 [entrez] PHST- 2014/04/12 06:00 [pubmed] PHST- 2015/01/24 06:00 [medline] PHST- 2014/01/01 00:00 [pmc-release] AID - thnov04p0642 [pii] AID - 10.7150/thno.8527 [doi] PST - epublish SO - Theranostics. 2014 Mar 24;4(6):642-59. doi: 10.7150/thno.8527. eCollection 2014.