title: Superior Performance of Aptamer in Tumor Penetration over Antibody: Implication of Aptamer-Based Theranostics in Solid Tumors.
abstract: Insufficient penetration of therapeutic agents into tumor tissues results in inadequate drug distribution and lower intracellular concentration of drugs, leading to the increase of drug resistance and resultant failure of cancer treatment. Targeted drug delivery to solid tumors followed by complete drug penetration and durable retention will significantly improve clinical outcomes of cancer therapy. Monoclonal antibodies have been commonly used in clinic for cancer treatment, but their limitation of penetrating into tumor tissues still remains because of their large size. Aptamers, as "chemical antibodies", are 15-20 times smaller than antibodies. To explore whether aptamers are superior to antibodies in terms of tumor penetration, we carried out the first comprehensive study to compare the performance of an EpCAM aptamer with an EpCAM antibody in theranostic applications. Penetration and retention were studied in in vitro three-dimensional tumorspheres, in vivo live animal imaging and mouse colorectal cancer xenograft model. We found that the EpCAM aptamer can not only effectively penetrate into the tumorsphere cores but can also be retained by tumor sphere cells for at least 24 h, while limited tumor penetration by EpCAM antibody was observed after 4 h incubation. As observed from in vivo live animal imaging, EpCAM aptamers displayed a maximum tumor uptake at around 10 min followed by a rapid clearance after 80 min, while the signal of peak uptake and disappearance of antibody appeared at 3 h and 6 h after intravenous injection, respectively. The signal of PEGylated EpCAM aptamers in xenograft tumors was sustained for 26 h, which was 4.3-fold longer than that of the EpCAM antibody. Consistently, there were 1.67-fold and 6.6-fold higher accumulation of PEGylated aptamer in xenograft tumors than that of antibody, at 3 h and 24 h after intravenous administration, respectively. In addition, the aptamer achieved at least a 4-time better tumor penetration in xenograft tumors than that of the antibody at a 200 μm distances from the blood vessels 3 h after intravenous injection. Taken together, these data indicate that aptmers are superior to antibodies in cancer theranostics due to their better tumor penetration, more homogeneous distribution and longer retention in tumor sites. Thus, aptamers are promising agents for targeted tumor therapeutics and molecular imaging.
authors.affiliation: 1. School of Medicine, Deakin University, Pigdons Road, Waurn Ponds, Victoria 3216, Australia.
authors.forename: Dongxi
authors.initials: D
authors.lastname: Xiang
authors.affiliation: 2. Department of Biology, Medical College, Dalian University, Liaoning, People's Republic of China.
authors.forename: Conglong
authors.initials: C
authors.lastname: Zheng
authors.affiliation: 3. Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL 33612, USA.
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Zhou
authors.affiliation: 4. Department of Pharmacology and Toxicology, College of Pharmacy and Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA.
authors.forename: Shuxi
authors.initials: S
authors.lastname: Qiao
authors.affiliation: 1. School of Medicine, Deakin University, Pigdons Road, Waurn Ponds, Victoria 3216, Australia.
authors.forename: Phuong Ha-Lien
authors.initials: PH
authors.lastname: Tran
authors.affiliation: 5. Dalian 6th People's Hospital, 269 Huibai Road, Lugang, Ganjingzi District, Dalian, Liaoning 116031, The People's Republic of China.
authors.forename: Chunwen
authors.initials: C
authors.lastname: Pu
authors.affiliation: 6. Cancer Care Centre, St George Hospital and St George Clinical School, University of New South Wales (UNSW), Kensington, NSW2052, Australia.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.affiliation: 7. Institute for Frontier Materials, Deakin University, 75 Pigdons Road, Waurn Ponds, Victoria, 3216, Australia.
authors.forename: Lingxue
authors.initials: L
authors.lastname: Kong
authors.affiliation: 8. School of Engineering, Deakin University, 75 Pigdons Road, Waurn Ponds, Victoria 3216, Australia.
authors.forename: Abbas Z
authors.initials: AZ
authors.lastname: Kouzani
authors.affiliation: 9. Department of Biochemistry and Molecular Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, P. R. China, 610041.
authors.forename: Jia
authors.initials: J
authors.lastname: Lin
authors.affiliation: 10. College of Life Sciences, Sichuan University, Chengdu, P. R. China, 610041.
authors.forename: Ke
authors.initials: K
authors.lastname: Liu
authors.affiliation: 11. Liaoning Key Laboratory of Cancer Stem Cell Research, Dalian Medical University, Dalian, China, 116044.
authors.forename: Lianhong
authors.initials: L
authors.lastname: Li
authors.affiliation: 1. School of Medicine, Deakin University, Pigdons Road, Waurn Ponds, Victoria 3216, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Shigdar
authors.affiliation: 1. School of Medicine, Deakin University, Pigdons Road, Waurn Ponds, Victoria 3216, Australia.
authors.forename: Wei
authors.initials: W
authors.lastname: Duan
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000493:pharmacokinetics; D052157:Aptamers, Nucleotide / Q000737:chemistry / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods*; D005260:Female; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D000068936:Theranostic Nanomedicine / Q000295:instrumentation / Q000379:methods*; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D052157:Aptamers, Nucleotide
keywords: aptamer; targeted tumor therapeutics; tumor penetration