title: Suppression of pancreatic tumor growth by targeted arsenic delivery with anti-CD44v6 single chain antibody conjugated nanoparticles.
abstract: Arsenic trioxide (As2O3) is a promising anticancer agent for solid tumors. However, the high toxicity to normal tissues resulting from the lack of tumor specificity remains a huge challenge in its systemic application. Targeted vectors enabling drug delivery to specific cancer cells bring about great potential for better therapeutic efficacy whereas low side effects in cancer treatments. Our previous work has demonstrated that the anti-CD44v6 single chain variable fragment (scFv(CD44v6)) screened out from the human phage-displayed scFv library possesses high specificity and affinity to membrane antigen CD44v6 over-expressing in a subset of epithelium-derived cancers, such as pancreatic, hepatocellular, colorectal and gastric cancers. Herein, a maleimide-functionalized amphiphilic diblock copolymer of poly (ethylene glycol) and poly (D, L-lactide) (mal-PEG-PDLLA) was synthesized and assembled to vesicles with arsenite ion (As) encapsulated in their cores (As-NPs). Conjugation of scFv(CD44v6) with mal-PEG-PDLLA (scFv-As-NPs) enabled more efficient delivery of As and exhibited higher cytotoxic activity than non-targeted ones (As-NPs) in human pancreatic cancer cells PANC-1. Furthermore, the targeted delivery of As induced more significant gene suppression in terms of the expression of anti-apoptotic Bcl-2 protein. Consequently, the expression level of cleaved caspase-3 which is a molecular indicator of cell apoptosis was remarkably elevated. In animal tests, scFv-As-NPs were found to greatly increase accumulation of drug in tumor site and potentiate the efficacy of As in inhibiting tumor growth owing to the enhanced cell apoptosis. These results imply that our tumor specific nanocarriers provide a highly efficient and safe platform for pancreatic cancer therapy.
authors.affiliation: Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
authors.forename: Chenchen
authors.initials: C
authors.lastname: Qian
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Yinting
authors.initials: Y
authors.lastname: Chen
authors.forename: Linjuan
authors.initials: L
authors.lastname: Zeng
authors.forename: Qiubo
authors.initials: Q
authors.lastname: Zhang
authors.forename: Xintao
authors.initials: X
authors.lastname: Shuai
authors.forename: Kaihong
authors.initials: K
authors.lastname: Huang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D001151:Arsenic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000737:chemistry / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D010179:Pancreas / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D057127:Single-Chain Antibodies / Q000737:chemistry / Q000276:immunology*
chemical_list: D000970:Antineoplastic Agents; C112697:CD44v6 antigen; D018960:Hyaluronan Receptors; D057127:Single-Chain Antibodies; D001151:Arsenic