ABSTRACT
Nuclear-targeted therapy by delivering anticancer drug directly into cancer cell nuclei can elicit synergistic therapeutic effects and kill these cancer cells with much enhanced efficiencies. Besides nuclear targeting, another difficulty in nuclear-targeted therapy is how to achieve real-time monitoring of the therapy process simultaneously. In this article we report on the development of multifunctional upconversion nanoparticles (UCNPs) which were able to target cancer cell nuclei, and thus deliver the anticancer drug directly to the nuclear region and simultaneously image cell nucleus by magnetic resonance (MR)/upconversion fluorescent for real-time guidance of their therapeutic action simultaneously. The Er/Yb-doped NaYF(4) core and NaGdF(4) shell endow the core/shell structured UCNPs with enhanced upconversion fluorescent imaging and more sensitive T(1)-MR imaging performances, and the surface conjugation of TAT peptide served as a key role in the nuclear targeting and nuclear transport process. This multifunctional UCNPs-based nano-theranostic was used to improve the efficacy of DOX in Hela humor tumor models, by direct DOX delivery to the nucleus under the synchronous monitoring of the nano-theranostics. Further development of this technology may provide more exciting opportunities in treating cancer disease by nuclear-targeted therapy.
Subject(s)
Cell Nucleus/metabolism , Drug Delivery Systems , Magnetic Resonance Imaging/methods , Nanoparticles/chemistry , Neoplasms/drug therapy , Animals , Antineoplastic Agents/pharmacology , Contrast Media/pharmacology , Dose-Response Relationship, Drug , Doxorubicin/chemistry , HeLa Cells , Humans , Mice , Microscopy, Confocal/methods , Microscopy, Electron, Transmission/methods , Microscopy, Fluorescence/methods , Oleic Acid/chemistry , Peptides/chemistryABSTRACT
A total of 100 H1N1 flu real-time-PCR positive throat swabs collected from fever patients in Zhejiang, Hubei and Guangdong between June and November 2009, were provided by local CDC laboratories. After MDCK cell culture, 57 Influenza A Pandemic (H1N1) viruses were isolated and submitted for whole genome sequencing. A total of 39 HA sequences, 52 NA sequences, 36 PB2 sequences, 31 PB1 sequences, 40 PA sequences, 48 NP sequences, 51 MP sequences and 36 NS sequences were obtained, including 20 whole genome sequences. Sequence comparison revealed they shared a high degree of homology (96%-99%) with known epidemic strains (A/California/04/2009(H1N1). Phylogenetic analysis showed that although the sequences were highly conserved, they clustered into a small number of groups with only a few distinct strains. Site analysis revealed three substitutions at loop 220 (221-228) of the HA receptor binding site in the 39 HA sequences: A/Hubei/86/2009 PKVRDQEG â PKVRDQEA, A/Zhejiang/08/2009 PKVRDQEG â PKVRDQER, A/Hubei/75/2009 PKVRDQEG â PKVRDQGG, the A/Hubei/75/2009 was isolated from an acute case, while the other two were from patients with mild symptoms. Other key sites such as 119, 274, 292 and 294 amino acids of NA protein, 627 of PB2 protein were conserved. Meanwhile, all the M2 protein sequences possessed the Ser32Asn mutation, suggesting that these viruses were resistant to adamantanes. Comparison of these sequences with other H1N1 viruses collected from the NCBI database provides insight into H1N1 transmission and circulation patterns.
