Normal cell division needs the formation of a mitotic spindle apparatus, which is directly related to microtubule (MT) assembly. Thus, if the MT assembly is inhibited by tubulin-binding agents, the mitotic spindle functions will be perturbed, resulting in the inhibition of cell division at the metaphase/anaphase transition of mitosis. Therefore, tubulin-binding agents are anti-cancer drugs that can inhibit cell division by perturbing the MT assembly and cause cancer cell death. However, the current tubulin-binding anti-cancer drugs cannot specifically recognize cancer cells and serve as imaging probes. Our lab has recently used phage display technique to successfully identify two types of peptides: tubulin-binding peptides and SKBR-3 breast cancer cell-targeting/internalizing peptides. Moreover, we have developed expertise in the synthesis of lanthanide ion doped upconversion nanoparticles (UCNPs) and their utilization as cancer cell imaging probes. In contrast to the down-conversion nanoparticles such as the widely used quantum dots (QDs), the UCNPs can be excited by a longer wavelength light such as near infrared (NIR) light (e.g., 980 nm) to emit a shorter wavelength light (e.g., green light). Due to their ability to be excited by NIR light, whic can penetrate cells and tissues relatively deeply, UCNPs can be used for cell/tissue imaging without causing either autofluorescence from or photodamage to the biomolecules, cells and tissues. This project is based on these successes and will conjugate both tubulin-binding and cancer-targeting/internalizing peptides onto the surface of UCNPs. Our hypothesis is that core-shell upconversion nanoparticles (Rare-earth doped ?-NaYF4:Yb,Er upconversion nanocrystal as a core and silica as a shell) with both tubulin-binding and SKBR-3 breast cancer cell- targeting/internalizing peptides conjugated to the surface will (1) recognize the breast cancer cells and be internalized;(2) bind tubulins to interrupt intracellular MT assembly, inhibit cell proliferation and cause cell death in vitro and in vivo;and (3) enable the selective fluorescent imaging of the cancer cells and tumor tissues under NIR excitation. We will carry out two specific aims: (1) Aim 1: Evaluate the in vitro MT assembly in the presence of UCNPs with both tubulin-binding peptides and SKBR-3 cancer cell-targeting/internalizing peptides conjugated to the surface to understand how cell-targeting tubulin-binding UCNPs interrupt MT assembly in vitro. (2) Aim 2: Evaluate in vitro SKBR-3 breast cancer cell proliferation and cell cycle as well as in vitro and in vivo targeted cancer cell imaging and killing after SKBR-3 cells interact with the cell-targeting tubulin-binding UCNPs in vitro or in vivo. This project will advance the targete cancer treatment and diagnosis by developing targeted cancer imaging and therapeutic agents. The cancer-targeting tubulin-binding UCNPs developed in this project are multi-functional theranostic agents that can target and kill cancer cells and at the same time be fluorescently detected and tracked inside the cancer cells and tumor tissues.
The assembly of tubulins into microtubules is one of the very important processes involved in the division of cancer cells and an agent that can prevent the assembly of this process will likely inhibit cell division and cause cell death. This project will develop a multi-functional nanoparticle that can not only specifically recognize cancer cells, bind to the tubulins to interrupt their assembly into microtubules, and as a result, to inhibit cancer cll division and cause cancer cell death, but also emit visible light under near infrared excitation to enable the optical detection of the cancer cells and tumor tissues associated with the nanoparticle.
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|Li, Li-Hua; Li, Mei; Li, Dan et al. (2014) Chemical functionalization of bone implants with nanoparticle-stabilized chitosan and methotrexate for inhibiting both osteoclastoma formation and bacterial infection. J Mater Chem B Mater Biol Med 2:5952-5961|
|Liao, Jingwen; Zhu, Ye; Yin, Zhaoyi et al. (2014) Tuning nano-architectures and improving bioactivity of conducting polypyrrole coating on bone implants by incorporating bone-borne small molecules. J Mater Chem B Mater Biol Med 2014:7872-7876|
|Cao, Binrui; Xu, Hong; Mao, Chuanbin (2014) Phage as a template to grow bone mineral nanocrystals. Methods Mol Biol 1108:123-35|
|Wang, Jianglin; Yang, Mingying; Zhu, Ye et al. (2014) Phage nanofibers induce vascularized osteogenesis in 3D printed bone scaffolds. Adv Mater 26:4961-6|
|Rajala, Ammaji; Wang, Yuhong; Zhu, Ye et al. (2014) Nanoparticle-assisted targeted delivery of eye-specific genes to eyes significantly improves the vision of blind mice in vivo. Nano Lett 14:5257-63|
|Hao, Lijing; Yang, Hui; Du, Chang et al. (2014) Directing the fate of human and mouse mesenchymal stem cells by hydroxyl-methyl mixed self-assembled monolayers with varying wettability. J Mater Chem B Mater Biol Med 2:4794-4801|
|Li, Xin; Mao, Chuanbin (2014) Using phage as a platform to select cancer cell-targeting peptides. Methods Mol Biol 1108:57-68|
|Cao, Binrui; Qiu, Penghe; Mao, Chuanbin (2013) Mesoporous iron oxide nanoparticles prepared by polyacrylic acid etching and their application in gene delivery to mesenchymal stem cells. Microsc Res Tech 76:936-41|
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