title: High-yield clicking and dissociation of doxorubicin nanoclusters exhibiting differential cellular uptakes and imaging.
abstract: Gold nanoparticles (AuNPs) and quantum dots (Qdots) were clicked into doxorubicin nanoclusters that showed enzyme-dependent dissociation behaviors for differential cellular uptakes and imaging. The AuNPs were co-functionalized with doxorubicin (DOX) and azide-terminated polymer (DOX/azide@AuNP), while an enzyme-cleavable peptide and alkyne-terminated polymer were sequentially conjugated on Qdot surface (Alkyne-MMP@Qdot). Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, and fluorescence imaging detected the azide and alkyne groups on DOX/azide@AuNP and Alkyne-MMP@Qdot, respectively, and the click-reactivity was also confirmed. In the presence of the catalyst, two nanoparticles were clicked to doxorubicin nanoclusters, which increased the volume of the particles ca. 343-fold within 30min. Upon matrix metalloproteinase-2 (MMP-2) digestion, the nanoclusters were clearly dissociated into smaller particles, and the fluorescence of the quenched Qdot was also recovered, which suggests that the nanoclusters respond to MMP-2 concentrations and can thus be employed for cancer imaging. Confocal microscopy and an elemental analysis of the cancer cells revealed that the cellular uptakes of doxorubicin nanoclusters significantly increased at higher MMP-2 concentrations, and doxorubicin could also be cleaved for anti-cancer effects. In vivo and in vitro cytotoxicity assay accordingly showed that the cytotoxicity of doxorubicin nanoclusters against cancer cells increased in MMP-2-rich environments such as tumor site. Thus, these nanoclusters containing DOX/azide@AuNP and Alkyne-MMP@Qdot are expected to be multifunctional carriers for targeted anti-cancer treatments and imaging.
authors: Department of Medical Biomaterials Engineering, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors: Hye Sung
authors: HS
authors: Kim
authors: Department of Medical Biomaterials Engineering, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors: Sujin
authors: S
authors: Yoon
authors: Department of Medical Biomaterials Engineering, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors: Young Ju
authors: YJ
authors: Son
authors: Department of Chemistry, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors: Yeonju
authors: Y
authors: Park
authors: Department of Chemistry, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors: Young Mee
authors: YM
authors: Jung
authors: Department of Medical Biomaterials Engineering, Kangwon National University, Chuncheon 200-701, Republic of Korea; Institute of Bioscience and Biotechnology, Kangwon National University, Republic of Korea. Electronic address: hsyoo@kangwon.ac.kr.
authors: Hyuk Sang
authors: HS
authors: Yoo
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology; D001386:Azides / Q000737:chemistry / Q000494:pharmacology; D001692:Biological Transport; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006046:Gold / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry / Q000494:pharmacology; D053768:Metal Nanoparticles / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D045663:Quantum Dots / Q000737:chemistry
chemical_list: D000903:Antibiotics, Antineoplastic; D001386:Azides; D004337:Drug Carriers; D006046:Gold; D004317:Doxorubicin; D020778:Matrix Metalloproteinase 2
keywords: Anti-cancer; Click reaction; Gold nanoparticle; Imaging; Quantum dot