Thermal decomposition based synthesis of Ag-In-S/ZnS quantum dots and their chlorotoxin-modified micelles for brain tumor cell targeting

Abstract

Cadmium-free silver-indium-sulfide (Ag-In-S or AIS) chalcopyrite quantum dots (QDs) as well as their core-shell structures (AIS/ZnS QDs) are being paid significant attention in biomedical applications because of their low toxicity and excellent optical properties. Here we report a simple and safe synthetic system to prepare high quality AIS and AIS/ZnS QDs using thermal decomposition. The synthetic system simply involves heating a mixture of silver acetate, indium acetate, and oleic acid in dodecanethiol at 170 °C to produce AIS QDs with a 13% quantum yield (QY). After ZnS shell growth, the produced AIS/ZnS QDs achieve a 41% QY. To facilitate phase transfer and bioconjugation of AIS/ZnS QDs for cellular imaging, these QDs were loaded into the core of PLGA-PEG (5k:5k) based micelles to form AIS/ZnS QD-micelles. Cellular imaging studies showed that chlorotoxin-conjugated QD-micelles can be specifically internalized into U-87 brain tumor cells. This work discloses that the scalable synthesis of AIS/ZnS QDs and the facile surface/interface chemistry for phase transfer and bioconjugation of these QDs may open an avenue for the produced QD-micelles to be applied to the detection of endogenous targets expressed on brain tumor cells, or more broadly to cell- or tissue-based diagnosis and therapy.

Progress and perspectives on targeting nanoparticles for brain drug delivery

“…Chlorotoxin is a 36-amino acid long peptide that can target matrix matalloproteinase-2 in brain tumors 157 . After anchoring to NPs, these peptides could effectively enhance the genes, drugs and imaging probe delivery to brain tumor cells 158 , 159 , 160 , 161 , 162 , 163 , 164 . For example, chlorotoxin-coupled lipid NPs effectively delivered anti-miR-21 oligonucleotides to glioma and promoted miR-21 silencing, resulting in decreased tumor cell proliferation and improved animal survival 165 .…”

Brightly luminescent colloidal Ag–In–S nanoparticles stabilized in aqueous solutions by branched polyethyleneimine

“…In particular, big expectations are associated with ternary indium-based chalcopyrites [1,19,20], such as CuInS 2 and CuInS 2 /ZnS NPs [13][14][15][16]20], non-stoichiometric Cu-In-S [20,21] and Ag-In-S NPs [10], CuInS x Se 2-x NPs [22], AgInS 2 and AgInS 2 /ZnS NPs [9,11,23,24] that can also be produced by the well-known "hot injection" methods with the PL QY reaching 40-65% [1,14,21,22]. Such compounds combine a series of very attractive features, including relatively low toxicity and ability to preserve chalcopyrite structure in a broad range of NP sizes and non-stoichiometries [1,19,20,24,25].…”

“…Typically, the NP-containing assemblies are produced using microball-like polymer macromolecules capable of binding to the NP surface (for example polyethylene glycol [3,5,6,[9][10][11], phospholipids [12,13], various block-copolymers, DNAs, etc. [3,5]).…”

Chlorotoxin—A Multimodal Imaging Platform for Targeting Glioma Tumors

“…NIR dyes are poorly absorbed by water or hemoglobin thereby limiting the amount of interference from auto-fluorescence and optimizes signal intensity [51]. One such application is the complex Cy5.5-CTX composed of CTX conjugated to Cy5.5 [31,47]. Cy5.5-CTX demonstrated specific binding toward tumor cells, transfer across the BBB, and enabled the detection of metastatic cancer foci comprised of a few hundred cells.…”

“…The outer shell of the QD could be modified by organic layers including PEG polymers, phospholipids, and peptides [78], thus preventing nonspecific absorption of proteins to their surface, increase blood half-life, and reducing toxicity [79,80]. CTX conjugated with cadmium-free silver-indium-sulfide (Ag-In-S or AIS) chalcopyrite QDs was used in cellular imaging studies [47]. This CTX-conjugated QD-micelles exhibited specific internalization into U-87 brain tumor cells.…”