Hashemkhani, M;
Demirci, G;
Bayir, A;
Muti, A;
Sennaroglu, A;
Mohammad-Hadi, L;
Yaghini, E;
... Yagci Acar, H; + view all
(2021)
Cetuximab-Ag₂S quantum dots for fluorescence imaging and highly effective combination of ALA-based photodynamic/chemo-therapy of colorectal cancer cells.
Nanoscale
, 13
(35)
pp. 14879-14899.
10.1039/d1nr03507j.
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Abstract
Colorectal cancer (CRC) has a poor prognosis and urgently needs better therapeutic approaches. 5-Aminolevulinic acid (ALA) induced protoprophyrin IX (PpIX) based photodynamic therapy (PDT) is already approved in the clinic for several cancers but not yet well investigated for CRC. Currently, systemic administration of ALA offers a limited degree of tumour selectivity, except for intracranial tumours, limiting its wider use in the clinic. Combination of effective ALA-PDT with chemotherapy may provide a promising alternative approach for CRC treatment. Herein, theranostic Ag2S quantum dots (AS-2MPA) optically trackable in near-infrared (NIR), conjugated with endothelial growth factor receptor (EGFR) targeting Cetuximab (Cet) and loaded with ALA for PDT monotherapy or ALA/5-fluorouracil (5FU) for the combination therapy is proposed for enhanced treatment of EGFR(+) CRC. AS-2MPA-Cet endowed excellent targeting of the high EGFR expressing cells and showed a strong intracellular signal for NIR optical detection in a comparative study performed on SW480, HCT116, and HT29 cells, which are high, medium and low EGFR expressers. Targeting provided enhanced uptake of the ALA loaded nanoparticles by strong EGFR expressing cells and formation of higher levels of PpIX. Cells also differ in their efficiency to convert ALA to PpIX, and SW480 was the best, followed by HT29, while HCT116 were determined as unsuitable for ALA-PDT. The therapeutic efficacy was evaluated in 2D cell cultures and 3D spheroids of SW480 and HT29 cells using AS-2MPA with either electrostatically loaded, hydrazone or amide linked ALA to achieve different levels of pH or enzyme sensitive release. Most effective phototoxicity was observed in SW480 cells using AS-2MPA-ALA-electrostatic-Cet due enhanced uptake of the particles, fast ALA release and effective ALA-to-PpIX conversion. Targeted delivery reduced the effective ALA concentration significantly which was further reduced with codelivery of 5FU. Delivery of ALA via covalent linkage was also effective for PDT, but required longer incubation time for the release of ALA in therapeutic doses. Phototoxicity was correlated with high levels of reactive oxygen species (ROS) and apoptotic/necrotic cell death. Hence, both AS-2MPA-ALA-Cet based PDT and AS-2MPA-ALA-Cet-5FU based Chemo/PDT combination therapy coupled with strong NIR tracking of the nanoparticles demonstrate an exceptional therapeutic effect on CRC cells and an excellent potential for synergistic multistage tumour targeting therapy.
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