Mitochondria-Localized Self-Reporting Small-Molecule-Decorated Theranostic Agents for Cancer-Organelle Transporting and Imaging

Abstract

Recently, fluorescent dyes with a structure-inherent mitochondria-targeting capability have obtained great attention as single-molecule self-reporting theranostic agents to distinguish cancer cells from normal cells. However, there was little attempt using these dyes as a self-reporting ligand for cancer-targeted delivery of nanomaterials or drugs for personalized therapy. Herein, we developed a mitochondria-localized multifunctional nanodelivery system for cancer-targeted drug delivery and dual-modal imaging. First, a series of cyanine-structural small molecules with different-charged substituent groups have been screened based on their mitochondria targeting capability. Furthermore, the cyanine-structural molecule with the best mitochondria-targeting ability was decorated on iron oxide nanoparticles (IONP) for dual-modal imaging. The nanoprobes entered into the cancer cell via the organic anion transporting polypeptide (OATP) pathway and anchored on mitochondria due to the strong interaction between the negative mitochondria membrane and the lipophilic cationic cyanine dye. This work opened an avenue using small molecules with structure-inherent-targeting and self-reporting characteristics as a chemical ligand to develop cancer-targeting and subcellular-localized delivery system.

MitoTracker Deep Red (MTDR) Is a Metabolic Inhibitor for Targeting Mitochondria and Eradicating Cancer Stem Cells (CSCs), With Anti-Tumor and Anti-Metastatic Activity In Vivo

“…Our results showed that all compounds tested were internalized after five days of treatment (Supplemental Figure S7). However, only Cy5-Alkyne and Cy5-Azide blocked 3D mammosphere growth and also targeted energized mitochondria in cancer cells (data not shown) within the nanomolar range, which is line with previous studies (33).…”

“…Therefore, one can speculate that this "nonselective", chemical intoxication by carbocyanines would presumably allow the avoidance of possible resistance to such broad, but yet organelle-specific, intoxication of cancer cell mitochondria. Indeed, after observing the Cy5-Alkyne mitochondrialdependent inhibition of breast CSCs, the same analog was found to show anti-tumor effect, both in in vitro and in vivo, in the nanomolar range (33), further confirming our findings. Interestingly, Cy5-NHS was found to successfully deliver nanoparticles and other compounds such as doxorubicin to mitochondria, and to retain their mitochondrial targeting of tumor cells.…”

“…OATP expression is positively regulated by the transcription factor of hypoxia induction factor 1 (HIF1a). Therefore, cellular hypoxia increases carbocyanine uptake in tumor cells via OATP (33,42), suggesting that hypoxic cancer cells would be more susceptible to carbocyanines, as compared to normoxic cells, and can be preferentially eliminated by using mitochondrially-targeted carbocyanine dyes.…”

Recent Advances in Cyanine-Based Phototherapy Agents

“…Cyanine derivatives, either indocyanine green ( Yuan et al, 2013 ) or heptamethine cyanine ( Shi et al, 2016 ), are the most preferred and promising ones since they induce both PDT and PTT. Additionally, some of the cyanine derivatives can be targeted to mitochondria due to their cationic lipophilic nature ( Weinberg and Chandel, 2015 ; Shi et al, 2016 ; Jung et al, 2017 ; Zhou et al, 2019 ). In the recent years, decorating these dyes with different heavy atoms improved the efficacy of the synergistic phototherapy by addressing the low singlet oxygen generation capacity of the cyanine cores ( Gorman et al, 2004 ; Atchison et al, 2017 ; Usama et al, 2018 ; Xu et al, 2019 ).…”

Reductase and Light Programmatical Gated DNA Nanodevice for Spatiotemporally Controlled Imaging of Biomolecules in Subcellular Organelles under Hypoxic Conditions

“…Once the constructed MOF@Y-apt entered the hypoxic cancer cells (Scheme ), MOF@Y-apt was degraded by the hypoxia-related high expressed reductase and thus cause the release of Y-apt. Significantly, cyanine dyes, such as Cy3, Cy5, and Cy5.5, possess the ability to specifically target mitochondria in cancer cells . Therefore, the released light-gated Y-apt can response to mitochondrial ATP and an output fluorescent signal under the targeting effect of cyanine dyes.…”