Mitochondrion- and nucleus-acting polymeric nanoagents for chemo-photothermal combination therapy

Abstract

Developing intrinsically mitochondria-targetable nanosystems for subcellular structure-oriented precise cancer therapy is highly desirable. Here, we conjugate the cluster determinant 44 (CD44)-targetable hyaluronic acid (HA) with cholesterol-poly(ethylene glycol) 2k -NH 2 and mitochondria-acting IR825-NH 2 (a cyanine dye) to construct a self-assembled nanostructure (abbreviated as HA-IR825-Chol) for photothermal therapy. The HA-IR825-Chol exhibits improved photostability and desirable photothermal properties, and can rapidly and substantially enter CD44-overexpressed cancer cells and selectively accumulate in the mitochondria of the cells. Upon near-infrared laser irradiation, it can induce severe mitochondrial damage, which causes cytochrome c release and triggers cell apoptosis. Furthermore, we demonstrate the feasibility of loading the chemotherapeutics 10-hydroxycamptothecin (HCPT) into the hydrophobic cores of HA-IR825-Chol NPs for combined chemophotothermal therapy. HCPT encapsulated within HA-IR825-Chol achieves significantly increased cellular uptake and simultaneous mitochondrial and nuclear localization, leading to the release of cytochrome c from mitochondria and upregulation of cleaved caspase-3, both of which contribute to the cell apoptosis/death. In vivo experiments reveal the excellent tumor-targeting ability of HA-IR825-Chol/HCPT, ensuring the efficient tumor eradication by the chemo-photothermal therapy. This work exemplifies the development of an intrinsically mitochondria-targetable nanocarrier for precise subcellular structure-localized drug delivery, and the Chol-mediated rapid and massive endocytosis of the nanoagents may represent a robust strategy for enhancing the efficacies of nanomedicines.

Mito‐Bomb: Targeting Mitochondria for Cancer Therapy

“…Chol, considered as a lipophilic anchor, was introduced into various nanosystems to enhance cellular uptake. [ 92,363 ] Liu and co‐workers conjugated the cyanine dye IR825‐NH 2 with HA and cholesterol‐PEG 2k ‐NH 2 to obtain a self‐assembled nanostructure, HA‐IR825‐Chol. [ 92 ] HA‐IR825‐Chol had excellent light stability, photothermal properties and water dispersibility.…”

“…[ 92,363 ] Liu and co‐workers conjugated the cyanine dye IR825‐NH 2 with HA and cholesterol‐PEG 2k ‐NH 2 to obtain a self‐assembled nanostructure, HA‐IR825‐Chol. [ 92 ] HA‐IR825‐Chol had excellent light stability, photothermal properties and water dispersibility. They were also preferentially accumulated in tumor cells owing to overexpression of HA.…”

NIR-absorbing superoxide radical and hyperthermia photogenerator via twisted donor-acceptor-donor molecular rotation for hypoxic tumor eradication

“…Nevertheless, rare efforts have been dedicated on developing highly photostable photothermal reagents with high PCE and large molar extinction coefficient at long irradiation wavelengths (e.g., 808 nm). Additionally, high cancer therapeutic efficacies could be achieved by the synergistic treatment of PTT with other therapeutic modalities [51][52][53][54][55]. In particular, several studies revealed that PTT showed an enhancement to the PDT efficacy for its ability to increase the blood flow rate [56][57][58].…”

Polymeric Nanoparticles for Mitochondria Targeting Mediated Robust Cancer Therapy

“…Enough internalization of IR780 dye in breast carcinoma cells treated with the modified nanoparticles, and subsequent NIRlaser irradiation dramatically resulted an imbalance of intracellular ROS and phototoxicity, which further induced cancer cells death. For instance, Liu et al constructed a HA and IR825 conjugated polymeric nanosystem based on cholesterol-PEG (Chol-PEG) and encapsulated chemotherapeutics 10-hydroxycamptothecin (HCPT) into this nanocarrier (HA-IR825-Chol/HCPT) for combined chemophotothermal therapy (Liu et al, 2020). It was found that HA-IR825-Chol/HCPT exhibited significantly enhanced accumulation in mitochondria, obviously upregulated apoptosis-related proteins, and demonstrated an amplified synergistic combination therapeutic efficacy, all of which were built on the basis of IR825-mediated mitochondria targeting.…”