Stimuli-responsive nanoparticles with target capacity are of great interest in drug delivery for cancer therapy. However, the challenge is to achieve highly smart release with precise spatiotemporal control for cancer therapy. Herein, we report the preparation and properties of multi-stimuli-responsive nanoparticles through the co-assembly of a 3-arm star quaterpolymer with a near-infrared (NIR) photothermal agent and chemotherapeutic compound. The nanoparticles can exhibit NIR light/pH/reduction-responsive drug release and intracellular drug translocation in cancer cells, which further integrate photoinduced hyperthermia for synergistic anticancer efficiency, thereby leading to tumor ablation without tumor regrowth. Thus, this rational design of nanoparticles with multiple responsiveness represents a versatile strategy to provide smart drug delivery paradigms for cancer therapy.
Stimuli-responsive nanostructures have shown great promise for intracellular delivery of anticancer compounds. A critical challenge remains in the exploration of stimuli-responsive nanoparticles for fast cytoplasmic delivery. Herein, near-infrared (NIR) light-responsive nanoparticles were rationally designed to generate highly efficient cytoplasmic delivery of anticancer agents for synergistic thermo-chemotherapy. The drug-loaded polymeric nanoparticles of selenium-inserted copolymer (I/D-Se-NPs) were rapidly dissociated in several minutes through reactive oxygen species (ROS)-mediated selenium oxidation upon NIR light exposure, and this irreversible dissociation of I/D-Se-NPs upon such a short irradiation promoted continuous drug release. Moreover, I/D-Se-NPs facilitated cytoplasmic drug translocation through ROS-triggered lysosomal disruption and thus resulted in highly preferable distribution to the nucleus even in 5 min postirradiation, which was further integrated with light-triggered hyperthermia for achieving synergistic tumor ablation without tumor regrowth.
Photothermal therapy (PTT) is of particular importance as a highly potent therapeutic modality in cancer therapy. However, a critical challenge still remains in the exploration of highly effective strategy to maximize the PTT efficiency due to tumor thermoresistance and thus frequent tumor recurrence. Here, a rational fabrication of the micelles that can achieve mutual synergy of PTT and molecularly targeted therapy (MTT) for tumor ablation is reported. The micelles generate both distinct photothermal effect from Cypate through enhanced photothermal conversion efficiency and pH-dependent drug release. The micelles further exhibit effective cytoplasmic translocation of 17-allylamino-17-demethoxygeldanamycin (17AAG) through reactive oxygen species mediated lysosomal disruption caused by Cypate under irradiation. Translocated 17AAG specifically bind with heat shock protein 90 (HSP90), thereby inhibiting antiapoptotic p-ERK1/2 proteins for producing preferable MTT efficiency through early apoptosis. Meanwhile, translocated 17AAG molecules further block stressfully overexpressed HSP90 under irradiation and thus inhibit the overexpression of p-Akt for achieving the reduced thermoresistance of tumor cells, thus promoting the PTT efficiency through boosting both early and late apoptosis of Cypate. Moreover, the micelles possess enhanced resistance to photobleaching, preferable cellular uptake, and effective tumor accumulation, thus facilitating mutually synergistic PTT/MTT treatments with tumor ablation. These findings represent a general approach for potent cancer therapy.
Clinically, intra-articular administration can hardly achieve the truly targeted therapy, and the drugs are usually insufficient to show local and long-term therapeutic effects because of their rapid clearance. Herein, inspired by the phenomenon that bees track the scent of flowers to collect nectar, we developed cartilage-targeting hydrogel microspheres with reactive oxygen species (ROS)-responsive ability via combining the microfluidic method and photopolymerization processes to integrate cartilagetargeting peptides and ROS-responsive nanoparticles in the hydrogel matrix. The hydrogel microspheres with cartilage-targeting properties promoted better retention in the joint cavity and enhanced cellular uptake of the nanoparticles. Moreover, the ROSresponsive nanoparticles could react with osteoarthritis (OA)-induced intracellular ROS, resulting in the depolymerization of nanoparticles, which could not only eliminate excess ROS and reduce inflammation but also promote the release of dexamethasone (Dex) and kartogenin (KGN) in situ, realizing effective OA therapy. It was demonstrated that this hydrogel microsphere showed favorable ROS-responsive ability and enhanced chondrogenic differentiation as well as the downregulation of pro-inflammatory factors in vitro. Additionally, the hydrogel microspheres, similar to bees, could target and effectively repair cartilage in the OA model. Thus, the injectable hydrogel microspheres exerted an excellent potential to repair OA and may also provide an effective avenue for inflammatory bowel disease therapy.
Local minimally invasive injection of anticancer therapies is a compelling approach to maximize the utilization of drugs and reduce the systemic adverse drug effects. However, the clinical translation is still hampered by many challenges such as short residence time of therapeutic agents and the difficulty in achieving multi‐modulation combination therapy. Herein, mesoporous silica‐coated gold nanorods (AuNR@SiO2) core‐shell nanoparticles are fabricated to facilitate drug loading while rendering them photothermally responsive. Subsequently, AuNR@SiO2 is anchored into a monodisperse photocrosslinkable gelatin (GelMA) microgel through one‐step microfluidic technology. Chemotherapeutic drug doxorubicin (DOX) is loaded into AuNR@SiO2 and 5,6‐dimethylxanthenone‐4‐acetic acid (DMXAA) is loaded in the microgel layer. The osteosarcoma targeting ligand alendronate is conjugated to AuNR@SiO2 to improve the tumor targeting. The microgel greatly improves the injectability since they can be dispersed in buffer and the injectability and degradability are adjustable by microfluidics during the fabrication. The drug release can, in turn, be modulated by multi‐round light‐trigger. Importantly, a single super low drug dose (1 mg kg−1 DOX with 5 mg kg−1 DMXAA) with peritumoral injection generates long‐term therapeutic effect and significantly inhibited tumor growth in osteosarcoma bearing mice. Therefore, this nanocomposite@microgel system can act as a peritumoral reservoir for long‐term effective osteosarcoma treatment.
Photothermal therapy (PTT) and photodynamic therapy (PDT) have emerged as highly prospective therapeutic modalities in cancer therapy. Notwithstanding, a critical challenge still remains in the exploration of an effective strategy to maximize the synergistic efficacy of PTT and PDT due to low photoconversion efficiency. Herein, inspired by the phospholipid bimolecular structure of the cell membrane, bionic cell membrane polymeric vesicles with photothermal/photodynamic synergy for prostate cancer therapy at one wavelength’s excitation are constructed in one step by the coordination of hexadecyl trimethyl ammonium bromide (CTAB) from the surface of hydrophobic gold nanorods (AuNRs) with indocyanine green (ICG) and polycaprolactone (PCL), achieving their self-assembly in aqueous solutions. Importantly, the aggregation of the assembly improves the stability of the vesicles, realizing the synergistic effect of PTT and PDT for prostate cancer therapy. After being assembled within polymeric vesicles, bifunctional photosensitizer ICG can generate reactive oxygen species (ROS) and photothermal effect under light treatment. Their ROS not only induce PDT efficacy but also destroy the integrity of the lysosomal membrane, promoting the translocation of ICG and another photosensitizer called gold nanorods (AuNRs) into the cytosol. Moreover, their photothermal effects produced by both photosensitizers are able to engender greater damage to the tumor cells because of the close distance with organelles. This structure manifests good cellular uptake, highly effective tumor accumulation, high photothermal conversion efficiency, and excellent properties of enhanced photobleaching resistance, which are beneficial to ICG-based fluorescence tumor imaging. Using the same near-infrared (NIR) wavelength for excitation, the AuNR/ICG vesicles can reduce the side effect rate of photodamage on the skin. In addition, by generating reactive oxygen species (ROS) and double photothermal effect, the vesicles under NIR excitation can promote the apoptosis of PC3 tumor cells. Taken together, the spontaneous self-assembled AuNR/ICG vesicles exhibit huge potential in advanced-stage prostate cancer therapy, especially for the prostate-specific membrane antigen (PSMA)-negative castration-resistant subtype.
Although great promise has been achieved with nanomedicines in cancer therapy, limitations are still encountered, such as short retention time in the tumor. Herein, a nanosystem that can modulate the particle size in situ by near‐infrared (NIR) light is self‐assembled by cross‐linking the surface‐modified poly(lactic‐co‐glycolic acid) from the up‐conversion nanoparticle with indocyanine green and doxorubicin–nitrobenezene–polyethylene glycol (DOX–NB–PEG). The nanosystem with its small size (≈100 nm) achieves better tumor targeting, while the PEG on the surface of the nanosystem can effectively shield the adsorption of proteins during blood circulation, maintaining a stable nanostructure and achieving good tumor targeting. Moreover, the nanosystem at the tumor realizes the rapid shedding of PEG on its surface by NIR irradiation, and the enhanced cellular uptake. At the same time, aggregation occurs inside the nanosystem to form bigger particles (≈600 nm) in situ, prolonging the retention time at the tumor and producing enhanced targeted therapeutic effects. In vitro data show higher cellular uptake and a higher rate of apoptosis after irradiation, and the in vivo data prove that the nanosystem have a longer residence time at the tumor site after NIR irradiation. This nanosystem demonstrates an effective therapeutic strategy in targeted synergistic tumors.
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