Ultrathin Polypyrrole Nanosheets via Space-Confined Synthesis for Efficient Photothermal Therapy in the Second Near-Infrared Window

Extensive efforts have been devoted to synthesizing photothermal agents (PTAs) that are active in the first near-infrared (NIR) region (650–950 nm). However, PTAs for photothermal therapy in the second NIR window (1000–1350 nm) are still rare. Here, it is shown that two-dimensional ultrathin polypyrrole (PPy) nanosheets prepared via a novel space-confined synthesis method could exhibit unique broadband absorption with a large extinction coefficient of 27.8 L g^–1 cm^–1 at 1064 nm and can be used as an efficient PTA in the second NIR window. This unique optical property is attributed to the formation of bipolaron bands in highly doped PPy nanosheets. The measured prominent photothermal conversion efficiency could achieve 64.6%, surpassing previous PTAs that are active in the second NIR window. Both in vitro and in vivo studies reveal that these ultrathin PPy nanosheets possess good biocompatibility and notable tumor ablation ability in the second NIR window. Our study highlights the potential of ultrathin two-dimensional polymers with unique optical properties in biomedical applications

Tumor Acidity/NIR Controlled Interaction of Transformable Nanoparticle with Biological Systems for Cancer Therapy

Precisely controlling the interaction of nanoparticles with biological systems (nanobio interactions) from the injection site to biological targets shows great potential for biomedical applications. Inspired by the ability of nanoparticles to alter their physicochemical properties according to different stimuli, we explored the tumor acidity and near-infrared (NIR) light activated transformable nanoparticle ^DATAT-NP_IR&DOX. This nanoparticle consists of a tumor acidity-activated TAT [the TAT lysine residues’ amines was modified with 2,3-dimethylmaleic anhydride (DA)], a flexible chain polyphosphoester core coencapsulated a NIR dye IR-780, and DOX (doxorubicin). The physicochemical properties of the nanoparticle can be controlled in a stepwise fashion using tumor acidity and NIR light, resulting in adjustable nanobio interactions. The resulting transformable nanoparticle ^DATAT-NP_IR&DOX efficiently avoids the interaction with mononuclear phagocyte system (MPS) (“stealth” state) due to the masking of the TAT peptide during blood circulation. Once it has accumulated in the tumor tissues, ^DATAT-NP_IR&DOX is reactivated by tumor acidity and transformed into the “recognize” state in order to promote interaction with tumor cells and enhance cellular internalization. Then, this nanoparticle is transformed into “attack” state under NIR irradiation, achieving the supersensitive DOX release from the flexible chain polyphosphoester core in order to increase the DOX–DNA interaction. This concept provides new avenues for the creation of transformable drug delivery systems that have the ability to control nanobio interactions

ROS-Sensitive Polymeric Nanocarriers with Red Light-Activated Size Shrinkage for Remotely Controlled Drug Release

Drug delivery systems with remotely controlled drug release capability are rather attractive options for cancer therapy. Herein, a reactive oxygen species (ROS)-sensitive polymeric nanocarrier TK-PPE@NP_Ce6/DOX was explored to realize remotely controlled drug release by light-activated size shrinkage. The TK-PPE@NP_Ce6/DOX encapsulating chlorin e6 (Ce6) and doxorubicin (DOX) was self-assembled from an innovative ROS-sensitive polymer TK-PPE with the assistance of an amphiphilic copolymer poly­(ethylene glycol)-<i>b</i>-poly­(ε-caprolactone) (PEG-<i>b</i>-PCL). Under the 660 nm red light irradiation, ROS generated by the encapsulated Ce6 were capable of cleaving the TK linker <i>in situ</i>, which resulted in the rapid degradation of the TK-PPE@NP_Ce6/DOX core. Consequently, the size of TK-PPE@NP_Ce6/DOX shrank from 154 ± 4 nm to 72 ± 3 nm, and such size shrinkage affected further triggered rapid DOX release. As evidenced by both <i>in vitro</i> and <i>in vivo</i> experiments, such ROS-sensitive polymeric nanocarriers with light-induced size shrinkage capability offer remarkable therapeutic effects in cancer treatment. This concept provides new avenues for the development of light-activated drug delivery systems for remotely controlled drug release <i>in vivo</i>

Enzyme Degradable Hyperbranched Polyphosphoester Micellar Nanomedicines for NIR Imaging-Guided Chemo-Photothermal Therapy of Drug-Resistant Cancers

Multidrug resistance (MDR) is the major cause for chemotherapy failure, which constitutes a formidable challenge in the field of cancer therapy. The synergistic chemo-photothermal treatment has been reported to be a potential strategy to overcome MDR. In this work, rationally designed enzyme-degradable, hyperbranched polyphosphoester nanomedicines were developed for reversing MDR via the codelivery of doxorubicin and IR-780 (hPPE_DOX&IR) as combined chemo-photothermal therapy. The amphiphilic hyperbranched polyphosphoesters with phosphate bond as the branching point were synthesized via a simple but robust one-step polycondensation reaction. The self-assembled hPPE_DOX&IR exhibited good serum stability, sustained release, preferable tumor accumulation, and enhanced drug influx of doxorubicin in resistant MCF-7/ADR cells. Moreover, the degradation of hPPE_DOX&IR was accelerated in the presence of alkaline phosphatase, which was overexpressed in various cancers, resulting in the fast release of encapsulated doxorubicin. The enzyme-degradable polymer generated synergistic chemo-photothermal cytotoxicity against MCF-7/ADR cells and, thus, the efficient ablation of DOX-resistant tumor without regrowth. This delivery system may open a new avenue for codelivery of chemo- and photothermal therapeutics for MDR tumor therapy

Hierarchical Multiplexing Nanodroplets for Imaging-Guided Cancer Radiotherapy via DNA Damage Enhancement and Concomitant DNA Repair Prevention

Clinical success of cancer radiotherapy is usually impeded by a combination of two factors, i.e., insufficient DNA damage and rapid DNA repair during and after treatment, respectively. Existing strategies for optimizing the radiotherapeutic efficacy often focus on only one facet of the issue, which may fail to function in the long term trials. Herein, we report a DNA-dual-targeting approach for enhanced cancer radiotherapy using a hierarchical multiplexing nanodroplet, which can simultaneously promote DNA lesion formation and prevent subsequent DNA damage repair. Specifically, the ultrasmall gold nanoparticles encapsulated in the liquid nanodroplets can concentrate the radiation energy and induce dramatic DNA damage as evidenced by the enhanced formation of γ-H2AX foci as well as <i>in vivo</i> tumor growth inhibition. Additionally, the ultrasound-triggered burst release of oxygen may relieve tumor hypoxia and fix the DNA radical intermediates produced by ionizing radiation, prevent DNA repair, and eventually result in cancer death. Finally, the nanodroplet platform is compatible with fluorescence, ultrasound, and magnetic resonance imaging techniques, allowing for real-time <i>in vivo</i> imaging-guided precision radiotherapy in an EMT-6 tumor model with significantly enhanced treatment efficacy. Our DNA-dual-targeting design of simultaneously enhancing DNA damage and preventing DNA repair presents an innovative strategy to effective cancer radiotherapy