Molecular Engineering of Activatable NIR-II Hemicyanine Reporters for Early Diagnosis and Prognostic Assessment of Inflammatory Bowel Disease.

Molecular imaging in the second near-infrared window (NIR-II) provides high-fidelity visualization of biopathological events in deep tissue. However, most NIR-II probes produce "always-on" output and demonstrate poor signal specificity toward biomarkers. Herein, we report a series of hemicyanine reporters (HBCs) with tunable emission to NIR-II window (715-1188 nm) and structurally amenable to constructing activatable probes. Such manipulation of emission wavelengths relies on rational molecular engineering by integrating benz[c,d]indolium, benzo[b]xanthonium, and thiophene moieties to a conventional hemicyanine skeleton. In particular, HBC4 and HBC5 possess bright and record long emission over 1050 nm, enabling improved tissue penetration depth and superior signal to background ratio for intestinal tract mapping than NIR-I fluorophore HC1. An activatable inflammatory reporter (AIR-PE) is further constructed for pH-triggered site-specific release in colon. Due to minimized background interference, oral gavage of AIR-PE allows clear delineation of irritated intestines and assessment of therapeutic responses in a mouse model of inflammatory bowel disease (IBD) through real-time NIRF-II imaging. Benefiting from its high fecal clearance efficiency (>90%), AIR-PE can also detect IBD and evaluate the effectiveness of colitis treatments via in vitro optical fecalysis, which outperforms typical clinical assays including fecal occult blood testing and histological examination. This study thus presents NIR-II molecular scaffolds that are not only applicable to developing versatile activatable probes for early diagnosis and prognostic monitoring of deeply seated diseases but also hold promise for future clinical translations.

Iron-chelated semiconducting oligomer nanoparticles for NIR-II fluorescence imaging-guided enhanced chemodynamic/photothermal combination therapy.

Chemodynamic therapy (CDT) has attracted increasing attention owing to its high tumor specificity and low number of side effects. However, the low absolute concentration of reactive oxygen species (ROS) within tumor cells restricts the CDT efficacy. Herein, we use dihydroartemisinin (DHA) to enhance the CDT efficacy and combine photothermal therapy (PTT) to further improve the anticancer effect. To achieve such a goal, an iron-containing semiconducting oligomer nanoparticle (DHA@FePSOD) is prepared by loading DHA into a Fe3+-chelated NIR-II fluorescent semiconducting oligomer (FePSOD). The Fe3+ ion within DHA@FePSOD can be reduced to the Fe2+ ion by glutathione (GSH) and subsequently catalyze the decomposition of hydrogen peroxide (H2O2) into the highly toxic hydroxyl radical (˙OH) for CDT. The loaded DHA may be further reduced by Fe2+ and generate a DHA radical to enhance the CDT efficacy. In addition, DHA@FePSOD shows a good photothermal effect and intense NIR-II fluorescence signal under 808 nm laser irradiation. Both in vitro and in vivo studies prove the better anticancer effect of DHA@FePSOD than FePSOD, which is attributed to the loaded DHA. Furthermore, DHA@FePSOD can effectively accumulate into a tumor and delineate the tumor via NIR-II fluorescence imaging. This study thus provides an efficient approach for developing a NIR-II fluorescence imaging-guided enhanced chemodynamic/photothermal combination therapeutic nanoplatform.

Prolonging Treatment Window of Photodynamic Therapy with Self-Amplified H2 O2 -Activated Photodynamic/Chemo Combination Therapeutic Nanomedicines.

Photodynamic therapy (PDT) is a promising approach to cancer therapy. However, the relatively short tumor retention time of photosensitizers (PSs) makes it difficult to catch the optimal treatment time and restricts multiple PDT within a single injection. In this study, a tumor-specific phototheranostic nanomedicine (DPPa NP) is developed for photodynamic/chemo combination therapy with a prolonged PDT treatment window. DPPa NP is prepared via encapsulating a hydrophobic oxidized bovine serum albumin (BSA-SOH)-conjugatable PS DPPa with amphiphilic H2 O2 -activatable chlorambucil (CL) prodrug mPEG-TK-CL. The released CL under H2 O2 treatment can not only kill tumor cells but also upregulate reactive oxygen species levels within tumor cells, leading to the almost full release of cargoes. The released DPPa may conjugate with overexpressed BSA-SOH, which results in the recovery of the fluorescence signal and photodynamic effect. More importantly, such conjugation transfers DPPa from a small molecule PS into a macromolecular PS with a long tumor retention time and treatment window of PDT, which enables multiple PDT. This study thus provides an effective strategy to prolong the treatment window of PDT and enables tumor-specific fluorescence imaging-guided combination therapy.

A targeted activatable NIR-II nanoprobe for positive visualization of anastomotic thrombosis and sensitive identification of fresh fibrinolytic thrombus.

Anastomotic thrombosis prevalently causes anastomosis failure, accompanied with ischemia and necrosis, the early diagnosis of which is restricted by inherent shortcomings of traditional imaging techniques in clinic and lack of appropriate prodromal biomarkers for thrombosis initiation. Herein, a fresh thrombus-specific molecular event, protein disulfide isomerase (PDI) is innovatively chosen as the activating factor, and a thrombosis targeting and PDI-responsive turn-on near infrared II (NIR-II) fluorescence nanoprobe is firstly developed. The supramolecular complex-based nanoprobe IR806-PDA@BSA-CREKA is fabricated by assembling NIR-II emitting cyanine derivative IR806-PDA with bovine serum albumin (BSA), which could ameliorate the stability and pharmacokinetics of the nanoprobe, addressing the contradiction in the balance of brightness and biocompatibility. The NIR-II-off nanoprobe exhibits robust turn-on NIR-II fluorescence upon PDI-specific activation, in vitro and in vivo. Of note, the constructed nanoprobe demonstrates superior photophysical stability, efficient fibrin targeting peptide-derived thrombosis binding and a maximum signal-to-background ratio (SBR) of 9.30 for anastomotic thrombosis in NIR-II fluorescent imaging. In conclusion, the exploited strategy enables positive visualized diagnosis for anastomotic thrombosis and dynamic monitoring for thrombolysis of fresh fibrinolytic thrombus, potentially contributes a novel strategy for guiding the therapeutic selection between thrombolysis and thrombectomy for thrombosis treatment in clinic.

A Renal-Clearable PEGylated Semiconducting Oligomer for the NIR-II Fluorescence Imaging of Tumor.

Second near-infrared window fluorescence imaging (NIR-II FI) has attracted tremendous attention in bioimaging. Until now, most probes for NIR-II FI are nanomaterials that are metabolized via hepatobiliary metabolism. Such a metabolic pathway may take several months, causing long-term toxicity. Herein, we design and synthesize a renal-clearable PEGylated semiconducting oligomer (PSO) for the NIR-II FI of tumor. PSO is composed of a semiconducting oligomer (SO) backbone as an NIR-II fluorescence reporter and four poly(ethylene glycol) (PEG) side chains as water-soluble enhancers. PSO can emit an NIR-II fluorescence signal with the maximum emission at 1000 nm under the excitation of 808 nm light. PSO shows good biocompatibility and can be partially cleared out of body via renal clearance. PSO can be utilized for the NIR-II FI of tumor as it can effectively accumulate into tumor.

Peptide-based semiconducting polymer nanoparticles for osteosarcoma-targeted NIR-II fluorescence/NIR-I photoacoustic dual-model imaging and photothermal/photodynamic therapies.

BACKGROUND: The overall survival rate of osteosarcoma (OS) patients has not been improved for 30 years, and the diagnosis and treatment of OS is still a critical issue. To improve OS treatment and prognosis, novel kinds of theranostic modalities are required. Molecular optical imaging and phototherapy, including photothermal therapy (PTT) and photodynamic therapy (PDT), are promising strategies for cancer theranostics that exhibit high imaging sensitivity as well as favorable therapeutic efficacy with minimal side effect. In this study, semiconducting polymer nanoparticles (SPN-PT) for OS-targeted PTT/PDT are designed and prepared, using a semiconducting polymer (PCPDTBT), providing fluorescent emission in the second near-infrared window (NIR-II, 1000 - 1700 nm) and photoacoustic (PA) signal in the first near-infrared window (NIR-I, 650 - 900 nm), served as the photosensitizer, and a polyethylene glycolylated (PEGylated) peptide PT, providing targeting ability to OS. RESULTS: The results showed that SPN-PT nanoparticles significantly accelerated OS-specific cellular uptake and enhanced therapeutic efficiency of PTT and PDT effects in OS cell lines and xenograft mouse models. SPN-PT carried out significant anti-tumor activities against OS both in vitro and in vivo. CONCLUSIONS: Peptide-based semiconducting polymer nanoparticles permit efficient NIR-II fluorescence/NIR-I PA dual-modal imaging and targeted PTT/PDT for OS.

Recent Advances in Crosslinked Nanogel for Multimodal Imaging and Cancer Therapy.

Nanomaterials have been widely applied in the field of cancer imaging and therapy. However, conventional nanoparticles including micelles and liposomes may suffer the issue of dissociation in the circulation. In contrast, crosslinked nanogels the structures of which are covalently crosslinked have better physiological stability than micelles and liposomes, making them more suitable for cancer theranostics. In this review, we summarize recent advances in crosslinked nanogels for cancer imaging and therapy. The applications of nanogels in drug and gene delivery as well as development of novel cancer therapeutic methods are first introduced, followed by the introduction of applications in optical and multimodal imaging, and imaging-guided cancer therapy. The conclusion and future direction in this field are discussed at the end of this review.