Bio-orthogonal click chemistry strategy for PD-L1-targeted imaging and pyroptosis-mediated chemo-immunotherapy of triple-negative breast cancer.

BACKGROUND: The combination of programmed cell death ligand-1 (PD-L1) immune checkpoint blockade (ICB) and immunogenic cell death (ICD)-inducing chemotherapy has shown promise in cancer immunotherapy. However, triple-negative breast cancer (TNBC) patients undergoing this treatment often face obstacles such as systemic toxicity and low response rates, primarily attributed to the immunosuppressive tumor microenvironment (TME). METHODS AND RESULTS: In this study, PD-L1-targeted theranostic systems were developed utilizing anti-PD-L1 peptide (APP) conjugated with a bio-orthogonal click chemistry group. Initially, TNBC was treated with azide-modified sugar to introduce azide groups onto tumor cell surfaces through metabolic glycoengineering. A PD-L1-targeted probe was developed to evaluate the PD-L1 status of TNBC using magnetic resonance/near-infrared fluorescence imaging. Subsequently, an acidic pH-responsive prodrug was employed to enhance tumor accumulation via bio-orthogonal click chemistry, which enhances PD-L1-targeted ICB, the pH-responsive DOX release and induction of pyroptosis-mediated ICD of TNBC. Combined PD-L1-targeted chemo-immunotherapy effectively reversed the immune-tolerant TME and elicited robust tumor-specific immune responses, resulting in significant inhibition of tumor progression. CONCLUSIONS: Our study has successfully engineered a bio-orthogonal multifunctional theranostic system, which employs bio-orthogonal click chemistry in conjunction with a PD-L1 targeting strategy. This innovative approach has been demonstrated to exhibit significant promise for both the targeted imaging and therapeutic intervention of TNBC.

Recent Progress of Multifunctional Molecular Probes for Triple-Negative Breast Cancer Theranostics.

Breast cancer (BC) poses a significant threat to women's health, with triple-negative breast cancer (TNBC) representing one of the most challenging and aggressive subtypes due to the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Traditional TNBC treatments often encounter issues such as low drug efficiency, limited tumor enrichment, and substantial side effects. Therefore, it is crucial to explore novel diagnostic and treatment systems for TNBC. Multifunctional molecular probes (MMPs), which integrate target recognition as well as diagnostic and therapeutic functions, introduce advanced molecular tools for TNBC theranostics. Using an MMP system, molecular drugs can be precisely delivered to the tumor site through a targeted ligand. Real-time dynamic monitoring of drug release achieved using imaging technology allows for the evaluation of drug enrichment at the tumor site. This approach enables accurate drug release, thereby improving the therapeutic effect. Therefore, this review summarizes the recent advancements in MMPs for TNBC theranostics, encompassing the design and synthesis of MMPs as well as their applications in the field of TNBC theranostics.

Recent Progress on Second Near-Infrared Emitting Carbon Dots in Biomedicine.

Second near-infrared (NIR-II) carbon dots, with absorption or emission between 1000 and 1700 nm, are gaining increasing attention in the biomaterial field due to their distinctive properties, which include straightforward preparation processes, stable photophysical characteristics, excellent biocompatibility, and low cost. As a result, there is a growing focus on the controlled synthesis and modulation of the photochemical and photophysical properties of NIR-II carbon dots, with the aim to further expand their biomedical applications, a current research hotspot. This account aims to provide a comprehensive overview of the recent advancements in NIR-II carbon dots within the biomedical field. The review will cover the following topics: (i) the design, synthesis, and purification of NIR-II carbon dots, (ii) the surface modification strategies, and (iii) the biomedical applications, particularly in the domain of cancer theranostics. Additionally, this account addresses the challenges encountered by NIR-II carbon dots and will outline future directions in the realm of cancer theranostics. By exploring carbon-based NIR-II biomaterials, we can anticipate that this contribution will garner increased attention and contribute to the development of next-generation advanced functional carbon dots, thereby offering enhanced tools and strategies in the biomedical field.

Recent Advances of Photoactive Near-Infrared Carbon Dots in Cancer Photodynamic Therapy.

Photodynamic therapy (PDT) is a treatment that employs exogenously produced reactive oxygen species (ROS) to kill cancer cells. ROS are generated from the interaction of excited-state photosensitizers (PSs) or photosensitizing agents with molecular oxygen. Novel PSs with high ROS generation efficiency is essential and highly required for cancer photodynamic therapy. Carbon dots (CDs), the rising star of carbon-based nanomaterial family, have shown great potential in cancer PDT benefiting from their excellent photoactivity, luminescence properties, low price, and biocompatibility. In recent years, photoactive near-infrared CDs (PNCDs) have attracted increasing interest in this field due to their deep therapeutic tissue penetration, superior imaging performance, excellent photoactivity, and photostability. In this review, we review recent progress in the designs, fabrication, and applications of PNCDs in cancer PDT. We also provide insights of future directions in accelerating the clinical progress of PNCDs.

Combined Photothermal and Photodynamic Therapy for Cancer Treatment Using a Multifunctional Graphene Oxide.

Graphene oxide (GO) is one of the most studied nanomaterials in many fields, including the biomedical field. Most of the nanomaterials developed for drug delivery and phototherapies are based on noncovalent approaches that lead to an unspecific release of physisorbed molecules in complex biological environments. Therefore, preparing covalently functionalized GO using straightforward and versatile methods is highly valuable. Phototherapies, including photothermal therapy (PTT) and photodynamic therapy (PDT), have shown great potential as effective therapeutic approaches against cancer. To overcome the limits of a single method, the combination of PTT and PDT can lead to a combined effect with a higher therapeutic efficiency. In this work, we prepare a folic acid (FA) and chlorin e6 (Ce6) double-functionalized GO for combined targeted PTT/PDT. This conjugate can penetrate rapidly into cancer cells and macrophages. A combined effect of PTT and PDT is observed, leading to a higher killing efficiency toward different types of cells involved in cancer and other diseases. Our work provides a simple protocol to prepare multifunctional platforms for the treatment of various diseases.

Comparative Effects of Graphene and Molybdenum Disulfide on Human Macrophage Toxicity.

Graphene and other 2D materials, such as molybdenum disulfide, have been increasingly used in electronics, composites, and biomedicine. In particular, MoS2 and graphene hybrids have attracted a great interest for applications in the biomedical research, therefore stimulating a pertinent investigation on their safety in immune cells like macrophages, which commonly engulf these materials. In this study, M1 and M2 macrophage viability and activation are mainly found to be unaffected by few-layer graphene (FLG) and MoS2 at doses up to 50 µg mL-1 . The uptake of both materials is confirmed by transmission electron microscopy, inductively coupled plasma mass spectrometry, and inductively coupled plasma atomic emission spectroscopy. Notably, both 2D materials increase the secretion of inflammatory cytokines in M1 macrophages. At the highest dose, FLG decreases CD206 expression while MoS2 decreases CD80 expression. CathB and CathL gene expressions are dose-dependently increased by both materials. Despite a minimal impact on the autophagic pathway, FLG is found to increase the expression of Atg5 and autophagic flux, as observed by Western blotting of LC3-II, in M1 macrophages. Overall, FLG and MoS2 are of little toxicity in human macrophages even though they are found to trigger cell stress and inflammatory responses.

Controlled functionalization of carbon nanodots for targeted intracellular production of reactive oxygen species.

Controlled intracellular release of exogenous reactive oxygen species (ROS) is an innovative and efficient strategy for cancer treatment. Well-designed materials, which can produce ROS in targeted cells, minimizing side effects, still need to be explored as new generation nanomedicines. Here, red-emissive carbon nanodots (CNDs) with intrinsic theranostic properties are devised, and further modified with folic acid (FA) ligand through a controlled covalent functionalization for targeted cell imaging and intracellular production of ROS. We demonstrated that covalent functionalization is an effective strategy to prevent the aggregation of the dots, leading to superior colloidal stability, enhanced luminescence and ROS generation. Indeed, the functional nanodots possess a deep-red emission and good dispersibility under physiological conditions. Importantly, they show excellent targeting properties and generation of high levels of ROS under 660 nm laser irradiation, leading to efficient cell death. These unique properties enable FA-modified carbon nanodots to act as a multifunctional nanoplatform for simultaneous targeted imaging and efficient photodynamic therapy to induce cancer cell death.

Physically-triggered nanosystems based on two-dimensional materials for cancer theranostics.

There is an increasing demand to develop effective methods for treating malignant diseases to improve healthcare in our society. Stimuli-responsive nanosystems, which can respond to internal or external stimuli are promising in cancer therapy and diagnosis due to their functionality and versatility. As a newly emerging class of nanomaterials, two-dimensional (2D) nanomaterials have attracted huge interest in many different fields including biomedicine due to their unique physical and chemical properties. In the past decade, stimuli-responsive nanosystems based on 2D nanomaterials have been widely studied, showing promising applications in cancer therapy and diagnosis, including phototherapies, magnetic therapy, drug and gene delivery, and non-invasive imaging. Here, we will focus our attention on the state-of-the-art of physically-triggered nanosystems based on graphene and two-dimensional nanomaterials for cancer therapy and diagnosis. The physical triggers include light, temperature, magnetic and electric fields.

Supramolecular assembly of fluorogenic glyco-dots from perylenediimide-based glycoclusters for targeted imaging of cancer cells.

Supramolecular self-assembly between perylenediimide-based glycoclusters and a red-emitting fluorophore produces structurally uniform and stable glyco-dots amenable to targeted fluorogenic imaging of liver and triple-negative breast cancer cells.

Receptor-targeting fluorescence imaging and theranostics using a graphene oxide based supramolecular glycocomposite.

Intercellular glycoligand-receptor interactions are implicated in a number of disease-related processes. Effective tools that target these receptors may facilitate disease theranostics. However, owing to their low binding affinity, multivalent presentation of glycoligands is needed to increase the avidity with transmembrane receptors. While previous strategies focus on the covalent coupling of glycoligands to a synthetic backbone, we show here that the use of graphene oxide (GO) greatly enhances the cellular and tissue imaging ability of a small-molecule fluorescence glycoprobe. We determine that GO with an optimum size may serve as a clustering platform to reinforce the interaction of the glycoprobe with its selective receptor on a cancer cell. This phenomenon has been consistently observed with the xenograft tissue of a tumor-bearing mouse. Using this principle we have further constructed a supramolecular glycocomposite by co-assembling the glycoprobe and an anticancer drug onto a single GO surface. In addition to imaging ability, this material displays improved toxicity for liver cancer cells that over express the glycoprotein receptor, when compared to the control cells.