Ultrasmall Carbon Nanodots as Theranostic Nanoheaters for Precision Breast Cancer Phototherapy: Establishing the Translational Potential in Tumor-in-a-Dish Models.

This study investigates the remarkable attributes of sulfur-doped carbon nanodots (CDs) synthesized in high yield and a narrow size distribution (4.8 nm). These CDs exhibit notable features, including potential bioelimination through renal clearance and efficient photothermal conversion in the near-infrared region with multicolor photoluminescence across the visible spectrum. Our research demonstrates high biocompatibility and effective near-infrared (NIR)-triggered photothermal toxicity when targeting mammospheres and patient-derived tumor organoids. Moreover, the study delves into the intricate cellular responses induced by CD-mediated hyperthermia. This involves efficient tumor mass death, activation of the p38-mitogen-activated protein kinase (MAPK) pathway, and upregulation of genes associated with apoptosis, hypoxia, and autophagy. The interaction of CDs with mammospheres reveals their ability to penetrate the complex microenvironment, impeded at 4 °C, indicating an energy-dependent endocytosis mechanism. This observation underscores the CDs' potential for targeted drug delivery, particularly in anticancer therapeutics. This investigation contributes to understanding the multifunctional properties of sulfur-doped CDs and highlights their promising applications in cancer therapeutics. Utilizing 3-D tumor-in-a-dish patients' organoids enhances translational potential, providing a clinically relevant platform for assessing therapeutic efficacy in a context mirroring the physiological conditions of cancerous tissues.

Gadolinium-Doped Carbon Nanodots as Potential Anticancer Tools for Multimodal Image-Guided Photothermal Therapy and Tumor Monitoring.

This study focuses on the synthesis and characterization of gadolinium-doped carbon nanodots (CDs-Gd) and their potential applications in multimodal imaging and precision cancer therapy. CDs-Gd were synthesized through a solvothermal decomposition method combining citric acid, GdCl3, and urea. The incorporation of Gd3+ ions within the carbonaceous structure resulted in stable CDs-Gd with a peculiar architecture that retained optical and paramagnetic properties. Combined characterization techniques confirmed the presence of pH-sensitive COOH functions on the CDs-Gd surface along with the unique lattice structure induced by Gd3+ doping. The optical properties of CDs-Gd exhibited a tunable emission spectrum displaying blue-green emission with pH-dependent behavior. Additionally, CDs-Gd exhibited contrast-enhancing properties in T1-weighted magnetic resonance imaging (MRI) experiments. MRI acquisitions at different Gd3+ concentrations and pH values demonstrated the potential of CDs-Gd as contrast agents for monitoring pH changes in an aqueous environment. We found that the relaxivity of CDs-Gd at pH 5.5 (tumor, 11.3 mM-1 s-1) is roughly 3-fold higher than that observed at pH 7.4 (physiological, 5.0 mM-1 s-1) and outperformed clinical standards such as γ-butyrol (3.3 mM-1 s-1). Monitoring pH changes in tumor microenvironment (TME) is crucial for evaluating the effectiveness of anticancer treatments and understanding tumor progression. Furthermore, CDs-Gd demonstrated concentration-dependent photothermal conversion ability in the near-infrared (NIR) region, allowing for efficient heat generation under laser irradiation. This indicates the potential application of CDs-Gd in image-guided photothermal therapy (IG-PTT) for cancer treatment. The in vitro studies on MCF-7 (breast cancer) and 16-HBE (healthy bronchial epithelium) cell lines demonstrated that CDs-Gd exhibited high biocompatibility (cell viability >80%). However, upon NIR activation, they showed potent anticancer effects by inhibiting tumor cell proliferation and inducing apoptosis selectively in cancer cells. In conclusion, the synthesized CDs-Gd nanoparticles possess unique optical, photothermal, and MRI contrast properties, making them promising candidates for multimodal imaging-guided precision cancer therapy applications.

Controlled delivery of sildenafil by ß-Cyclodextrin-decorated sulfur-doped carbon nanodots: a synergistic activation of ROS signaling in tumors overexpressing PDE-5.

Fluorescent sulfur- and nitrogen-doped carbon nanodots (CDs) are zero-dimensional nanoparticles that mediate ROS production in cancer cells, displaying inherent anticancer properties. Thus, they have been proposed as nanotheranostic tools useful in image-guided cancer therapy. Here, we try to show that cancerous cells (high PDE-5 expression) receiving sildenafil delivered by CDs-based nanostructures promote positive reinforcement of PDE-5-mediated cell death via the overexpression of genes involved in the production of ROS. We explored the regioselective Huisgen cycloaddition between azide-ß-cyclodextrin and CDs-alkyne to synthetize homogeneous nanostructures, named CDs-PEG4-ß-Cdx, consisting of CDs functionalized at the surface with ß-cyclodextrins capable of including high amount drugs such as sildenafil (>20 % w/w), and releasing them in a controlled manner. We investigated how CDs-PEG4-ß-Cdx bearing sildenafil enter cells, enhancing ROS production and cell death specifically in cancer cells overexpressing PDE-5. These nanoplatforms go beyond the bounds of EPR-based nanomedicines in which carriers are conceived as inert vehicles of toxic drugs. Our findings enable the development of clever anticancer nanoplatforms that synergistically combine nanomedicines that perturb the mitochondrial electron transport chain (ROS production) with PDE-5 inhibitors which trigger oxidative stress specifically in cancer cells regardless of their location.

Cholesterol-Inulin Conjugates for Efficient SN38 Nuclear Delivery: Nanomedicines for Precision Cancer Therapy.

An amphiphilic inulin-thiocholesterol conjugate (INU-Cys-TC) was strategically designed as a biodegradable core-shell nanocarrier of 7-ethyl-10-hydroxy-camptothecin (SN38) to enhance its solubility and stability in aqueous media, thus exploiting its brilliant anticancer effect. INU-Cys-TC was designed to have the hydrophilic inulin backbone (external shell) partially functionalized with hydrophobic thiocholesterol moieties (internal core) through a biodegradable disulfide bond due to cysteamine bridges. Thiocholesterol moieties impair redox-sensitive self-assembling abilities, yielding to nano-sized micelles in aqueous media capable of efficiently encapsulating a high amount of SN38 (DL = 8.1%). Micelles (INU-Cys-TC@SN38) were widely characterized, demonstrating an effective and stable delivery strategy to overcome the poor water-solubility of SN38. SN38-loaded micelles showed a gradual and prolonged release of SN38 over time, and a cell- and time-dependent cytotoxicity. In particular, we show that micelles efficiently deliver SN38 inside cell nuclei, and, compared to normal cell lines, they can also enter cancer cells by endo-lysosomes, where a complete degradation can occur releasing the drug payload. Overall, the proposed micelles appear potentially effective as nanomedicines for precision cancer therapies of colorectal and breast cancer, thus improving the SN38 therapeutic index and extending its use in a huge plethora of cancers.