In this work, we developed a new pH- and temperature-responsive nanochemotherapeutic system based on Doxorubicin (DOX) noncovalently bound to biosynthesized gelatin-coated gold nanoparticles ...(DOX-AuNPs@gelatin). The real-time release profile of DOX was evaluated at different pH values (7.4, 5.3, and 4.6) and temperatures (22–45 °C) in aqueous solutions, and its therapeutic performance was examined in vitro against MCF-7 breast cancer cells. TEM, dark-field scattering, and wide-field fluorescence microscopy indicated the effective uptake of nanochemotherapeutics with the subsequent release and progressive accumulation of DOX in cell nuclei. MTT assays clearly showed the effectiveness of the treatment by inhibiting the growth of MCF-7 breast cancer cells for a loaded drug concentration of 5 μg/mL. The most informative data about the dynamic release and localization were provided by scanning confocal microscopy using time-resolved fluorescence and surface-enhanced Raman scattering (SERS) techniques. In particular, fluorescence-lifetime imaging (FLIM) recorded under 485 nm pulsed diode laser excitation revealed the bimodal distribution of DOX in cells. The shorter fluorescence lifetime of DOX localized in nuclei (1.52 ns) than in the cytoplasm (2.4 ns) is consistent with the cytotoxic mechanism induced by DOX–DNA intercalation. Remarkably, the few DOX molecules captured between nanoparticles (“electromagnetic hotspots”) after most drug is released act as SERS reporters for the localization of plasmonic nanocarriers in MCF-7 cells. The high drug loading capacity and effective drug release under pH control combined with the advantage of multimodal visualization inside cells clearly indicate the high potential of our DOX–AuNPs@gelatin delivery system for implementation in nanomedicine.
In this study we present a clean, nontoxic, environmentally friendly synthesis procedure to generate a large variety of gold nanoparticles (GNPs) by using chitosan, a biocompatible, biodegradable, ...natural polymer, as reducing and stabilizing agent. The formation of gold-chitosan nanocomposites was characterized by UV-vis absorption spectroscopy, transmission electron microscopy (TEM), x-ray diffraction (XRD) and Raman spectroscopy. The results show that the reaction temperature plays a crucial role in controlling the size, shape and crystalline structure of GNPs. In addition, it is demonstrated that chitosan can perform as a scaffold for the assembly of GNPs, which were successfully applied as substrate for surface-enhanced Raman scattering (SERS). To test the SERS activity, a relevant biological molecule--tryptophan--was adopted as the analyte.
In recent times, researchers have aimed for new strategies to combat cancer by the implementation of nanotechnologies in biomedical applications. This work focuses on developing protein-based ...nanoparticles loaded with a newly synthesized NIR emitting and absorbing phthalocyanine dye, with photodynamic and photothermal properties. More precisely, we synthesized highly reproducible bovine serum albumin-based nanoparticles (75% particle yield) through a two-step protocol and successfully encapsulated the NIR active photosensitizer agent, achieving a good loading efficiency of 91%. Making use of molecular docking simulations, we confirm that the NIR photosensitizer is well protected within the nanoparticles, docked in site I of the albumin molecule. Encouraging results were obtained for our nanoparticles towards biomedical use, thanks to their negatively charged surface (−13.6 ± 0.5 mV) and hydrodynamic diameter (25.06 ± 0.62 nm), favorable for benefitting from the enhanced permeability and retention effect; moreover, the MTT viability assay upholds the good biocompatibility of our NIR active nanoparticles. Finally, upon irradiation with an NIR 785 nm laser, the dual phototherapeutic effect of our NIR fluorescent nanoparticles was highlighted by their excellent light-to-heat conversion performance (photothermal conversion efficiency 20%) and good photothermal and size stability, supporting their further implementation as fluorescent therapeutic agents in biomedical applications.
Colorectal cancer remains one of the most frequent malignancies (third place at both genders) worldwide in the last decade, owing to significant changes in modern dietary habits. Approximately half ...of the patients develop metastases during the course of their disease. The available therapeutic armamentarium is constantly evolving, raising questions regarding the best approach for improving survival. Bevacizumab remains one of the most widely used therapies for treating metastatic colorectal cancer and can be used after progression. This study aimed to identify the best chemotherapy partner for bevacizumab after progression. We performed a retrospective analysis of patients with metastatic colorectal cancer who were treated with bevacizumab as first- and second-line chemotherapy. Data were collected for 151 patients, 40 of whom were treated with double-dose bevacizumab after the first progression. The two standard chemotherapy regimens combined with bevacizumab were FOLFIRI/CAPIRI and FOLFOX4/CAPEOX. The initiation of first-line treatment with irinotecan-based chemotherapy improved progression-free survival and time to treatment failure but not overall survival. After the first progression, retreatment with the same regimen as that used in the induction phase was the best approach for improving overall survival (median overall survival: 46.5 vs. 27.0 months for the same vs. switched strategy, respectively). No correlations were observed between the dose intensity of irinotecan, oxaliplatin, 5-fluorouracil, or bevacizumab and the overall survival, progression-free survival in the first-/second-line treatment, and time to treatment failure. Interaction between an irinotecan-based regimen as a second-line treatment and double-dose bevacizumab after progression was associated with an improved overall survival (p = 0.06). Initiating systemic treatment with an irinotecan-based regimen in combination with bevacizumab improved the progression-free survival in the first-line treatment and time to treatment failure. In terms of overall survival, bevacizumab treatment after the first progression is better partnered with the same regimen as that used in the induction phase.
Anthracycline treatments are known to cause cardiotoxic long-term side effects in cancer survivors. Recently, a decrease in heart rate variability (HRV) has been identified in these patients, ...signaling autonomic dysfunction and altered cardiac fitness. This study aimed at evaluating changes in HRV in children treated with anthracyclines. A total of 35 pediatric patients with acute lymphoblastic leukemia were evaluated by means of a 24 h Holter ECG, at baseline and after reaching half the total cumulative dose of doxorubicin equivalent (120 mg/m2). Parameters of HRV were assessed, as well as any arrhythmic episodes, bradycardia and tachycardia percentages. The results showed a significant decrease in both time-domain and frequency-domain HRV parameters, following anthracycline treatment. The low-frequency (LF) to high-frequency (HF) parameters’ ratio also displayed a significant difference (p = 0.035), suggestive of early cardiac autonomic dysfunction. Of note, none of the patients presented symptoms of heart disease or elevated troponins, and only two patients presented echocardiographic signs of diastolic dysfunction. The present study showed that cardiac autonomic nervous system regulation is compromised in children treated with anthracyclines even before reaching the total cumulative dose. Therefore, HRV parameters could be the first indicators of subclinical cardiac toxicity, making Holter ECG monitoring of the oncological patient a necessity.
Colorectal cancer (CRC) is the third most common cancer in Europe, with an annual increase in incidence ranging between 0.4 and 3.6% in various countries. Although the development of CRC was ...extensively studied, limited number of new therapies were developed in the last few years. Bevacizumab is frequently used as first- and second-line therapy for management of metastatic CRC (mCRC). The aim of this study is to present our experience with using bevacizumab beyond disease progression at different dosage levels in mCRC patients, in terms of overall survival, progression-free survival, time to treatment failure, and toxicities.
We performed a consecutive retrospective analysis of patients with confirmed mCRC who were treated with bevacizumab at "Prof Dr. Ion Chiricuta" Institute of Oncology, Cluj-Napoca, Romania. We included patients who had received bevacizumab as first- or second-line therapy and further stratified them according to the dose administered as a second-line (either standard dose of 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks, or double dose of 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks-depending on the classical chemotherapy partner). All patients had received bevacizumab beyond progression (BYP) which is defined as continuing bevacizumab administration through second-line treatment despite disease progression. In each group, we evaluated the prognostic factors that influenced survival and treatment outcome.
One hundred and fifty-one (151) patients were included in the study. Themedian age of patients receiving double dose bevacizumab (DDB) and standard dose bevacizumab (SDB) was 58 years (range 41-71) and 57 years (range 19-75), respectively. The median overall survival in the DDB group was 41 months (range 27-49) compared to 25 months (range 23-29) in the SDB group (
= 0.01 log-rank test). First-line oxaliplatin-based treatment was used more frequently regardless of group, while irinotecan-based more frequently used as a second-line treatment (
= 0.014). Both oxaliplatin- and irinotecan-based regimens were found to be suitable partners for BYP. Statistical analysis revealed that dose intensity, primary tumor location, and cumulative exposure to BYP had significant influence on survival.
Doubling the dose of bevacizumab after first progression may improve survival in mCRC patients. Increasing bevacizumab dose intensity could override the prognostic impact of primary tumor location in patients receiving double the dose of bevacizumab after first disease progression.
In this work, we design new plasmonic paper-based nanoplatforms with interesting capabilities in terms of sensitivity, efficiency, and reproducibility for promoting multimodal biodetection via ...Localized Surface Plasmon Resonance (LSPR), Surface Enhanced Raman Spectroscopy (SERS), and Metal Enhanced Fluorescence (MEF). To succeed, we exploit the unique optical properties of gold nanobipyramids (AuBPs) deposited onto the cellulose fibers via plasmonic calligraphy using a commercial pen. The first step of the biosensing protocol was to precisely graft the previously chemically-formed p-aminothiophenol@Biotin system, as active recognition element for target streptavidin detection, onto the plasmonic nanoplatform. The specific capture of the target protein was successfully demonstrated using three complementary sensing techniques. As a result, while the LSPR based sensing capabilities of the nanoplatform were proved by successive 13-18 nm red shifts of the longitudinal LSPR associated with the change of the surface RI after each step. By employing the ultrasensitive SERS technique, we were able to indirectly confirm the molecular identification of the biotin-streptavidin interaction due to the protein fingerprint bands assigned to amide I, amide III, and Trp vibrations. Additionally, the formed biotin-streptavidin complex acted as a spacer to ensure an optimal distance between the AuBP surface and the Alexa 680 fluorophore for achieving a 2-fold fluorescence emission enhancement of streptavidin@Alexa 680 on the biotinylated nanoplatform compared to the same complex on bare paper (near the plasmonic lines), implementing thus a novel MEF sensing nanoplatform. Finally, by integrating multiple LSPR, SERS, and MEF nanosensors with multiplex capability into a single flexible and portable plasmonic nanoplatform, we could overcome important limits in the field of portable point-of-care diagnostics.
Metallic multilayer structures consisting of self-assembled nanoparticles are prepared by successive immersion of a functionalized glass substrate in a gold colloidal suspension, and are ...characterized by UV/Vis spectroscopy and atomic force microscopy. The ability of the thin film to concomitantly enhance the Raman and IR signals of an adsorbed molecule is evaluated and a detailed analysis of the recorded spectra is provided, which emphasizes the capability of these complementary methods to provide information about the adsorbed species. This unique surface-enhanced Raman spectroscopy (SERS) and surface-enhanced infrared absorption (SEIRA) substrate could be further used for applications in the elucidation of the structure of a great variety of adsorbed samples.
We designed a fluorescence resonance energy transfer system consisting of fluorophore Rhodamine B and gold nanoparticles for sensing of zinc ions in aqueous solution. The electrostatic attraction ...between positively charged N-atoms in Rhodamine molecules and negatively charged citrate corona of gold nanoparticles led to substantial fluorescence quenching. However, the quenching is switched off in the presence of zinc ions and therefore the system can be used as an effective "turn-on" fluorescence sensor. UV-Vis absorption, fluorescence spectroscopy, and transmission electron microscopy were used for sensor evaluation. The approach of "turn-on" fluorescence has real potential for sensing metallic ions in water.
•FT-IR technique confirmed the successful formation of the AuBPs-based immunosensor.•Theoretical calculations were performed to sustain the experimental results.•The SEIRA LOD of the immunosensor was ...determined to reach pM values.
Surface enhanced spectroscopies are proven to be highly efficient in biosensing applications. Their implementation as analytical tools in the detection of medically relevant target analytes demonstrated their ability to considerably decrease the minimum detected analyte concentration, thus showing improved sensitivity compared to commercially available detection kits. In this work, we propose the employment of Surface Enhanced Infrared Absorption (SEIRA), a less exploited analysis tool, for the efficient, specific, and ultrasensitive detection of the biotin-streptavidin recognition interaction using a gold nano-bipyramid-based (AuBPs) immunosensor. The unique optical properties of the AuBPs, such as tunability of the LSPR band ranging from the visible to NIR regions of the spectrum, great absorption capabilities and locally enhanced electromagnetic field at their tips and edges, enable an improved efficiency of the IR absorption of the target analytes. To the as-synthesized AuBPs, a chemically formed p-ATP@biotin recognition element was grafted due to the strong Au-S interaction, followed by the exposure of the obtained biotinylated nanosystem to the streptavidin target analyte. FT-IR experimental measurements as well as theoretical simulations confirm both the successful grafting of the p-ATP@biotin onto the Au surface and successful capture of the target streptavidin protein. A limit of detection of 10−12 M streptavidin concentration was determined, thus standing as a “proof-of-concept” for the development of efficient ultrasensitive SEIRA biosensing devices for more complex biologically relevant applications.
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