Single pulse nanosecond laser‐stimulated targeted delivery of anti‐cancer drugs from hybrid lipid nanoparticles containing 5 nm gold nanoparticles

ABSTRACT: Encapsulating chemotherapeutic drugs like doxorubicin (DOX) inside lipid nanoparticles (LNPs) can overcome their acute, systematic toxicity. However, a precise drug release at the tumor microenvironment for improving the maximum tolerated dose and reducing side effects has yet to be well-established by implementing a safe stimuli-responsive strategy. This study proposes an integrated nanoscale perforation to trigger DOX release from hybrid plasmonic multilamellar LNPs composed of 5 nm gold (Au) NPs clustered at the internal lamellae interfaces. To promote site-specific DOX release, a single pulse irradiation strategy is developed by taking advantage of the resonant interaction between nanosecond pulsed laser radiation (527 nm) and the plasmon mode of the hybrid nanocarriers. This approach enlarges the amount of DOX in the target cells up to 11-fold compared to conventional DOX-loaded LNPs, leading to significant cancer cell death. The simulation of the pulsed laser interactions of the hybrid nanocarriers suggests a release mechanism mediated by either explosive vaporization of thin water layers adjacent to AuNP clusters or thermo-mechanical decomposition of overheated lipid layers. This simulation indicates an intact DOX integrity following irradiation since the temperature distribution is highly localized around AuNP clusters and highlights a controlled light-triggered drug delivery system

Insights into Theranostic Properties of Titanium Dioxide for Nanomedicine

Titanium dioxide (TiO(2)) nanostructures exhibit a broad range of theranostic properties that make them attractive for biomedical applications. TiO(2) nanostructures promise to improve current theranostic strategies by leveraging the enhanced quantum confinement, thermal conversion, specific surface area, and surface activity. This review highlights certain important aspects of fabrication strategies, which are employed to generate multifunctional TiO(2) nanostructures, while outlining post-fabrication techniques with an emphasis on their suitability for nanomedicine. The biodistribution, toxicity, biocompatibility, cellular adhesion, and endocytosis of these nanostructures, when exposed to biological microenvironments, are examined in regard to their geometry, size, and surface chemistry. The final section focuses on recent biomedical applications of TiO(2) nanostructures, specifically evaluating therapeutic delivery, photodynamic and sonodynamic therapy, bioimaging, biosensing, tissue regeneration, as well as chronic wound healing. [Image: see text

Intracellular Drug Delivery with Anodic Titanium Dioxide Nanotubes and Nanocylinders

Titanium dioxide (TiO2) holds remarkable promises for developing current theranostic strategies. Anodic TiO2 nanostructures as a porous scaffold have offered a broad range of useful theranostic properties; however, previous attempts to generate single and uniform TiO2 one-dimensional nanocarriers from anodic nanotube arrays have resulted in a broad cluster size distribution of arbitrarily broken tubes that are unsuitable for therapeutic delivery systems due to poor biodistribution and the risk of introducing tissue inflammation. Here, we achieve well-separated, uniformly shaped anodic TiO2 nanotubes and nanocylinders through a time-varying electrochemical anodization protocol that leads to the generation of planar sheets of weakly connected nanotubes with a defined fracture point near the base. Subsequent sonication cleanly detaches the nanotubes from the base. Depending on the position of the fracture point, we can fabricate single-anodic nanocylinders that are open on both ends and nanotubes that are closed on one end. We proceed to show that anodic nanotubes and nanocylinders are nontoxic at therapeutic concentrations. When conjugated with the anticancer drug doxorubicin using a pH-responsive linker, they are readily internalized by cells and subsequently release their drug cargo into acidic intracellular compartments. Our results demonstrate that uniformly sized anodic TiO2 nanotubes and nanocylinders are suitable for subcellular delivery of therapeutic agents in cancer therapy

Functionalized Hybrid Iron Oxide–Gold Nanoparticles Targeting Membrane Hsp70 Radiosensitize Triple-Negative Breast Cancer Cells by ROS-Mediated Apoptosis

Triple-negative breast cancer (TNBC) a highly aggressive tumor entity with an unfavorable prognosis, is treated by multimodal therapies, including ionizing radiation (IR). Radiation-resistant tumor cells, as well as induced normal tissue toxicity, contribute to the poor clinical outcome of the disease. In this study, we investigated the potential of novel hybrid iron oxide (Fe3O4)-gold (Au) nanoparticles (FeAuNPs) functionalized with the heat shock protein 70 (Hsp70) tumor-penetrating peptide (TPP) and coupled via a PEG4 linker (TPP-PEG4-FeAuNPs) to improve tumor targeting and uptake of NPs and to break radioresistance in TNBC cell lines 4T1 and MDA-MB-231. Hsp70 is overexpressed in the cytosol and abundantly presented on the cell membrane (mHsp70) of highly aggressive tumor cells, including TNBCs, but not on corresponding normal cells, thus providing a tumor-specific target. The Fe3O4 core of the NPs can serve as a contrast agent enabling magnetic resonance imaging (MRI) of the tumor, and the nanogold shell radiosensitizes tumor cells by the release of secondary electrons (Auger electrons) upon X-ray irradiation. We demonstrated that the accumulation of TPP-PEG4-FeAuNPs into mHsp70-positive TNBC cells was superior to that of non-conjugated FeAuNPs and FeAuNPs functionalized with a non-specific, scrambled peptide (NGL). After a 24 h co-incubation period of 4T1 and MDA-MB-231 cells with TPP-PEG4-FeAuNPs, but not with control hybrid NPs, ionizing irradiation (IR) causes a cell cycle arrest at G2/M and induces DNA double-strand breaks, thus triggering apoptotic cell death. Since the radiosensitizing effect was completely abolished in the presence of the ROS inhibitor N-acetyl-L-cysteine (NAC), we assume that the TPP-PEG4-FeAuNP-induced apoptosis is mediated via an increased production of ROS

Multiplexed Plasmonic Nano-Labeling for Bioimaging of Cytological Stained Samples

Reliable cytopathological diagnosis requires new methods and approaches for the rapid and accurate determination of all cell types. This is especially important when the number of cells is limited, such as in the cytological samples of fine-needle biopsy. Immunoplasmonic-multiplexed- labeling may be one of the emerging solutions to such problems. However, to be accepted and used by the practicing pathologists, new methods must be compatible and complementary with existing cytopathology approaches where counterstaining is central to the correct interpretation of immunolabeling. In addition, the optical detection and imaging setup for immunoplasmonic-multiplexed-labeling must be implemented on the same cytopathological microscope, not interfere with standard H&E imaging, and operate as a second easy-to-use imaging method. In this article, we present multiplex imaging of four types of nanoplasmonic markers on two types of H&E-stained cytological specimens (formalin-fixed paraffin embedded and non-embedded adherent cancer cells) using a specially designed adapter for SI dark-field microscopy. The obtained results confirm the effectiveness of the proposed optical method for quantitative and multiplex identification of various plasmonic NPs, and the possibility of using immunoplasmonic-multiplexed-labeling for cytopathological diagnostics