Graphene Quantum Dots Modified Upconversion Nanoparticles for Photodynamic Therapy

Photodynamic therapy (PDT), as a novel technique, has been extensively employed in cancer treatment by utilizing reactive oxygen species (ROS) to kill malignant cells. However, most photosensitizers (PSs) are short of ROS yield and affect the therapeutic effect of PDT. Thus, there is a substantial demand for the development of novel PSs for PDT to advance its clinical translation. In this study, we put forward a new strategy for PS synthesis via modifying graphene quantum dots (GQDs) on the surface of rare-earth elements doped upconversion nanoparticles (UCNPs) to produce UCNPs@GQDs with core-shell structure. This new type of PSs combined the merits of UCNPs and GQDs and produced ROS efficiently under near-infrared light excitation to trigger the PDT process. UCNPs@GQDs exhibited high biocompatibility and obvious concentration-dependent PDT efficiency, shedding light on nanomaterials-based PDT development.     

Recent Advances in the Photoreactions Triggered by Porphyrin-Based Triplet–Triplet Annihilation Upconversion Systems: Molecular Innovations and Nanoarchitectonics

Triplet–triplet annihilation upconversion (TTA-UC) is a very promising technology that could be used to convert low-energy photons to high-energy ones and has been proven to be of great value in various areas. Porphyrins have the characteristics of high molar absorbance, can form a complex with different metal ions and a high proportion of triplet states as well as tunable structures, and thus they are important sensitizers for TTA-UC. Porphyrin-based TTA-UC plays a pivotal role in the TTA-UC systems and has been widely used in many fields such as solar cells, sensing and circularly polarized luminescence. In recent years, applications of porphyrin-based TTA-UC systems for photoinduced reactions have emerged, but have been paid little attention. As a consequence, this review paid close attention to the recent advances in the photoreactions triggered by porphyrin-based TTA-UC systems. First of all, the photochemistry of porphyrin-based TTA-UC for chemical transformations, such as photoisomerization, photocatalytic synthesis, photopolymerization, photodegradation and photochemical/photoelectrochemical water splitting, was discussed in detail, which revealed the different mechanisms of TTA-UC and methods with which to carry out reasonable molecular innovations and nanoarchitectonics to solve the existing problems in practical application. Subsequently, photoreactions driven by porphyrin-based TTA-UC for biomedical applications were demonstrated. Finally, the future developments of porphyrin-based TTA-UC systems for photoreactions were briefly discussed.     

Self-Assembled BODIPY Derivative with A-D-A Structure as Organic Nanoparticles for Photodynamic/Photothermal Cancer Therapy

Organic nanomaterials have attracted considerable attention in the area of photodynamic and photothermal therapy, owing to their outstanding biocompatibility, potential biodegradability, well-defined chemical structure, and easy functionalization. However, it is still a challenge to develop a single organic molecule that obtains both photothermal and photodynamic effects. In this contribution, we synthesized a new boron-dipyrromethene (BODIPY)-based derivative (DPBDP) with an acceptor–donor–acceptor (A-D-A) structure by coupling 3,6-di(2-thienyl)-2,5-dihydropyrrolo [3,4-c] pyrrole-1,4-dione (DPP) and BODIPY. To enhance the hydrophilicity of the BODIPY derivative, the polyethylene glycol (PEG) chains were introduced to the meso- position of BODIPY core. The amphiphilic DPBDP was then self-assembled into related nanoparticles (DPBDP NPs) with improved hydrophilicity and enhanced absorbance in the NIR region. DPBDP NPs could simultaneously generate the singlet oxygen (¹O₂) and heat under the irradiation of a single laser (690 nm). The ¹O₂ quantum yield and photothermal conversion efficiency (PCE) of DPBDP NPs were calculated to be 14.2% and 26.1%, respectively. The biocompatibility and phototherapeutic effect of DPBDP NPs were evaluated through cell counting kit-8 (CCK-8) assay. Under irradiation of 690 nm laser (1.0 W/cm²), the half maximal inhibitory concentration (IC₅₀) of DPBDP NPs was calculated to be 16.47 µg/mL. Thus, the as-prepared DPBDP NPs could be acted as excellent candidates for synergistic photodynamic/photothermal therapy.     

Design Principles of Hybrid Nanomaterials for Radiotherapy Enhanced by Photodynamic Therapy

Radiation (RT) remains the most frequently used treatment against cancer. The main limitation of RT is its lack of specificity for cancer tissues and the limited maximum radiation dose that can be safely delivered without damaging the surrounding healthy tissues. A step forward in the development of better RT is achieved by coupling it with other treatments, such as photodynamic therapy (PDT). PDT is an anti-cancer therapy that relies on the light activation of non-toxic molecules—called photosensitizers—to generate ROS such as singlet oxygen. By conjugating photosensitizers to dense nanoscintillators in hybrid architectures, the PDT could be activated during RT, leading to cell death through an additional pathway with respect to the one activated by RT alone. Therefore, combining RT and PDT can lead to a synergistic enhancement of the overall efficacy of RT. However, the involvement of hybrids in combination with ionizing radiation is not trivial: the comprehension of the relationship among RT, scintillation emission of the nanoscintillator, and therapeutic effects of the locally excited photosensitizers is desirable to optimize the design of the hybrid nanoparticles for improved effects in radio-oncology. Here, we discuss the working principles of the PDT-activated RT methods, pointing out the guidelines for the development of effective coadjutants to be tested in clinics.     

Sequential Release of Paclitaxel and Imatinib from Core–Shell Microparticles Prepared by Coaxial Electrospray for Vaginal Therapy of Cervical Cancer

To optimize the anti-tumor efficacy of combination therapy with paclitaxel (PTX) and imatinib (IMN), we used coaxial electrospray to prepare sequential-release core–shell microparticles composed of a PTX-loaded sodium hyaluronate outer layer and an IMN-loaded PLGA core. The morphology, size distribution, drug loading, differential scanning calorimetry (DSC), Fourier transform infrared spectra (FTIR), in vitro release, PLGA degradation, cellular growth inhibition, in vivo vaginal retention, anti-tumor efficacy, and local irritation in a murine orthotopic cervicovaginal tumor model after vaginal administration were characterized. The results show that such core–shell microparticles were of spherical appearance, with an average size of 14.65 μm and a significant drug-loading ratio (2.36% for PTX, 19.5% for IMN, w/w), which might benefit cytotoxicity against cervical-cancer-related TC-1 cells. The DSC curves indicate changes in the phase state of PTX and IMN after encapsulation in microparticles. The FTIR spectra show that drug and excipients are compatible with each other. The release profiles show sequential characteristics in that PTX was almost completely released in 1 h and IMN was continuously released for 7 days. These core–shell microparticles showed synergistic inhibition in the growth of TC-1 cells. Such microparticles exhibited prolonged intravaginal residence, a >90% tumor inhibitory rate, and minimal mucosal irritation after intravaginal administration. All results suggest that such microparticles potentially provide a non-invasive local chemotherapeutic delivery system for the treatment of cervical cancer by the sequential release of PTX and IMN.     

Theranostic Agent Combining Fullerene Nanocrystals and Gold Nanoparticles for Photoacoustic Imaging and Photothermal Therapy

Developing photoactivatable theranostic platforms with integrated functionalities of biocompatibility, targeting, imaging contrast, and therapy is a promising approach for cancer diagnosis and therapy. Here, we report a theranostic agent based on a hybrid nanoparticle comprising fullerene nanocrystals and gold nanoparticles (FGNPs) for photoacoustic imaging and photothermal therapy. Compared to gold nanoparticles and fullerene crystals, FGNPs exhibited stronger photoacoustic signals and photothermal heating characteristics by irradiating light with an optimal wavelength. Our studies demonstrated that FGNPs could kill cancer cells due to their photothermal heating characteristics in vitro. Moreover, FGNPs that are accumulated in tumor tissue via the enhanced permeation and retention effect can visualize tumor tissue due to their photoacoustic signal in tumor xenograft model mice. The theranostic agent with FGNPs shows promise for cancer therapy.     

The Enhancement of Antimicrobial Photodynamic Therapy of Escherichia Coli by a Functionalized Combination of Photosensitizers: In Vitro Examination of Single Cells by Quantitative Phase Imaging

The prevention of biofilm formation is crucial for the limitation of bacterial infections typically associated with postoperative infections, complications in bedridden patients, and a short-term prognosis in affected cancer patients or mechanically ventilated patients. Antimicrobial photodynamic therapy (aPDT) emerges as a promising alternative for the prevention of infections due to the inability of bacteria to become resistant to aPDT inactivation processes. The aim of this study was to demonstrate the use of a functionalized combination of Chlorin e6 and Pheophorbide as a new approach to more effective aPDT by increasing the accumulation of photosensitizers (PSs) within Escherichia coli cells. The accumulation of PSs and changes in the dry mass density of single-cell bacteria before and after aPDT treatment were investigated by digital holotomography (DHT) using the refractive index as an imaging contrast for 3D label-free live bacteria cell imaging. The results confirmed that DHT can be used in complex examination of the cell–photosensitizer interaction and characterization of the efficiency of aPDT. Furthermore, the use of Pheophorbide a as an efflux pomp inhibitor in combination with Chlorin e6 increases photosensitizers accumulation within E. coli and overcomes the limited penetration of Gram-negative cells by anionic and neutral photosensitizers.     

Labeling of Anti-MUC-1 Binding Single Chain Fv Fragments to Surface Modified Upconversion Nanoparticles for an Initial in Vivo Molecular Imaging Proof of Principle Approach

In vivo optical Imaging is an inexpensive and highly sensitive modality to investigate and follow up diseases like breast cancer. However, fluorescence labels and specific tracers are still works in progress to bring this promising modality into the clinical day-to-day use. In this study an anti-MUC-1 binding single-chain antibody fragment was screened, produced and afterwards labeled with newly designed and surface modified NaYF(4):Yb,Er upconversion nanoparticles as fluorescence reporter constructs. The MUC-1 binding of the conjugate was examined in vitro and in vivo using modified state-of-the-art small animal Imaging equipment. Binding of the newly generated upconversion nanoparticle based probe to MUC-1 positive cells was clearly shown via laser scanning microscopy and in an initial proof of principal small animal optical imaging approach.     

BaGdF5 Nanophosphors Doped with Different Concentrations of Eu3+ for Application in X-ray Photodynamic Therapy

X-ray photodynamic therapy (XPDT) has been recently considered as an efficient alternative to conventional radiotherapy of malignant tissues. Nanocomposites for XPDT typically consist of two components—a nanophosphor which re-emits X-rays into visible light that in turn is absorbed by the second component, a photosensitizer, for further generation of reactive oxygen species. In this study, BaGdF₅ nanophosphors doped with different Eu:Gd ratios in the range from 0.01 to 0.50 were synthesized by the microwave route. According to transmission electron microscopy (TEM), the average size of nanophosphors was ~12 nm. Furthermore, different coatings with amorphous SiO₂ and citrates were systematically studied. Micro-CT imaging demonstrated superior X-ray attenuation and sufficient contrast in the liver and the spleen after intravenous injection of citric acid-coated nanoparticles. In case of the SiO₂ surface, post-treatment core–shell morphology was verified via TEM and the possibility of tunable shell size was reported. Nitrogen adsorption/desorption analysis revealed mesoporous SiO₂ formation characterized by the slit-shaped type of pores that should be accessible for methylene blue photosensitizer molecules. It was shown that SiO₂ coating subsequently facilitates methylene blue conjugation and results in the formation of the BaGdF₅: 10% Eu³⁺@SiO₂@MB nanocomposite as a promising candidate for application in XPDT.     

Hybrid Nanoparticles and Composite Hydrogel Systems for Delivery of Peptide Antibiotics

The growing number of drug-resistant pathogenic bacteria poses a global threat to human health. For this reason, the search for ways to enhance the antibacterial activity of existing antibiotics is now an urgent medical task. The aim of this study was to develop novel delivery systems for polymyxins to improve their antimicrobial properties against various infections. For this, hybrid core–shell nanoparticles, consisting of silver core and a poly(glutamic acid) shell capable of polymyxin binding, were developed and carefully investigated. Characterization of the hybrid nanoparticles revealed a hydrodynamic diameter of approximately 100 nm and a negative electrokinetic potential. The nanoparticles demonstrated a lack of cytotoxicity, a low uptake by macrophages, and their own antimicrobial activity. Drug loading and loading efficacy were determined for both polymyxin B and E, and the maximal loaded value with an appropriate size of the delivery systems was 450 µg/mg of nanoparticles. Composite materials based on agarose hydrogel were prepared, containing both the loaded hybrid systems and free antibiotics. The features of polymyxin release from the hybrid nanoparticles and the composite materials were studied, and the mechanisms of release were analyzed using different theoretical models. The antibacterial activity against Pseudomonas aeruginosa was evaluated for both the polymyxin hybrid and the composite delivery systems. All tested samples inhibited bacterial growth. The minimal inhibitory concentrations of the polymyxin B hybrid delivery system demonstrated a synergistic effect when compared with either the antibiotic or the silver nanoparticles alone.     

Enzyme Replacement Therapy with Pabinafusp Alfa for Neuronopathic Mucopolysaccharidosis II: An Integrated Analysis of Preclinical and Clinical Data

Enzyme replacement therapy (ERT) improves somatic manifestations in mucopolysaccharidoses (MPS). However, because intravenously administered enzymes cannot cross the blood–brain barrier (BBB), ERT is ineffective against the progressive neurodegeneration and resultant severe central nervous system (CNS) symptoms observed in patients with neuronopathic MPS. Attempts to surmount this problem have been made with intrathecal and intracerebroventricular ERT in order to achieve CNS effects, but the burdens on patients are inimical to long-term administrations. However, since pabinafusp alfa, a human iduronate-2-sulfatase fused with a BBB-crossing anti-transferrin receptor antibody, showed both central and peripheral efficacy in a mouse model, subsequent clinical trials in a total of 62 patients with MPS-II (Hunter syndrome) in Japan and Brazil substantiated this dual efficacy and provided an acceptable safety profile. To date, pabinafusp alfa is the only approved intravenous ERT that is effective against both the somatic and CNS symptoms of patients with MPS-II. This article summarizes the previously obtained preclinical and clinical evidence related to the use of this drug, presents latest data, and discusses the preclinical, translational, and clinical challenges of evaluating, ameliorating, and preventing neurodegeneration in patients with MPS-II.     

A Novel Yolk–Shell Fe3O4@ Mesoporous Carbon Nanoparticle as an Effective Tumor-Targeting Nanocarrier for Improvement of Chemotherapy and Photothermal Therapy

Owing to their good stability and high photothermal conversion efficiency, the development of carbon-based nanoparticles has been intensively investigated, while the limitation of unsatisfactory cellular internalization impedes their further clinical application. Herein, we report a novel strategy for fabrication of Fe₃O₄ yolk–shell mesoporous carbon nanocarriers (Fe₃O₄@hmC) with monodispersity and uniform size, which presented significantly higher cell membrane adsorption and cellular uptake properties in comparison with common solid silica-supported mesoporous carbon nanoparticles with core–shell structure. Moreover, the MRI performance of this novel Fe-based nanoparticle could facilitate precise tumor diagnosis. More importantly, after DOX loading (Fe₃O₄@hmC-DOX), owing to synergistic effect of chemo–phototherapy, this therapeutic agent exhibited predominant tumor cell ablation capability under 808 nm NIR laser irradiation, both in vitro and in vivo. Our work has laid a solid foundation for therapeutics with hollowed carbon shell for solid tumor diagnosis and therapy in clinical trials.     

Study on Maximum Specific Loss Power in Fe3O4 Nanoparticles Decorated with Biocompatible Gamma-Cyclodextrins for Cancer Therapy with Superparamagnetic Hyperthermia

Different chemical agents are used for the biocompatibility and/or functionality of the nanoparticles used in magnetic hyperthermia to reduce or even eliminate cellular toxicity and to limit the interaction between them (van der Waals and magnetic dipolar interactions), with highly beneficial effects on the efficiency of magnetic hyperthermia in cancer therapy. In this paper we propose an innovative strategy for the biocompatibility of these nanoparticles using gamma-cyclodextrins (γ-CDs) to decorate the surface of magnetite (Fe₃O₄) nanoparticles. The influence of the biocompatible organic layer of cyclodextrins, from the surface of Fe₃O₄ ferrimagnetic nanoparticles, on the maximum specific loss power in superparamagnetic hyperthermia, is presented and analyzed in detail in this paper. Furthermore, our study shows the optimum conditions in which the magnetic nanoparticles covered with gamma-cyclodextrin (Fe₃O₄–γ-CDs) can be utilized in superparamagnetic hyperthermia for an alternative cancer therapy with higher efficiency in destroying tumoral cells and eliminating cellular toxicity.