Doxorubicin-Based Ionic Nanomedicines for Combined Chemo-Phototherapy of Cancer.

Synergistic combination therapy approach offers lots of options for delivery of materials with anticancer properties, which is a very promising strategy to treat a variety of malignant lesions with enhanced therapeutic efficacy. The current study involves a detailed investigation of combination ionic nanomedicines where a chemotherapeutic drug is coupled with a photothermal agent to attain dual mechanisms (chemotherapy (chemo) and photothermal therapy (PTT)) to improve the drug's efficacy. An FDA-approved Doxorubicin hydrochloride (DOX·HCl) is electrostatically attached with a near-infrared cyanine dye (ICG, IR783, and IR820), which serves as a PTT drug using ionic liquid chemistry to develop three ionic material (IM)-based chemo-PTT drugs. Carrier-free ionic nanomedicines (INMs) are derived from ionic materials (IMs). The photophysical properties of the developed combination IMs and their INMs were studied in depth. The phototherapeutic efficiency of the combination drugs was evaluated by measuring the photothermal conversion efficiency and singlet-oxygen quantum yield. The improved photophysical properties of the combination nanomedicines in comparison to their parent compounds significantly enhanced INMs' photothermal efficiency. Cellular uptake, dark and light toxicity studies, and cell death mechanisms of the chemo-PTT nanoparticles were also studied in vitro. The combination INMs exhibited enhanced cytotoxicity compared to their respective parent compounds. Moreover, the apoptosis cell death mechanism was almost doubled for combination nanomedicine than the free DOX, which is attributed to enhanced cellular uptake. Examination of the combination index and improved in vitro cytotoxicity results revealed a great synergy between chemo and PTT drugs in the developed combination nanomedicines.

Synergistic chemo-photothermal therapy using gold nanorods supported on thiol-functionalized mesoporous silica for lung cancer treatment.

Cancer therapy necessitates the development of novel and effective treatment modalities to combat the complexity of this disease. In this project, we propose a synergistic approach by combining chemo-photothermal treatment using gold nanorods (AuNRs) supported on thiol-functionalized mesoporous silica, offering a promising solution for enhanced lung cancer therapy. To begin, mesoporous MCM-41 was synthesized using a surfactant-templated sol-gel method, chosen for its desirable porous structure, excellent biocompatibility, and non-toxic properties. Further, thiol-functionalized MCM-41 was achieved through a simple grafting process, enabling the subsequent synthesis of AuNRs supported on thiol-functionalized MCM-41 (AuNR@S-MCM-41) via a gold-thiol interaction. The nanocomposite was then loaded with the anticancer drug doxorubicin (DOX), resulting in AuNR@S-MCM-41-DOX. Remarkably, the nanocomposite exhibited pH/NIR dual-responsive drug release behaviors, facilitating targeted drug delivery. In addition, it demonstrated exceptional biocompatibility and efficient internalization into A549 lung cancer cells. Notably, the combined photothermal-chemo therapy by AuNR@S-MCM-41-DOX exhibited superior efficacy in killing cancer cells compared to single chemo- or photothermal therapies. This study showcases the potential of the AuNR@S-MCM-41-DOX nanocomposite as a promising candidate for combined chemo-photothermal therapy in lung cancer treatment. The innovative integration of gold nanorods, thiol-functionalized mesoporous silica, and pH/NIR dual-responsive drug release provides a comprehensive and effective therapeutic approach for improved outcomes in lung cancer therapy. Future advancements based on this strategy hold promise for addressing the challenges posed by cancer and transforming patient care.

Microfluidics for Development of Lipid Nanoparticles: Paving the Way for Nucleic Acids to the Clinic.

Nucleic acid therapeutics hold an unprecedented promise toward treating many challenging diseases; however, their use is hampered by delivery issues. Microfluidics, dealing with fluids in the microscale dimensions, have provided a robust means to screening raw materials for development of nano delivery vectors, in addition to controlling their size and minimizing their polydispersity. In this mini-review, we are briefly highlighting the different types of nucleic acid therapies with emphasis on the delivery requirement for each type. We provide a thorough review of available methods for the development of nanoparticles, especially lipid nanoparticles (LNPs) that resulted in FDA approval of the first ever nucleic acid nanomedicine. We then focus on recent research attempts for how microfluidic synthesis of lipid nanoparticles and discuss the various parameters required for successful formulation of LPNs including chip design, flow regimes, and lipid composition. We then identify key areas of research in microfluidics and related fields that require attention for future success in clinical translation of nucleic acid nanomedicines.

Enhanced photothermal heating and combination therapy of NIR dye via conversion to self-assembled ionic nanomaterials.

Combination nanodrugs are promising therapeutic agents for cancer treatment. However, they often require the use of complex nanovehicles for transportation into the tumor site. Herein, a new class of carrier-free ionic nanomaterials (INMs) is presented, which are self-assembled by the drug molecules themselves. In this regard, a photothermal therapy (PTT) mechanism is combined with a chemotherapy (chemo) mechanism using ionic liquid chemistry to develop a combination drug to deliver multiple cytotoxic mechanisms simultaneously. Nanodrugs were developed from an ionic material-based chemo-PTT combination drug by using a simple reprecipitation method. Detailed examination of the photophysical properties (absorption, fluorescence emission, quantum yield, radiative and non-radiative rate) of the INMs revealed significant spectral changes which are directly related to their therapeutic effect. The reactive oxygen species quantum yield and the light to heat conversion efficiency of the photothermal agents were shown to be enhanced in combination nanomedicines as compared to their respective parent compounds. The ionic nanodrugs exhibited an improved dark and light cytotoxicity in vitro as compared to either the chemotherapeutic or photothermal parent compounds individually, due to a synergistic effect of the combined therapies, improved photophysical properties and their nanoparticles' morphology that enhanced the cellular uptake of the drugs. This study presents a general framework for the development of carrier-free dual-mechanism nanotherapeutics.

Localized Plasmonic Photothermal Therapy as a Life-saving Treatment Paradigm for Hospitalized COVID-19 Patients.

Lung failure is the main reason for mortality in COVID-19 patients, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To date, no drug has been clinically approved for treatment of COVID-19. Nanotechnology has a great potential in contributing significantly to the fight against COVID-19 by developing effective therapies that can selectively eradicate the respiratory virus load. We propose a novel COVID-19 management approach that is efficient in eliminating the virus load from the airways and protecting the lungs from the fatal effects of the virus. This approach relies on targeting the virus using ACE-2-functionalized gold nanorods (AuNRs) followed by irradiation with near-infrared (NIR) light for the selective eradication of SARS-CoV-2 without off-target effects, i.e., targeted plasmonic photothermal therapy. Using discrete dipole approximation (DDA), we quantitatively determined the efficiency of AuNRs (31 nm × 8 nm) in absorbing NIR when present at different orientations relative to one another on the surface of the virus. The safety and the local administration of AuNRs using a well-tolerated flexible bronchoscopy technique, commonly used for hospitalized COVID-19 patients, ensure feasibility and clinical translation. While requiring further research, we anticipate this approach to result in a first-line treatment for hospitalized COVID-19 patients that are experiencing severe respiratory conditions or belong to a high-risk population, e.g., seniors and diabetic patients.

Plasmonic and chiroplasmonic nanobiosensors based on gold nanoparticles.

Development of optical nanobiosensors has emerged as one of the most important bioresearch areas of interest over the past decades especially in the modern innovations in the design and utilization of sensing platforms. The application of nanobiosensors has been accelerated with the introduction of plasmonic NPs, which overcome the most of the limitations in the case of conventional optical nanobiosensors. Since the plasmonic AuNPs-based nanobiosensors provide high potential achievements to develop promising platforms in fully integrated multiplex assays, some well-developed investigations are clearly required to improve the current technologies and integration of multiple signal inputs. Therefore, in this literature, we summarized the performance and achievements of optical nanobiosensors according to plasmonic rules of AuNPs, including SPR, LSPR, SERS and chiroptical phenomena. Also, we investigated the effects of the physicochemical properties of AuNPs such as size, shape, composition, and assembly on the plasmonic signal propagation in AuNPs-based nanobiosensors. Moreover, we presented an overview on the current state of plasmonic AuNPs-based nanobiosensors in the biomedical activities. Besides, this paper looks at the current and future challenges and opportunities of ongoing efforts to achieve the potential applications of AuNPs-based optical plasmonic nanobiosensors in integration with other nanomaterials. Taken together, the main focus of this paper is to provide some applicable information to develop current methodologies in fabrication of potential AuNPs-based nanobiosensors for detection of a wide range of analytes.

Gold nanomaterials as key suppliers in biological and chemical sensing, catalysis, and medicine.

BACKGROUND: Gold nanoparticles (AuNPs) with unique physicochemical properties have received a great deal of interest in the field of biological, chemical and biomedical implementations. Despite the widespread use of AuNPs in chemical and biological sensing, catalysis, imaging and diagnosis, and more recently in therapy, no comprehensive summary has been provided to explain how AuNPs could aid in developing improved sensing and catalysts systems as well as medical settings. SCOPE OF REVIEW: The chemistry of Au-based nanosystems was followed by reviewing different applications of Au nanomaterials in biological and chemical sensing, catalysis, imaging and diagnosis by a number of approaches, and finally synergistic combination therapy of different cancers. Afterwards, the clinical impacts of AuNPs, future application of AuNPs, and opportunities and challenges of AuNPs application were also discussed. MAJOR CONCLUSIONS: AuNPs show exclusive colloidal stability and are considered as ideal candidates for colorimetric detection, catalysis, imaging, and photothermal transducers, because their physicochemical properties can be tuned by adjusting their structural dimensions achieved by the different manufacturing methods. GENERAL SIGNIFICANCE: This review provides some details about using AuNPs in sensing and catalysis applications as well as promising theranostic nanoplatforms for cancer imaging and diagnosis, and sensitive, non-invasive, and synergistic methods for cancer treatment in an almost comprehensive manner.

Collective multipole oscillations direct the plasmonic coupling at the nanojunction interfaces.

We present a systematic study of the effect of higher-multipolar order plasmon modes on the spectral response and plasmonic coupling of silver nanoparticle dimers at nanojunction separation and introduce a coupling mechanism. The most prominent plasmonic band within the extinction spectra of coupled resonators is the dipolar coupling band. A detailed calculation of the plasmonic coupling between equivalent particles suggests that the coupling is not limited to the overlap between the main bands of individual particles but can also be affected by the contribution of the higher-order modes in the multipolar region. This requires an appropriate description of the mechanism that goes beyond the general coupling phenomenon introduced as the plasmonic ruler equation in 2007. In the present work, we found that the plasmonic coupling of nearby Ag nanocubes does not only depend on the plasmonic properties of the main band. The results suggest the decay length of the higher-order plasmon mode is more sensitive to changes in the magnitude of the interparticle axis and is a function of the gap size. For cubic particles, the contribution of the higher-order modes becomes significant due to the high density of oscillating dipoles localized on the corners. This gives rise to changes in the decay length of the plasmonic ruler equation. For spherical particles, as the size of the particle increases (i.e., ≥80 nm), the number of dipoles increases, which results in higher dipole-multipole interactions. This exhibits a strong impact on the plasmonic coupling, even at long separation distances (20 nm).

Plasmonic gold nanoparticles: Optical manipulation, imaging, drug delivery and therapy.

Over the past two decades, the development of plasmonic nanoparticle (NPs), especially gold (Au) NPs, is being pursued more seriously in the medical fields such as imaging, drug delivery, and theranostic systems. However, there is no comprehensive review on the effect of the physical and chemical parameters of AuNPs on their plasmonic properties as well as the use of these unique characteristic in medical activities such as imaging and therapeutics. Therefore, in this literature the surface plasmon resonance (SPR) modeling of AuNPs was accurately captured toward precision medicine. Indeed, we investigated the importance of plasmonic properties of AuNPs in optical manipulation, imaging, drug delivery, and photothermal therapy (PTT) of cancerous cells based on their physicochemical properties. Finally, some challenges regarding the commercialization of AuNPs in future medicine such as, cytotoxicity, lack of standards for medical applications, high cost, and time-consuming process were discussed.

Monitoring the dynamics of hemeoxygenase-1 activation in head and neck cancer cells in real-time using plasmonically enhanced Raman spectroscopy.

We report for the first time the usage of plasmonically enhanced Raman spectroscopy (PERS) to directly monitor the dynamics of pharmacologically generated hemeoxygenase-1 (HO-1) by evaluating the kinetics of formation of carbon monoxide (CO), one of the metabolites of HO-1 activation, in live cells during cisplatin treatment. Being an endogenous signaling molecule, CO plays an important role in cancer regression. Many aspects of HO-1's and CO's functions in biology are still unclear largely due to the lack of technological tools for the real-time monitoring of their dynamics in live cells and tissues. In this study, we found that, together with nuclear region-targeted gold nanocubes (AuNCs), cisplatin treatment can dramatically trigger the activation of HO-1 and thereby the rate and production of CO in mammalian cells in a dose-dependent manner. Though quantitative molecular data revealed that a lower concentration of cisplatin up-regulates HO-1 expression in cancer cells, PERS data suggest that it poorly facilitates the activation of HO-1 and thereby the production of CO. However, at a higher dose, cisplatin along with AuNCs could significantly enhance the activation of HO-1 in cancer cells, which could be probed in real-time by monitoring the CO generation by using PERS. Under the same conditions, the rate of formation of CO in healthy cells was relatively higher in comparison to the cancer cells. Additionally, molecular data revealed that AuNCs have the potential to suppress the up-regulation of HO-1 in cancer cells during cisplatin treatment at a lower concentration. As up-regulation of HO-1 has a significant role in cell adaptation to oxidative stress in cancer cells, the ability of AuNCs in suppressing the HO-1 overexpression will have a remarkable impact in the development of nanoformulations for combination cancer therapy. This exploratory study demonstrates the unique possibilities of PERS in the real-time monitoring of endogenously generated CO and thereby the dynamics of HO-1 in live cells, which could expedite our understanding of the signaling action of CO and HO-1 in cancer progression.

Intracellular Assembly of Nuclear-Targeted Gold Nanosphere Enables Selective Plasmonic Photothermal Therapy of Cancer by Shifting Their Absorption Wavelength toward Near-Infrared Region.

Despite the important applications of near-infrared (NIR) absorbing nanomaterials in plasmonic photothermal therapy (PPT), their high yield synthesis and nonspecific heating during the active- and passive-targeted cancer therapeutic strategies remain challenging. In the present work, we systematically demonstrate that in situ aggregation of typical non-NIR absorbing plasmonic nanoparticles at the nuclear region of the cells could translate them into an effective NIR photoabsorber in plasmonic photothermal therapy of cancer due to a significant shift of the plasmonic absorption band to the NIR region. We evaluated the potential of nuclear-targeted AuNSs as photoabsorber at various stages of endocytosis by virtue of their inherent in situ assembling capabilities at the nuclear region of the cells, which has been considered as one of the most thermolabile structures within the cells, to selectively destruct cancer cells with minimal damage to healthy cells. Various plasmonic nanoparticles such as rods and cubes have been exploited to elucidate the role of plasmonic field coupling in assembled nanoparticles and their subsequent killing efficiency. The NIR absorbing capabilities of aggregated AuNSs have been further demonstrated both experimentally and theoretically using discrete dipolar approximation (DDA) techniques, which was in concordance with the observed results in plasmonic photothermal therapeutic studies. While the current work was able to demonstrate the utility of non-NIR absorbing plasmonic nanoparticles as a potential alternative for plasmonic photothermal therapy by inducing localized plasmonic heating at the nuclear region of the cells, these findings could potentially open up new possibilities in developing more efficient nanoparticles for efficient cancer treatment modalities.

The Coupling between Gold or Silver Nanocubes in Their Homo-Dimers: A New Coupling Mechanism at Short Separation Distances.

Using the DDA method, we investigated the near-field coupling between two excited Au or Ag 42 nm nanocubes in a face-to-face dimer configuration at small separation distances where the exponential coupling behavior distinctly changes. This could be due to the failure of the dipole approximation at short distances or a change in the electromagnetic field distribution between the adjacent monomers. A detailed calculation of the plasmonic field distribution strongly suggests that the latter mechanism is responsible for the failure of the expected exponential coupling behavior at small separation distances. The results suggest that the observed optical properties of the pair of Au or Ag nanocubes separated by distances larger than 6 nm, result from the electromagnetic coupling between the oscillating dipoles at the corners of the adjacent facets of the nanocubes. At separations smaller than 6 nm, the distribution of the plasmonic dipoles along both the facets and the corners of the adjacent monomers control the plasmonic spectra and the distance dependent optical properties of the dimer.

Spectroscopy of homo- and heterodimers of silver and gold nanocubes as a function of separation: a DDA simulation.

The plasmonic fields of silver and gold nanocubes are known to be among the strongest of any plasmonic metallic nanoparticles. Aggregation dominates their use in imaging and sensing applications due to the resulting enhancement of the plasmonic field in between the nanoparticles (hot spots). The first step in the aggregation process is dimerization. In the present work, we used the discrete dipole approximation (DDA) to calculate the interdimer separation dependence of the absorption and scattering components of the localized surface plasmon resonance (LSPR) extinction of homo and heterodimers of Ag and Au nanocubes when excited parallel to their interparticle axis. We also examined the changes in the nanocube surface plasmonic field distributions as the dimer separation was varied. The results from the homodimers were as expected: as the cubes were brought together, there was a red shift in the primary plasmon band in accordance with the universal scaling law. Additionally, as the particles moved together, scattering contributed more to the overall extinction. By examining the E-field distributions, we found that the hot spot geometry changes abruptly at small separations. At very short distances, the hot spot is located between the adjacent faces and away from the corners of these faces. At larger separations it moves toward the adjacent corners. We observed apparently anomalous behavior for the heterodimer. First, the E-field resulting from excitation of the Ag dominated plasmon resonance was significantly weaker than expected. Second, the red shift of the gold dominated plasmon resonance did not follow the universal scaling law. The most likely explanation for these observations is that the silver plasmon mixes strongly with the energetically resonant, but nonplasmonic, gold interband transition to form a hybrid resonance that produces weaker overall field intensity on the two nanocubes at short separation.

Are Hot Spots between Two Plasmonic Nanocubes of Silver or Gold Formed between Adjacent Corners or Adjacent Facets? A DDA Examination.

Of all the plasmonic solid nanoparticles, single Ag or Au nanocubes are known to be plasmonic nanoparticles with strong plasmonic fields, which are concentrated around their corners. However, when nanoparticles aggregate, they do so in a face-to face arrangement. The formation of hot spots between plasmonic nanoparticles in close proximity to each other is known to greatly enhance their plasmonic fields which are important in the field of imaging. Thus, what is the structural development of hot spots between two nanocubes in a dimer? Do they form between the corners or are they between the adjacent facets, and what does this depend on? A detailed discrete dipole approximation (DDA) simulation of Au-Au and Ag-Ag dimers suggests that there is a competition between their formation in these two locations, which depends on the polarization direction of the exciting light (with respect to the interparticle axis in the dimer), its intensity and the wavelength as well as the interparticle separation of the dimer.