Theranostic Nanoparticles Research Articles

Theranostic mesoporous silica nanoparticles made of multi-nuclear gold or carbon quantum dots particles serving as pH responsive drug delivery system

Mesoporous silica nanoparticles are promising candidates to deliver proteins, antibodies, and anticancer drugs and to be served as an adsorbent of various types of substrate. Herein, a theranostic approach, in the preparation of fluorescence-type mesoporous silica for pH-responsive delivery of anticancer drug, doxorubicin, is introduced. By this mean, three types of mesoporous silica were synthesized. The ordinary type of mesoporous silica nanoparticles containing propylamine functional groups was synthesized by a controlled-size technique. Two types of fluorescence mesoporous silica were prepared, doped with gold or quantum dots nanoparticles. The fluorescence imaging has shown that the optical properties of the gold or carbon quantum dots have been transferred to the mesoporous matrix in doping processes. The as-prepared mesoporous materials were conjugated to doxorubicin via Schiff-base linkage. Several characterization techniques were utilized to detect the structure of the particles including FT-IR spectroscopy, XRD, N 2 adsorption/desorption, transition, and scanning electron microscopy. The amount of conjugated doxorubicin was analyzed by UV–Vis spectroscopy. The pH-responsive character was proved assessing the release profile in different pH ranges including physiological pH. The safety of the particles was evaluated by cell cytotoxicity assay on breast cancer cell line, MCF-7. As-prepared particles showed no cytotoxic behavior, but when they were loaded by doxorubicin, the appreciable release of the drug and subsequent cytotoxicity resulted against MCF-7 cells. The hemolytic study was conducted to prove the biocompatibility of these particles in the blood. Altogether, the proposed materials are suitable to be considered as safe and to be used as a theranostic platform for therapeutic and imaging purposes. • Three types of MSN were prepared and applied for drug delivery. • The fluorophore MSNs of GNP@MSN and QCD@MSN were organized for theranostic purpose. • DOX was conjugated to MSNs, and released through pH responsive profile. • The fluorophore MSNs showed biocompatibility and fluorescent contrast in MCF-7 cells. • MSNs@DOX showed toxicity in parallel and even higher than of free DOX in MCF-7 cell.

Theranostic Squalene-NIR Dye Nanoparticles with Photodynamic/Photothermal and Mitochondria Targeting Properties

Theranostic Squalene-NIR Dye Nanoparticles with Photodynamic/Photothermal and Mitochondria Targeting Properties

Multifunctional theranostic nanoparticles for multi-modal imaging-guided CAR-T immunotherapy and chemo-photothermal combinational therapy of non-Hodgkin's lymphoma.

Accurate and effective tumor diagnosis, detection, and treatment are key for improving the survival rates of patients. Chimeric antigen receptor T (CAR-T) cell therapy has shown remarkable clinical success in eradicating hematologic malignancies. However, the hostile microenvironment in solid tumors severely prevents CAR-T cells from migrating and from infiltrating and killing malignant cells. Tumor microenvironment modulation strategies have attracted much attention in the field of cancer immunotherapy. Multifunctional nanoplatforms that integrate the advantages of different therapeutic techniques can allow for the multimodal synergistic treatment of tumors. In this study, a biocompatible, tumor-targeting, on-demand approach combining CAR-T cell immunotherapy and a chemo-photothermal therapy nanoplatform (FA-Gd-GERTs@Ibrutinib) based on gadolinium-loaded gap-enhanced Raman tags (Gd-GERTs) has been developed for multimodal imaging, and it provides a reliable treatment strategy for solid tumor immunotherapy via microenvironment reconstruction. In our study, folate (FA) receptor targeted molecules are used to improve the accuracy and sensitivity of computed tomography/magnetic resonance/Raman multimodal tumor imaging. The photothermal effect of the nanoprobe can promote the angiogenesis of lymphoma tissue, destroy the extracellular matrix, loosen compact tissue, stimulate chemokine secretion, and effectively enhance the infiltration ability in the case of non-Hodgkin's lymphoma, without dampening the CD19 CAR-T cell activity. The treatment results in tumor-bearing mice proved the existence of excellent synergistic therapy; photothermal therapy improves the accumulation and effector function of CAR-T cells within solid tumors. It is believed that multifunctional nanomaterials with targeted multi-modal imaging capabilities that support combination therapy can provide an efficient route for accurate diagnosis and efficient treatment.

Targeted Theranostic 111In/Lu-Nanotexaphyrin for SPECT Imaging and Photodynamic Therapy.

Theranostic nanoparticles aim to integrate diagnostic imaging and therapy to facilitate image-guided treatment protocols. Herein, we present a theranostic nanotexaphyrin for prostate-specific membrane antigen (PSMA)-targeted radionuclide imaging and focal photodynamic therapy (PDT) accomplished through the chelation of metal isotopes (In, Lu). To realize nanotexaphyrin's theranostic properties, we developed a rapid and robust 111In/Lu-nanotexaphyrin radiolabeling method using a microfluidic system that achieved a high radiochemical yield (>90%). The optimized metalated nanotexaphyrin displayed excellent chemical, photo, and colloidal stabilities, potent singlet oxygen generation, and favorable plasma circulation half-life in vivo (t1/2 = 6.6 h). Biodistribution, including tumor accumulation, was characterized by NIR fluorescence, SPECT/CT imaging, and γ counting. Inclusion of the PSMA-targeting ligand enabled the preferential accumulation of 111In/Lu-nanotexaphyrin in PSMA-positive (PSMA+) prostate tumors (3.0 ± 0.3%ID/g) at 48 h with tumor vs prostate in a 2.7:1 ratio. In combination with light irradiation, the PSMA-targeting nanotexaphyrin showed a potent PDT effect and successfully inhibited PSMA+ tumor growth in a subcutaneous xenograft model. To the best of our knowledge, this study is the first demonstration of the inherent metal chelation-driven theranostic capabilities of texaphyrin nanoparticles, which, in combination with PSMA targeting, enabled prostate cancer imaging and therapy.

Microfluidic Synthesis of Theranostic Nanoparticles with Near-Infrared Scintillation: Toward Next-Generation Dosimetry in X-ray-Induced Photodynamic Therapy.

We developed a microfluidic synthesis to grow GdF3:Eu theranostic scintillating nanoparticles to simultaneously monitor the X-ray dose delivered to tumors during treatments with X-ray activated photodynamic therapy (X-PDT). The flow reaction was optimized to enhance scintillation emission from the Eu3+ ions. The as-prepared ∼15 nm rhombohedral-shaped nanoparticles self-assembled into ∼100 nm mesoporous flower-like nanostructures, but the rhombohedral units remained intact and the scintillation spectra unaltered. The conjugation of the ScNPs with multilayers of methylene blue (MB) in a core-shell structure (GdF@MB) resulted in enhanced singlet oxygen (1O2) generation under X-ray irradiation, with maximum 1O2 production for nanoparticles with 4 MB layers (GdF@4MB). High 1O2 yield was further evidenced in cytotoxicity assays, demonstrating complete cell death only for the association of ScNPs with MB and X-rays. Because the scintillating Eu3+ emission at 694 nm is within the therapeutic window and was only partially absorbed by the MB molecules, it was explored for getting in vivo dosimetric information. Using porcine skin and fat to simulate the optical and radiological properties of the human tissues, we showed that the scintillation light can be detected for a tissue layer of ∼16 mm, thick enough to be employed in radiotherapy treatments of breast cancers, for instance. Therefore, the GdF3:Eu ScNPs and the GdF@4MB nanoconjugates are strong candidates for treating cancer with X-PDT while monitoring the treatment and the radiation dose delivered, opening new avenues to develop a next-generation modality of real-time in vivo dosimetry.

Folic Acid-Decorated β-Cyclodextrin-Based Poly(ε-caprolactone)-dextran Star Polymer with Disulfide Bond-Linker as Theranostic Nanoparticle for Tumor-Targeted MRI and Chemotherapy.

β-cyclodextrin(βCD)-based star polymers have attracted much interest because of their unique structures and potential biomedical and biological applications. Herein, a well-defined folic acid (FA)-conjugated and disulfide bond-linked star polymer ((FA-Dex-SS)-βCD-(PCL)14) was synthesized via a couple reaction between βCD-based 14 arms poly(ε-caprolactone) (βCD-(PCL)14) and disulfide-containing α-alkyne dextran (alkyne-SS-Dex), and acted as theranostic nanoparticles for tumor-targeted MRI and chemotherapy. Theranostic nanoparticles were obtained by loading doxorubicin (DOX), and superparamagnetic iron oxide (SPIO) particles were loaded into the star polymer nanoparticles to obtain ((FA-Dex-SS)-βCD-(PCL)14@DOX-SPIO) theranostic nanoparticles. In vitro drug release studies showed that approximately 100% of the DOX was released from disulfide bond-linked theranostic nanoparticles within 24 h under a reducing environment in the presence of 10.0 mM GSH. DOX and SPIO could be delivered into HepG2 cells efficiently, owing to the folate receptor-mediated endocytosis process of the nanoparticles and glutathione (GSH), which triggered disulfide-bonds cleaving. Moreover, (FA-Dex-SS)-βCD-(PCL)14@DOX-SPIO showed strong MRI contrast enhancement properties. In conclusion, folic acid-decorated reduction-sensitive star polymeric nanoparticles are a potential theranostic nanoparticle candidate for tumor-targeted MRI and chemotherapy.

A Reduction Active Theranostic Nanoparticle for Enhanced Near-Infrared Imaging and Phototherapy by Reducing Glutathione Level in Cancer Cells.

Facile preparation of a tumoral-stimuli-activated theranostic nanoparticle with simple constituents remains a challenge for tumor theranostic nanosystems. Herein we design a simple reductionresponsive turn-on theranostic nanoparticle for achieving fluorescent imaging and phototherapy combination. The theranostic nanoparticle is prepared by a simple one-step dialysis method of reduction active amphiphilic hyperbranched poly(β-amidoamines) and a near-infrared (NIR) dye indocyanine green (ICG). The fluorescence of ICG is quenched by the aggregation-caused quenching (ACQ) effect. The fluorescent intensity of free ICG at 816 nm was ∼40 times as high as that of particulate ICG. After reductive nanoparticles incubated with dithiothreitol (DTT), the size of the nanoparticles increased from 160 nm to 610 nm by Dynamic light scattering (DLS). As nanoparticles were internalized by cancer cells, the disulfide bonds would be cleaved by intracellular reduction agents like glutathione (GSH), leading to the release of entrapped ICG. The released ICG regained its fluorescence for self-monitoring the release and therapeutic effect of ICG by fluorescence spectra and the quantitative evaluation of NIR fluorescence intensity. Remarkably, nanoparticles can also reinforce antitumor efficacy through photodynamic therapy and GSH depletion property. This study provides new insights into designing turn-on theranostic systems.

Smart transformable nanoparticles for enhanced tumor theranostics

The physical morphologies of nanoparticles, especially size and shape, always significantly influence their biological behaviors. In the past, nanoparticles with constant physical morphologies have been widely investigated and applied in tumor theranostics. With the increased in-depth knowledge of tumors and physiological microenvironments, nanoparticles are required to self-adjust their physical morphologies during their circulation in varying physiological microenvironments and when reaching tumor site that possess distinct microenvironments. Therefore, smart transformable nanomaterials, which can alter their morphologies under different physiological conditions, show great potential in advanced tumor theranostics. This review summarizes the influence of nanoparticles' physical morphologies on their biological behaviors under different physiological conditions, highlights the designs of transformable nanoparticles serving as a guideline for their construction, intensively discusses the recent biomedical applications of these smart transformable nanoparticles for tumor theranostics, and also proposes future challenges and perspectives in the development of smart transformable nanoparticles for tumor theranostics.

PH-Responsive Multifunctional Theranostic Rapamycin-Loaded Nanoparticles for Imaging and Treatment of Acute Ischemic Stroke.

Stroke is the second leading cause of death globally and the most common cause of severe disability. Several barriers need to be addressed more effectively to treat stroke, including efficient delivery of therapeutic agents, rapid release at the infarct site, precise imaging of the infarct site, and drug distribution monitoring. The present study aimed to develop a bio-responsive theranostic nanoplatform with signal-amplifying capability to deliver rapamycin (RAPA) to ischemic brain tissues and visually monitor drug distribution. A pH-sensitive theranostic RAPA-loaded nanoparticle system was designed since ischemic tissues have a low-pH microenvironment compared with normal tissues. The nanoparticles demonstrated good stability and biocompatibility and could efficiently load rapamycin, followed by its rapid release in acidic environments, thereby improving therapeutic accuracy. The nano-drug-delivery system also exhibited acid-enhanced magnetic resonance imaging (MRI) and near-infrared fluorescence (NIRF) imaging signal properties, enabling accurate multimodal imaging with minimal background noise, thus improving drug tracing and diagnostic accuracy. Finally, in vivo experiments confirmed that the nanoparticles preferentially aggregated in the ischemic hemisphere and exerted a neuroprotective effect in rats with transient middle cerebral artery occlusion (tMCAO). These pH-sensitive multifunctional theranostic nanoparticles could serve as a potential nanoplatform for drug tracing as well as the treatment and even diagnosis of acute ischemic stroke. Moreover, they could be a universal solution to achieve accurate in vivo imaging and treatment of other diseases.

Dye-loaded mesoporous polydopamine nanoparticles for multimodal tumor theranostics with enhanced immunogenic cell death

BackgroundTumor phototherapy especially photodynamic therapy (PDT) or photothermal therapy (PTT), has been considered as an attractive strategy to elicit significant immunogenic cell death (ICD) at an optimal tumor retention of PDT/PTT agents. Heptamethine cyanine dye (IR-780), a promising PDT/PTT agent, which can be used for near-infrared (NIR) fluorescence/photoacoustic (PA) imaging guided tumor phototherapy, however, the strong hydrophobicity, short circulation time, and potential toxicity in vivo hinder its biomedical applications. To address this challenge, we developed mesoporous polydopamine nanoparticles (MPDA) with excellent biocompatibility, PTT efficacy, and PA imaging ability, facilitating an efficient loading and protection of hydrophobic IR-780.ResultsThe IR-780 loaded MPDA (IR-780@MPDA) exhibited high loading capacity of IR-780 (49.7 wt%), good physiological solubility and stability, and reduced toxicity. In vivo NIR fluorescence and PA imaging revealed high tumor accumulation of IR-780@MPDA. Furthermore, the combined PDT/PTT of IR-780@MPDA could induce ICD, triggered immunotherapeutic response to breast tumor by the activation of cytotoxic T cells, resulting in significant suppression of tumor growth in vivo.ConclusionThis study demonstrated that the as-developed compact and biocompatible platform could induce combined PDT/PTT and accelerate immune activation via excellent tumor accumulation ability, offering multimodal tumor theranostics with negligible systemic toxicity.Graphical

Synthesis and Preliminary Biological Assessment of Carborane-Loaded Theranostic Nanoparticles to Target Prostate-Specific Membrane Antigen.

Boron neutron capture therapy (BNCT) is an encouraging therapeutic modality for cancer treatment. Prostate-specific membrane antigen (PSMA) is a cell membrane protein that is abundantly overexpressed in prostate cancer and can be targeted with radioligand therapies to stimulate clinical responses in patients. In principle, a spatially targeted neutron beam together with specifically targeted PSMA ligands could enable prostate cancer-targeted BNCT. Thus, we developed and tested PSMA-targeted poly(lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-b-PEG) nanoparticles (NPs) loaded with carborane and tethered to the radiometal chelator deferoxamine B (DFB) for simultaneous positron emission tomography (PET) imaging and selective delivery of boron to prostate cancer. Monomeric PLGA-b-PEGs were covalently functionalized with either DFB or the PSMA ligand ACUPA. Different nanoparticle formulations were generated by nanoemulsification of the corresponding unmodified and DFB- or ACUPA-modified monomers in varying percent fractions. The nanoparticles were efficiently labeled with 89Zr and were subjected to in vitro and in vivo evaluation. The optimized DFB(25)ACUPA(75) NPs exhibited strong in vitro binding to PSMA in direct binding and competition radioligand binding assays in PSMA(+) PC3-Pip cells. [89Zr]DFB(25) NPs and [89Zr]DFB(25)ACUPA(75) NPs were injected to mice with bilateral PSMA(-) PC3-Flu and PSMA(+) PC3-Pip dual xenografts. The NPs demonstrated twofold superior accumulation in PC3-Pip tumors to that of PC3-Flu tumors with a tumor/blood ratio of 25; however, no substantial effect of the ACUPA ligands was detected. Moreover, fast release of carborane from the NPs was observed, resulting in a low boron delivery to tumors in vivo. In summary, these data demonstrate the synthesis, characterization, and initial biological assessment of PSMA-targeted, carborane-loaded PLGA-b-PEG nanoparticles and establish the foundation for future efforts to enable their best use in vivo.

Nanoparticles for Cancer Diagnosis, Radionuclide Therapy and Theranostics.

Nanoparticles have unique properties that can be exploited for cancer diagnosis and therapy. Intravenously injected nanoparticles accumulate predominantly in organs of the mononuclear phagocytic system, in addition to localizing in tumors and at sites of inflammation and infection. Accumulation in the liver and spleen lowers nanoparticles' ability to target pathological sites and compromises their use for radionuclide therapy. As described by Lee et al. in this issue of ACS Nano, radionuclide retention in liver and spleen can be greatly reduced by using liposomes that are surface-modified with esterase-cleavable radionuclide anchors. Because esterase activity is high in healthy tissues and low in tumors, the authors found that liposome-associated radioactivity rapidly cleared from the body and remained high only in tumors. The resulting images had high contrast-to-background ratios and remarkable tumor delineation. In this Perspective, we discuss these advances from early detection, cancer diagnosis, radionuclide therapy, and theranostics points of view. We outline the current clinical landscape of radionuclide targeting, imaging and therapy, and reflect on the roles that nanoparticles can play in these applications. We highlight the potential of nanoparticles that are responsive to endogenous stimuli for intraoperative imaging and, particularly, for individualized and improved radionuclide treatment. Taking these advances into account, future studies exploring the robustness and the clinical feasibility of nanomedicine-based radiotheranostic probes are eagerly awaited.

Pluronic stabilized conjugated polymer nanoparticles for NIR fluorescence imaging and dual phototherapy applications

• Pluronic stabilized conjugated polymer nanoparticles (CP-NP-Plu) are prepared. • CP-NP-Plu present photothermal conversion efficiency of 61% under NIR irradiation. • 2-fold increase of singlet oxygen generation quantum yield due to encapsulation with Plu • NIR fluorescence imaging ability validated at single nanoparticle level. Besides their intensive application as solar photovoltaic materials, low bandgap conjugated polymers have been recently exploited in cell imaging and phototherapeutic applications due to their photoactivity in the near-infrared (NIR) spectral domain, also known as the “biologically transparent window”. Herein, Poly[2,6-(4,4-bis-(2-ethylhexyl)-4H-cyclopenta [2,1-b;3,4-b′]dithiophene)-alt-4,7(2,1,3-benzothiadiazole) (PCPDTBT) conjugated polymer was used to prepare novel NIR activatable theranostic nanoparticles, via nanoprecipitation method, for fluorescence imaging and dual photothermal-photodynamic therapy (PTT-PDT) applications. To overcome the drawback of hydrophobicity of PCPDTBT, the approach of encapsulating the obtained nanoparticles with a layer of Pluronic F127 amphiphilic block co-polymer was herein applied. The Pluronic layer not only provides excellent colloidal stability, but also ensures enhanced fluorescence emission, improved photothermal heating and singlet oxygen generation ability of the nanoparticles in aqueous dispersion. Specifically, upon irradiation with a NIR laser at 785 nm, the obtained nanoparticles exhibit good thermal response and excellent photostability leading to a photothermal conversion efficiency of 61%. Moreover, a near two-fold increase in the singlet oxygen generation quantum yield due to encapsulation with Pluronic is also detected. Furthermore, fluorescence imaging measurements on single nanoparticle immobilized on glass substrate reveal their potential as fluorescence contrast agents. The enhanced fluorescence and improved therapeutic properties of our nanoparticles suggest the possibility to be employed as NIR activatable theranostic agents via dual phototherapy combined with high-resolution fluorescence tracking.

CoNi alloy nanoparticles for cancer theranostics: synthesis, physical characterization, in vitro and in vivo studies

Nanomaterials are attracting increasing interest in many biomedical fields, including the fight against cancer. In this context, we successfully synthesized CoNi alloy nanoparticles (NPs) by a simple polyol process. The magnetic characteristics of the products were measured by vibration sample magnometry, which revealed that the samples have soft ferromagnetic behavior. The microstructure and morphology were inspected by X-ray diffraction and scanning electron microscopy, respectively. Human cancer cells derived from the breast (MCF7) and oral cavity (C152) and normal cells derived from human umbilical vein endothelial cells (HUVECs) were treated with increasing concentrations of CoNi NPs, and their cytotoxic effect was measured via MTT and lactate dehydrogenase (LDH) leakage assays. We found that treatments by using 12.5 to 400 µg/mL of Co0.5Ni0.5, Co0.6Ni0.4, and Co0.4Ni0.6 NPs were associated with significant concentration-dependent toxicity toward such cell lines and profoundly enhanced LDH leakage following 48 h of exposure (P < 0.05 compared with untreated cells). Besides, a NP dose of 6.25 µg/mL did not affect the survival of HUVECs while leading to marked cell death in MCF7 and C152 cells. In vivo experiments in rats were done to investigate the biochemical and histopathological changes over three weeks, following intraperitoneal administration of Co0.5Ni0.5, Co0.6Ni0.4, and Co0.4Ni0.6 NPs (100 mg/kg). As compared with the controls, the exposure to NPs caused significant elevations in aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, serum creatinine, serum catalase activity, serum superoxide dismutase, and liver malondialdehyde levels. Also, rats treated with Co0.6Ni0.4 NPs showed more severe histopathological changes of the liver and kidney. Our findings represent an essential step toward developing theranostic nanoplatforms for selective cancer treatment.

Preparation of Near-Infrared/Photoacoustic Dual-Mode Imaging and Photothermal/Chemo Synergistic Theranostic Nanoparticles and Their Imaging and Treating of Hepatic Carcinoma.

At present, the clinical diagnosis of and treatment methods for hepatic carcinoma still fail to fully meet the needs of patients. The integrated theranostic system, in which functional materials are used to load different active molecules, created a new developmental direction for the combination treatment of hepatic carcinoma, realizing the synchronization of diagnosis and treatment. In this study, polydopamine (PDA), which has the functions of self-assembly, encapsulation, photothermal conversion, and photoacoustic interaction, was used as the carrier material. The IR780, a near-infrared fluorescence imaging (NIFI), photoacoustic imaging (PAI), and photothermal therapy (PTT) agent, and paclitaxel (PTX), a broad-spectrum chemotherapy drug, were selected to build the NIF/PA dual-mode imaging and PTT/chemo synergistic theranostic nanoparticles (DIST NPs). The DIST NPs have a 103.4 ± 13.3 nm particle size, a weak negative charge on the surface, good colloidal stability, slow and controlled drug release, and high photothermal conversion ability. The experiments results showed that the DIST NPs have a long circulation in vivo, high bioavailability, high biocompatibility, and low effective dose. DIST NPs showed an excellent NIFI/PAI dual-mode imaging and significant synergistic antitumor effect in hepatic carcinoma models. DIST NPs met the initial design requirements. A set of fast and low-cost preparation methods was established. This study provides an experimental basis for the development of new clinical theranostic methods for hepatic carcinoma.

Hitchhiking Nanoparticles: Mesenchymal Stem Cell-Mediated Delivery of Theranostic Nanoparticles.

Nanotechnology has emerged as a promising solution to permanent elimination of cancer. However, nanoparticles themselves lack specificity to tumors. Due to enhanced migration to tumors, mesenchymal stem cells (MSCs) were suggested as cell-mediated delivery vehicles of nanoparticles. In this study, we have constructed a complex composed of photoluminescent quantum dots (QDs) and a photosensitizer chlorin e6 (Ce6) to obtain multifunctional nanoparticles, combining cancer diagnostic and therapeutic properties. QDs serve as energy donors-excited QDs transfer energy to the attached Ce6 via Förster resonance energy transfer, which in turn generates reactive oxygen species. Here, the physicochemical properties of the QD-Ce6 complex and singlet oxygen generation were measured, and the stability in protein-rich media was evaluated, showing that the complex remains the most stable in protein-free medium. In vitro studies on MSC and cancer cell response to the QD-Ce6 complex revealed the complex-loaded MSCs' potential to transport theranostic nanoparticles and induce cancer cell death. In vivo studies proved the therapeutic efficacy, as the survival of tumor-bearing mice was statistically significantly increased, while tumor progression and metastases were slowed down.

Development of Dextran-Coated Magnetic Nanoparticles Loaded with Protocatechuic Acid for Vascular Inflammation Therapy.

Vascular inflammation plays a crucial role in the progression of various pathologies, including atherosclerosis (AS), and thus it has become an attractive therapeutic target. The protocatechuic acid (PCA), one of the main metabolites of complex polyphenols, is endowed with anti-inflammatory activity, but its formulation into nanocarriers may increase its bioavailability. In this study, we developed and characterized dextran shell‒iron oxide core nanoparticles loaded with PCA (MNP-Dex/PCA) and assessed their cytotoxicity and anti-inflammatory potential on cells acting as key players in the onset and progression of AS, namely, endothelial cells (EC) and monocytes/macrophages. The results showed that MNP-Dex/PCA exert an anti-inflammatory activity at non-cytotoxic and therapeutically relevant concentrations of PCA (350 μM) as supported by the reduced levels of inflammatory molecules such as MCP-1, IL-1β, TNF-α, IL-6, and CCR2 in activated EC and M1-type macrophages and functional monocyte adhesion assay. The anti-inflammatory effect of MNP-Dex/PCA was associated with the reduction in the levels of ERK1/2 and p38-α mitogen-activated protein kinases (MAPKs) and NF-kB transcription factor. Our data support the further development of dextran shell-magnetic core nanoparticles as theranostic nanoparticles for guidance, imaging, and therapy of vascular inflammation using PCA or other anti-inflammatory compounds.

Bi/Se-Based Nanotherapeutics Sensitize CT Image-Guided Stereotactic Body Radiotherapy through Reprogramming the Microenvironment of Hepatocellular Carcinoma.

The particular characteristics of hypoxia, immune suppression in the tumor microenvironment, and the lack of accurate imaging guidance lead to the limited effects of stereotactic body radiotherapy (SBRT) in reducing the recurrence rate and mortality of hepatocellular carcinoma (HCC). This research developed a novel theranostic agent based on Bi/Se nanoparticles (NPs), synthesized by a simple reduction reaction method for in vivo CT image-guided SBRT sensitization in mice. After loading Lenvatinib (Len), the obtained Bi/Se-Len NPs had excellent performance in reversing hypoxia and the immune suppression status of HCC. In vivo CT imaging results uncovered that the radiotherapy (RT) area could be accurately labeled after the injection of Bi/Se-Len NPs. Under Len's unique and robust properties, in vivo treatment was then carried out upon injection of Bi/Se-Len NPs, achieving excellent RT sensitization effects in a mouse HCC model. Comprehensive tests and histological stains revealed that Bi/Se-Len NPs could reshape and normalize tumor blood vessels, reduce the hypoxic situation of the tumor, and upregulate tumor-infiltrating CD4+ and CD8+ T lymphocytes around the tumors. Our work highlights an excellent proposal of Bi/Se-Len NPs as theranostic nanoparticles for image-guided HCC radiotherapy.

A Rational design of multi-functional nanoplatform: Fluorescent-based "off-on" theranostic gold nanoparticles modified with D-α-Tocopherol succinate.

It is crucial to develop nanocarrier systems to detect and treat drug-resistant micro tumors to prevent recurrence and/or metastasis of cancer. Due to their exceptional features such as biocompatibility, easy surface modification, serving as imaging and therapeutic agent, gold nanoparticles (AuNPs) draw attention as theranostic agents. It is beneficial to combine AuNPs with a second imaging and/or treatment modality such as photodynamic therapy (PDT). PDT is a non-mutagenic treatment approach in which photosensitizer is activated with light, generating reactive oxygen species and/or free radicals to destroy tumor cells. With the aim of developing "off-on" theranostic system, citrate stabilized spherical 13nm AuNPs were densely coated with polyethylene glycol (PEG). To advance the theranostic feature of PEGylated AuNPs, they were further functionalized with FDA-Approved photosensitizer, Verteporfin (BPD-MA). Due to static quenching between BPD-MA and AuNPs as well as in between nearby BPD-MA molecules, the fluorescence of the ground state complex is quenched and the system is in "off" state. When BPD-MA molecules are cleaved from the AuNPs surface and diffuse away, fluorescence is recovered. Consequently, the system switches to the "on" state. Among the various mole ratios of BPD-MA carrying conjugates prepared, the most promising candidate was selected based on stability, quenching factor, and fluorescence recovery rate. The conjugate was further decorated with D-α-Tocopherol succinate (VitES) to increase the therapeutic efficacy of the theranostic agent via enhancing cellular uptake. Our results showed that it was possible to achieve as high as 80 times fluorescence quenching when the system was "off". As the system switched from "off" to "on" state, 51% of the fluorescence was recovered. When BPD-MA was immobilized on the PEGylated AuNPs, the phototoxic effect of BPD-MA increased twice against the MCF-7 cell line. Moreover, the developed system showed four times more phototoxicity than BPD-MA alone after it was decorated with VitES. Since the developed system is capable of dual imaging (computed tomography and fluorescence) and dual treatment (PDT and hyperthermia), it potentially offers superior imaging and therapy options for various types of in vitro/in vivo applications.

Development and evaluation of a multi-functional organic–inorganic nanotheranostic hybrid for pancreatic cancer therapy

Pancreatic cancer is a highly invasive disease with low survival rates. The high death rates associated with pancreatic cancer are due to multiple factors including late stage diagnosis, multi-drug resistance, invasive nature and restricted access of the therapeutic moiety to the cancer cells due to the stroma. Smart multifunctional nanocarriers that deliver the therapeutic agent in to the cancer tissue as well as enable imaging of the tissue represent an emerging paradigm in cancer therapy. Accurate and reliable detection of cancerous lesions in pancreas is essential for designing appropriate therapeutic strategy to annihilate the highly aggressive pancreatic cancer. A combination of imaging modalities can enhance the reliability of cancer detection. In this context, we report here a hybrid iron oxide-gold nanoparticle with dual contrast enhancing ability for both magnetic resonance imaging (MRI) and micro-computed tomography (micro-CT) that is co-encapsulated with the nucleotide analogue gemcitabine in a chitosan matrix. The theranostic system displayed enhanced cytotoxicity against PanC-1 pancreatic cancer cells when compared to normal cells over 48 h due to differences in cell internalization. The iron oxide-gold hybrid enabled visualization of the theranostic nanoparticle by MRI as well as micro-CT. Further, the magnetocaloric effect of the iron oxide enabled faster release of the chemotherapeutic agent as well as augmented the cytotoxicity by inducing hyperthermia. This system holds promise for further exploration as an integrated diagnostic and therapeutic platform for pancreatic cancer.