Multifunctional Theranostic Nanoparticles Research Articles

Multifunctional Ultrasmall Theranostic Nanohybrids Developed by Ultrasonic Atomizer for Drug Delivery and Magnetic Resonance Imaging.

Theranostic nanoparticulate systems (TNPs) have shown potential in addressing problems related to spatial localization and temporally controlled release of drugs with the capabilities of real-time imaging to evaluate the progress of therapy. The current study reports the ultrasonic atomization-led synthesis of in vitro and in vivo evaluations of ultrasmall chitosan-based theranostic nanohybrid formulations with encapsulated doxorubicin (DOX) and iron-oxide magnetic nanoparticles. The nanohybrid particles are characterized using transmission electron microscopy, powder X-ray diffraction, FTIR, DOX encapsulation efficiency, in vitro release, cellular uptake, and toxicity. These formulations were also tested for the capability of invivo tumor reduction and simultaneous magnetic resonance imaging using Swiss albino mice. Ultrasonic atomizer-led synthesis resulted in chitosan-magnetic nanohybrids (CMNPs) having sizes of 15 ± 3 nm which comprise MNP of 10 ± 3 nm. The encapsulation of DOX in CMNP was around 25%, resulting in an 80% sustained release over 10 days at pH 5 and 7. CMNP was also found to be an efficient DOX delivery vehicle tested on cancer cells (HeLa). The CMNPs were able to reduce the tumor volume by 60% in 15 days. The inherent magnetic property and nanoscale size of CMNPs also provided for enhanced contrast efficiency in magnetic resonance imaging of tumors. Thus, such multifunctional theranostic nanoparticles can be an efficient tool for targeted diagnostic and therapeutic success.

NIR absorptive croconic acid/quercetin/CaO2 nanoplatform for tumor calcium overload therapy combined mild photothermal therapy

With excellent biocompatibility, stable chemical and optical properties, small organic molecules-based agents have always been a research hotspot in cancer photothermal therapy (PTT). In this work, a novel croconic acid-based molecule (CR) was designed and synthesized as an ideal photothermal agent (PTA), which showed abundant near-infrared (NIR) light absorption, high photothermal conversion ability, and excellent photothermal stability. By loading CR and quercetin (Qu) in CaO2, and coated with DSPE-PEG2000, a multifunctional theranostic nanoparticle (CCQ) was successfully prepared for calcium overloading mitochondrial metabolism inhibition synergetic mild PTT. Upon entering tumor microenvironment, CCQ can produce abundant H2O2 and a large amount of calcium ions, which lead to the imbalance of calcium concentration in the internal environment of tumor cells and induced mitochondrial apoptosis. With the existence of Qu, CCQ can effectively inhibit the expression of heat shock proteins (Hsp) during the PTT process, which weaken the heat resistance of tumors, ablate tumors at lower temperature (~45 °C), and reduce the damage to normal tissues. Guided by photoacoustic imaging (PAI), CCQ showed excellent multimodal therapeutic effect of tumors. This study provided a novel CR organic molecule-based theranostic nanoplatform that can be used to treat tumors via calcium overload therapy synergetic PTT at safe temperatures, which has promising potential for the future clinical cancer treatment.

Multifunctional Theranostic Nanoparticles for Enhanced Tumor Targeted Imaging and Synergistic FUS/Chemotherapy on Murine 4T1 Breast Cancer Cell.

PurposeTriple negative breast cancer (TNBC) is challenging for effective remission due to its very aggressive, extremely metastatic and resistant to conventional chemotherapy. Herein, a multifunctional theranostic nanoparticle was fabricated to enhance tumor targeted imaging and promote focused ultrasound (FUS) ablation and chemotherapy and sonodynamic therapy (SDT). A multi-modal synergistic therapy can improve the therapeutic efficacy and prognosis of TNBC.MethodsAS1411 aptamer modified PEG@PLGA nanoparticles encapsulated with perfluorohexane (PFH) and anti-cancer drug doxorubicin (DOX) were constructed (AS1411-DOX/PFH-PEG@PLGA) to enhance tumor targeted imaging to guide ablation and synergistic effect of FUS/chemotherapy. FUS was utilized to trigger the co-release of doxorubicin and simultaneously PFH phase transition and activate DOX for SDT effect. The physicochemical, phase-changeable imaging capability, biosafety of nanoparticles and multi-mode synergistic effects on growth of TNBC were thoroughly evaluated in vivo and in vitro.ResultsThe synthesized AS1411-DOX/PFH-PEG@PLGA (A-DPPs) nanoparticles are uniformly round with an average diameter of 306.03 ± 5.35 nm and the zeta potential of −4.05 ± 0.13 mV, displaying high biosafety and FUS-responsive drug release in vitro and in vivo. AS1411 modified NPs specifically bind to 4T1 cells and elevate the ultrasound contrast agent (UCA) image contrast intensity via PFH phase-transition after FUS exposure. Moreover, the combined treatment of A-DPPs nanoparticles with FUS exhibited significantly higher apoptosis rate, stronger inhibitory effect on 4T1 cell invasion in vitro, induced more reactive oxygen species (ROS), and enhanced anti-tumor effect compared to a single therapy (p < 0.05). Additionally, the joint strategy resulted in more intense cavitation effect and larger ablated areas and reduced energy efficiency factor (EEF) both in vitro and in vivo.ConclusionThe multifunctional AS1411-DOX/PFH-PEG@PLGA nanoparticles can perform as a marvelous synergistic agent for enhanced FUS/chemotherapy, promote real-time contrast enhanced US imaging and improve the therapeutic efficacy and prognosis of TNBC.

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.

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.

Complete ablation of tumors using synchronous chemoradiation with bimetallic theranostic nanoparticles

Synchronous chemotherapy and radiotherapy, termed chemoradiation therapy, is now an important standard regime for synergistic cancer treatment. For such treatment, nanoparticles can serve as improved carriers of chemotherapeutics into tumors and as better radiosensitizers for localized radiotherapy. Herein, we designed a Schottky-type theranostic heterostructure, Bi2S3–Au, with deep level defects (DLDs) in Bi2S3 as a nano-radiosensitizer and CT imaging contrast agent which can generate reactive free radicals to initiate DNA damage within tumor cells under X-ray irradiation. Methotrexate (MTX) was conjugated onto the Bi2S3–Au nanoparticles as a chemotherapeutic agent showing enzymatic stimuli-responsive release behavior. The designed hybrid system also contained curcumin (CUR), which cannot only serve as a nutritional supplement for chemotherapy, but also can play an important role in the radioprotection of normal cells. Impressively, this combined one-dose chemoradiation therapeutic injection of co-drug loaded bimetallic multifunctional theranostic nanoparticles with a one-time clinical X-ray irradiation, completely eradicated tumors in mice after approximately 20 days after irradiation showing extremely effective anticancer efficacy which should be further studied for numerous anti-cancer applications.

Hypoxia modulation by dual-drug nanoparticles for enhanced synergistic sonodynamic and starvation therapy

BackgroundSonodynamic therapy (SDT) is an emerging non-invasive therapeutic technique. SDT-based cancer therapy strategies are presently underway, and it may be perceived as a promising approach to improve the efficiency of anti-cancer treatment. In this work, multifunctional theranostic nanoparticles (NPs) were synthesized for synergistic starvation therapy and SDT by loading glucose oxidase (GOx, termed G) and 5,10,15,20-tetrakis (4-chlorophenyl) porphyrin) Cl (T (p-Cl) PPMnCl, termed PMnC) in Poly (lactic-co-glycolic) acid (PLGA) NPs (designated as MG@P NPs).ResultsOn account of the peroxidase-like activity of PMnC, MG@P NPs can catalyze hydrogen peroxide (H2O2) in tumor regions to produce oxygen (O2), thus enhancing synergistic therapeutic effects by accelerating the decomposition of glucose and promoting the production of cytotoxic singlet oxygen (1O2) induced by ultrasound (US) irradiation. Furthermore, the NPs can also serve as excellent photoacoustic (PA)/magnetic resonance (MR) imaging contrast agents, effectuating imaging-guided cancer treatment.ConclusionMultifunctional MG@P NPs can effectuate the synergistic amplification effect of cancer starvation therapy and SDT by hypoxia modulation, and act as contrast agents to enhance MR/PA dual-modal imaging. Consequently, MG@P NPs might be a promising nano-platform for highly efficient cancer theranostics.Graphical

Mucin-1 conjugated polyamidoamine-based nanoparticles for image-guided delivery of gefitinib to breast cancer

PAMAM dendrimers (PAMs) are a group of polymeric macromolecules with distinctive physicochemical features, which can make them multifunctional theranostic nanoparticles (NPs). This study was designed to examine the impact of mucin-1 aptamer-conjugated NPs which were engineered using PAM for image-guided delivery of gefitinib (GEF) in the breast cancer cells/tumor. For this, PAMAM was conjugated with diethylenetriaminepentaacetic acid (DTPA) and modified with PEG2000 to prepare a multi-functionalized NPs. Subsequently, GEF was loaded onto the DTPA-PAM-PEG NPs, which were then armed with MUC-1 aptamer to form the DTPA-PAM-PEG/GEF@MUC-1 nanosystem. Finally, aptamer-conjugated NPs were radiolabeled by gallium-67 as an imaging agent to construct image-guided nanoplatforms. The prepared NPs were characterized by different techniques. The kinetic release models of gefitinib from radiolabeled NPs offer the sustained-release mechanism of the encapsulated drug for over 7 days. In vitro evaluation showed higher cytotoxicity and enhanced uptake of the mucin-grafted NPs in MCF-7 cells. Nuclear medicine imaging and in vivo investigations revealed significant accumulation of 67Ga-DTPA-PAM-PEG/GEF@MUC-1 in the tumor site of the animal models. These data suggest that the engineered NPs are a promising image-guided nanosystem for mucin-expressing breast cells/tumors with the assistance of nuclear medicine.

Multifunctional FeS2 theranostic nanoparticles for photothermal-enhanced chemodynamic/photodynamic cancer therapy and photoacoustic imaging

Chemodynamic therapy (CDT) and photodynamic therapy (PDT) mediated by reactive oxygen species (ROS) hold great potential for cancer therapy. However, they are still limited by rigorous reaction conditions of efficacious Fenton reaction, reliance on oxygen, and inherent defects of traditional common photosensitizers (PSs). Herein, we reported an L-Buthionine-sulfoximine (BSO) modified FeS2 nanoparticles (BSO-FeS2 NPs) with enhanced ROS generation under single wavelength (808 nm) laser irradiation. First, FeS2 NPs showed high photothermal conversion efficiency (49.5%) and enhanced O2− and OH generation capability via direct electron transfer presenting photothermal-improved Fenton reaction and photocatalytic ability. With the BSO modification, BSO-FeS2 NPs could inhibit the synthesis of glutathione (GSH) and accelerate the accumulation of ROS, which further enhanced the PDT/CDT treatment efficacy and resulted in high in vivo tumor inhibition rate (95%). Second, BSO-FeS2 NPs could activate the repolarization of macrophages from M2 to M1 for potential tumor immunotherapy. Last, BSO-FeS2 NPs showed good performance on photoacoustic imaging (PAI). All these results establish the capability of BSO-FeS2 NPs as nano-theranostic agents in PAI guided PTT/CDT/PDT combination therapy for cancer treatment.

Fluorescence imaging-guided multifunctional liposomes for tumor-specific phototherapy for laryngeal carcinoma.

Reliable diagnosis and efficient targeted therapy are important and may lead to the effective treatment of laryngeal carcinoma. Multifunctional nano-theranostic agents demonstrate great potential in tumor theranostic applications. Thus, herein, we report novel targeting multifunctional theranostic nanoparticles, internalized RGD (iRGD)-modified indocyanine green (ICG) encapsulated liposomes (iLIPICG), for imaging-guided photothermal therapy (PTT) and photodynamic therapy (PDT) for the treatment of laryngeal carcinoma. The iRGD-PEG-DSPE lipid endowed iLIPICG with high affinity for tumor vascular targeting, tumor-penetration and tumor cell targeting. The in vivo results showed that iLIPICG exhibited excellent blood circulation and tumor accumulation. iLIPICG could be spatially and temporally controlled, simultaneously producing hyperthermia and reactive oxygen species as well as a fluorescence-guided effect through ICG to ablate laryngeal carcinoma cells under irradiation from an 808 nm laser. iLIPICG generated synergistic photodynamic-photothermal cytotoxicity against Hep-2 cells, resulting in the efficient ablation of laryngeal carcinoma. Thus, the iLIPICG system provides a promising strategy to improve the precision imaging and effective phototherapy for the treatment of laryngeal carcinoma.

Thermo-responsive Fluorescent Nanoparticles for Multimodal Imaging and Treatment of Cancers.

Theranostic systems capable of delivering imaging and therapeutic agents at a specific target are the focus of intense research efforts in drug delivery. To overcome non-degradability and toxicity concerns of conventional theranostic systems, we formulated a novel thermo-responsive fluorescent polymer (TFP) and conjugated it on the surface of iron oxide magnetic nanoparticles (MNPs) for imaging and therapeutic applications in solid tumors. Methods: TFP-MNPs were synthesized by copolymerizing poly(N-isopropylacrylamide), allylamine and a biodegradable photoluminescent polymer, and conjugating it on MNPs via a free radical polymerization reaction. Physicochemical properties of the nanoparticles were characterized using Fourier transform infrared spectroscopy, dynamic light scattering, and vibrational sample magnetometry. Nanoparticle cytocompatibility, cellular uptake and cytotoxicity were evaluated using in vitro cell assays. Finally, in vivo imaging and therapeutic efficacy studies were performed in subcutaneous tumor xenograft mouse models. Results: TFP-MNPs of ~135 nm diameter and -31 mV ζ potential maintained colloidal stability and superparamagnetic properties. The TFP shell was thermo-responsive, fluorescent, degradable, and released doxorubicin in response to temperature changes. In vitro cell studies showed that TFP-MNPs were compatible to human dermal fibroblasts and prostate epithelial cells. These nanoparticles were also taken up by prostate and skin cancer cells in a dose-dependent manner and exhibited enhanced killing of tumor cells at 41°C. Preliminary in vivo studies showed theranostic capabilities of the nanoparticles with bright fluorescence, MRI signal, and therapeutic efficacy under magnetic targeting after systemic administration in tumor bearing mice. Conclusion: These results indicate the potential of TFP-MNPs as multifunctional theranostic nanoparticles for various biological applications, including solid cancer management.

From one to all: self-assembled theranostic nanoparticles for tumor-targeted imaging and programmed photoactive therapy

BackgroundIn recent years, multifunctional theranostic nanoparticles have been fabricated by integrating imaging and therapeutic moieties into one single nano-formulations. However, Complexity of production and safety issues limits their further application.ResultsHerein, we demonstrated self-assembled nanoparticles with single structure as a “from one to all” theranostic platform for tumor-targeted dual-modal imaging and programmed photoactive therapy (PPAT). The nanoparticles were successfully developed through self-assembling of hyaluronic acid (HA)-cystamine-cholesterol (HSC) conjugate, in which IR780 was simultaneously incorporated (HSCI NPs). Due to the proper hydrodynamic size and intrinsic targeting ability of HA, the HSCI NPs could accumulate at the tumor site effectively after systemic administration. In the presence of incorporated IR780, in vivo biodistribution and accumulation behaviors of HSCI NPs could be monitored by photoacoustic imaging. After cellular uptake, the HSCI NPs would disintegrate resulting from cystamine reacting with over-expressed GSH. The released IR780 would induce fluorescence “turn-on” conversion, which could be used to image tumor sites effectively. Upon treatment with 808 nm laser irradiation, PPAT could be achieved in which generated reactive oxygen species (ROS) would produce photodynamic therapy (PDT), and subsequently the raised temperature would be beneficial to tumor photothermal therapy (PTT).ConclusionThe self-assembled HSCI NPs could act as “from one to all” theranostic platform for high treatment efficiency via PPAT pattern, which could also real-time monitor NPs accumulation by targeted and dual-modal imaging in a non-invasive way.

Rodlike MSN@Au Nanohybrid-Modified Supermolecular Photosensitizer for NIRF/MSOT/CT/MR Quadmodal Imaging-Guided Photothermal/Photodynamic Cancer Therapy.

Recently, rodlike nanomaterials with specific aspect ratio for efficient cellular uptake have received enormous attention. For functional nanomaterials, such as photothermal agents, large surface areas for their rod-shaped exterior that increase the amount of light absorbed would lead to a higher absorption coefficient as well as drug-loading property. In this project, we coated rodlike mesoporous silica with gold nanoshells (MSNR@Au hybrid), modifying them with ultrasmall gadolinium (Gd)-chelated supramolecular photosensitizers, TPPS4 (MSNR@Au-TPPS4(Gd)), which could be applied to near-infrared fluorescence/multispectral optoacoustic tomography/computed tomography/magnetic resonance imaging and imaging-guided remotely controlled photothermal (PTT)/photodynamic (PDT) combined antitumor therapy. Gold nanoshells, as a perfect PTT agent, were used to assemble the rodlike mesoporous silica nanoparticles with larger superficial area and higher drug loading, thus obtaining the MSNR@Au hybrid. HS-β-CD, which was used as the host, was adsorbed on the gold nanoshell (MSNR@Au-β-CD) to link TPPS4(Gd) through the host-guest reaction, thus forming CD-TPPS4 supramolecular photosensitizers (supraPSs). Compared with conventional PSs, supraPSs have host screens, which could reduce the self-aggregation of TPPS4, and consequently generate 1O2 with high efficiency. The in vivo quadmodal imaging of MSNR@Au-TPPS4(Gd) nanoparticles revealed an intensive tumor uptake effect after injection. The in vivo antitumor efficacy further testified that the synergistic therapy, which was more efficient than any other monotherapy, exhibited an excellent tumor inhibition therapeutic effect. As a result, this encourages to further explore multifunctional theranostic nanoparticles based on gold shells for combined cancer therapy.

A disassembling strategy overcomes the EPR effect and renal clearance dilemma of the multifunctional theranostic nanoparticles for cancer therapy

Despite multifunctional nanoparticles using for photothermal therapy can efficiently kill cancer cells, their further application is still hindered by the intrinsic high uptake in the reticuloendothelial system (RES) organs, causing the slow elimination from the body and potential toxicity to the body. Therefore, it is ideal to develop multifunctional nanoparticles which process the ability to effectively accumulate in tumors, while the nanoparticles can be rapidly excreted from the body via renal clearance after effective treatment. Herein, we report the multifunctional nanoparticles (FeTNPs) based on the coordination interaction of phenolic group and metal iron, which are composed of ferric iron, tannic acid (TA) and poly (glutamic acid)-graft-methoxypoly (ethylene glycol) (PLG-g-mPEG). FeTNPs exhibit the following highlighted features: (1) The effective accumulation in the tumor tissue is achieved based on EPR effect. (2) The dual photoacoustic (PA)/magnetic resonance (MR) imaging capacity can provide guidance for the photothermal therapy (PTT). (3) FeTNPs can be dynamically disassembled by deferoxamine mesylate (DFO) to accelerate elimination of the nanoparticles, thus reducing the potential toxicity for the body. The DFO triggered dynamic disassembling strategy may open a new avenue to overcome the dilemma between EPR effect and renal clearance.

Bioimaging predictors of rilpivirine biodistribution and antiretroviral activities

Antiretroviral therapy (ART) has changed the outcome of human immunodeficiency virus type one (HIV-1) infection from certain death to a life free of disease co-morbidities. However, infected people must remain on life-long daily ART. ART reduces but fails to eliminate the viral reservoir. In order to improve upon current treatment regimens, our laboratory created long acting slow effective release (LASER) ART nanoformulated prodrugs from native medicines. LASER ART enables antiretroviral drugs (ARVs) to better reach target sites of HIV-1 infection while, at the same time, improve ART's half-life and potency. However, novel ARV design has been slowed by prolonged pharmacokinetic testing requirements. To such ends, tri-modal theranostic nanoparticles were created with single-photon emission computed tomography (SPECT/CT), magnetic resonance imaging (MRI) and fluorescence capabilities to predict LASER ART biodistribution. The created theranostic ARV probes were then employed to monitor drug tissue distribution and potency. Intrinsically 111Indium (111In) radiolabeled, europium doped cobalt-ferrite particles and rilpivirine were encased in a polycaprolactone core surrounded by a lipid shell (111InEuCF-RPV). Particle cell and tissue distribution, and antiretroviral activities were sustained in macrophage tissue depots. 111InEuCF-PCL/RPV particles injected into mice demonstrated co-registration of MRI and SPECT/CT tissue signals with RPV and cobalt. Cell and animal particle biodistribution paralleled ARV activities. We posit that particle selection can predict RPV distribution and potency facilitated by multifunctional theranostic nanoparticles.

Multifunctional Theranostic Nanoparticles Derived from Fruit-Extracted Anthocyanins with Dynamic Disassembly and Elimination Abilities.

Low toxic theranostic nanoparticles that can simultaneously achieve effective tumor accumulation and rapid renal clearance are highly desired for imaging contrast agents and photothermal therapy (PTT) in tumor diagnosis and therapy. Herein, we report a one-pot method for preparing multifunctional nanoparticles (FeAP-NPs) based on the coordination interaction of natural polyphenols (anthocyanins) extracted from fruits, FeIII ions, and poly(l-glutamic acid)- g-methoxy poly(ethylene glycol) copolymers. The FeAP-NPs possess the following favorable advantages: (1) The components of FeAP-NPs originate from natural products, an endogenous element, and poly(amino acid) derivatives, guaranteeing their safety for in vivo application. (2) FeAP-NPs exhibit excellent dual photoacoustic (PA)/magnetic resonance (MR) imaging capacity and high photothermal efficiency. (3) FeAP-NPs can overcome the intractable dilemma of the enhanced permeability and retention (EPR) effect and renal clearance for nanomedicine through the dynamic disassembling ability, which induces a switch of the elimination pathway. Complete tumor ablation is realized by PTT in MCF-7-bearing nude mice under the precise guide of PA and MR imaging. The detailed evaluation of the safety, biodistribution, and elimination behaviors of FeAP-NPs is conducted in vitro or in vivo. This work provides a promising comprehensive solution for nanomedicine clinical application.

Polymer-based gadolinium oxide nanocomposites for FL/MR/PA imaging guided and photothermal/photodynamic combined anti-tumor therapy

Recently, ultrasmall gadolinium oxide (Gd2O3) nanoparticles with high longitudinal relaxation rate have received enormous attention. However, it can't be concentrated in tumor site through intravenous administration due to its ultrasmall size. In this project, we coated ultrasmall Gd2O3 nanoparticles with a near-infrared (NIR) light-absorbing polymer polypyrrole (PPy), modifying with hyaluronic acid (HA) and loaded aluminum phthalocyanine (AlPc), the Gd2O3@PPy/AlPc-HA nanoparticles could be used for fluorescence (FL)/magnetic resonance (MR)/photoacoustic (PA) imaging guided as well as remotely controlled PTT/PDT combined anti-tumor therapy. Polymerized PPy with high photothermal conversion efficiency was introduced to assemble the ultrasmall Gd2O3 nanoparticles which have high longitudinal relaxation rate and signal-to-noise ratio, thus obtaining Gd2O3@PPy nanoparticles which possess a larger particle size and can be more suitable for tumor targeting based on the EPR effect. HA and AlPc were adsorbed on PPy for HA-mediated tumor targeting and photodynamic therapy respectively. The in vivo triple-modal imaging revealed that Gd2O3@PPy/AlPc-HA nanoparticles possess enhanced tumor uptake effect after intravenous injection. More importantly, the nanoparticles exhibited an obvious photothermal effect, which can trigger the release and de-quench of AlPc. The anti-tumor efficiency further corroborated that the combined therapy achieved an excellent tumor inhibition therapeutic effect which was much better than any other mono-therapy. Consequently, our work encouraged further exploration of polymer-based multifunctional theranostic nanoparticles for cancer combination therapy under remote near-infrared (NIR) light controls.

Folic acid-functionalized polyethylenimine superparamagnetic iron oxide nanoparticles as theranostic agents for magnetic resonance imaging and PD-L1 siRNA delivery for gastric cancer

Programmed death ligand-1 (PD-L1), which is highly expressed in gastric cancers, interacts with programmed death-1 (PD-1) on T cells and is involved in T-cell immune resistance. To increase the therapeutic safety and accuracy of PD-1/PD-L1 blockade, RNA interference through targeted gene delivery was performed in our study. We developed folic acid (FA)- and disulfide (SS)–polyethylene glycol (PEG)-conjugated polyethylenimine (PEI) complexed with superparamagnetic iron oxide Fe3O4 nanoparticles (SPIONs) as a siRNA-delivery system for PD-L1 knockdown. The characterization, binding ability, cytotoxicity, transfection efficiency, and cellular internalization of the polyplex were determined. At nitrogen:phosphate (N:P) ratios of 10 or above, the FA-PEG-SS-PEI-SPIONs bound to PD-L1 siRNA to form a polyplex with a diameter of approximately 120 nm. Cell-viability assays showed that the polyplex had minimal cytotoxicity at low N:P ratios. The FA-conjugated polyplex showed higher transfection efficiency and cellular internalization in the folate receptor-overexpressing gastric cancer cell line SGC-7901 than a non-FA-conjugated polyplex. Subsequently, we adopted the targeted FA-PEG-SS-PEI-SPION/siRNA polyplexes at an N:P ratio of 10 for function studies. Cellular magnetic resonance imaging (MRI) showed that the polyplex could also act as a T2-weighted contrast agent for cancer MRI. Furthermore, one of four PD-L1 siRNAs exhibited effective PD-L1 knockdown in PD-L1-overexpressing SGC-7901. To determine the effects of the functionalized polyplex on T-cell function, we established a coculture model of activated T cells and SGC-7901 cells and demonstrated changes in secreted cytokines. Our findings highlight the potential of this class of multifunctional theranostic nanoparticles for effective targeted PD-L1-knockdown therapy and MRI diagnosis in gastric cancers.

Redox-responsive dextran based theranostic nanoparticles for near-infrared/magnetic resonance imaging and magnetically targeted photodynamic therapy.

Photodynamic therapy (PDT) is a site-specific treatment of cancer using much lower optical power densities with minimal nonspecific damage to normal tissues. To improve the therapeutic efficiency of PDT, we fabricated a multifunctional theranostic nanoparticle system (DSSCe6@Fe3O4 NPs) by loading Fe3O4 nanoparticles in redox-responsive chlorin e6 (Ce6)-conjugated dextran nanoparticles for near-infrared (NIR)/magnetic resonance (MR) dual-modality imaging and magnetic targeting. The obtained DSSCe6@Fe3O4 NPs demonstrated a uniform nanospherical morphology consisting of Fe3O4 clusters. The fluorescence signal of Ce6 of this theranostic system could turn "ON" from a self-quenching state in a reductive intracellular environment. T2-Weighted MR imaging revealed a high transverse relaxivity (r2) measured to be 194.4 S-1 mM-1, confirming that it was also a distinctive contrast agent in T2-weighted MR imaging. Confocal images and flow cytometry results showed that the cellular uptake of DSSCe6@Fe3O4 NPs was enhanced effectively under an extra magnetic field, which resulted in promoted PDT therapeutic efficiency. In vivo MR imaging showed that DSSCe6@Fe3O4 NPs effectively accumulated in tumors under an extra magnetic field. These results illustrated that the DSSCe6@Fe3O4 NPs could be a promising theranostic system for both NIR/MR imaging-guided PDT precision therapy.

Fabrication and in vitro characterization of gadolinium-based nanoclusters for simultaneous drug delivery and radiation enhancement

We report the synthesis of a gadolinium hydroxide (Gd(OH)3) nanorod based doxorubicin (Dox) delivery system that can enhance both magnetic resonance imaging contrast and radiation sensitivity. A simple and cost effective wet-chemical method was utilized in the presence of manganese (Mn) ions and Dox to produce the Gd(OH)3:Mn·Dox nanocluster structure. The Gd(OH)3:Mn·Dox nanocluster was composed of Mn-doped Gd(OH)3 nanorods arranged in parallel with Dox as a linker molecule between the adjacent nanorods. No other studies have utilized Dox as both the linker and therapeutic molecule in a nanostructure to date. The Gd(OH)3 nanorod is reported to have no significant cellular or in vivo toxicity, which makes it an ideal base material for this biomedical application. The Gd(OH)3:Mn·Dox nanocluster exhibited paramagnetic behavior and was stable in a colloidal solution. The nanocluster also enabled high Dox loading capacity and specifically released Dox in a sustained and pH-dependent manner. The positively charged Gd(OH)3:Mn·Dox nanoclusters were readily internalized into MDA-MB-231 breast cancer cells via endocytosis, which resulted in intracellular release of Dox. The released Dox in cells was effective in conferring cytotoxicity and inhibiting proliferation of cancer cells. Furthermore, a synergistic anticancer effect could be observed with radiation treatment. Overall, the Gd(OH)3:Mn·Dox nanocluster drug delivery system described herein may have potential utility in clinics as a multifunctional theranostic nanoparticle with combined benefits in both diagnosis and therapy in the management of cancer.