Multifunctional Theranostic System Research Articles

Bio-orthogonal click chemistry strategy for PD-L1-targeted imaging and pyroptosis-mediated chemo-immunotherapy of triple-negative breast cancer

BackgroundThe combination of programmed cell death ligand-1 (PD-L1) immune checkpoint blockade (ICB) and immunogenic cell death (ICD)-inducing chemotherapy has shown promise in cancer immunotherapy. However, triple-negative breast cancer (TNBC) patients undergoing this treatment often face obstacles such as systemic toxicity and low response rates, primarily attributed to the immunosuppressive tumor microenvironment (TME).Methods and resultsIn this study, PD-L1-targeted theranostic systems were developed utilizing anti-PD-L1 peptide (APP) conjugated with a bio-orthogonal click chemistry group. Initially, TNBC was treated with azide-modified sugar to introduce azide groups onto tumor cell surfaces through metabolic glycoengineering. A PD-L1-targeted probe was developed to evaluate the PD-L1 status of TNBC using magnetic resonance/near-infrared fluorescence imaging. Subsequently, an acidic pH-responsive prodrug was employed to enhance tumor accumulation via bio-orthogonal click chemistry, which enhances PD-L1-targeted ICB, the pH-responsive DOX release and induction of pyroptosis-mediated ICD of TNBC. Combined PD-L1-targeted chemo-immunotherapy effectively reversed the immune-tolerant TME and elicited robust tumor-specific immune responses, resulting in significant inhibition of tumor progression.ConclusionsOur study has successfully engineered a bio-orthogonal multifunctional theranostic system, which employs bio-orthogonal click chemistry in conjunction with a PD-L1 targeting strategy. This innovative approach has been demonstrated to exhibit significant promise for both the targeted imaging and therapeutic intervention of TNBC.Graphical abstract

Multifunctional polypeptide-based polymersome for chemophotothermal therapy of melanoma in vitro and in vivo

To date, combination therapy using chemo-photothermal therapy (Ch-PTT) has attracted tremendous interest due to its efficient ablation of cancerous cells. Furthermore, there are several advantages to using peptide-based nanocarriers for theranostic nanoplatforms, such as excellent biocompatibility and biodegradability, significant encapsulation efficacy for lipophilic drugs with negligible drug leakage, excellent stability, and excellent enzymatic degradation. In the current study, a multifunctional theranostic system based on polymersome (vesicular nanocarrier of self-assembled amphiphilic polymer) was developed for targeted Ch-PTT and x-ray CT imaging of melanoma cancer. For this purpose, using ring opening polymerization (ROP) of γ-benzyl l-glutamate-N-carboxyanhydride (LG-NCA) lipophilic polypeptide PLG (poly(γ-benzyl-l-glutamate) was synthesized and covalently linked to bifunctional COOH-PEG-NH2. Next, polypeptide-based polymersome nanocarier based on amphiphilc PEG-PLG was fabricated and co-encapsulated with hydrophilic gold nanorod (AuNR) and lipophilic curcumin (CUR) in aqueous core and lipophilic bilayer of polymersome (P-AuNR-CUR), respectively. Then, Sgc8-c aptamer were decorated on the polymersome surface (Apt-P-AuNR-CUR) for targeted delivery, and the size of P-AuNR-CUR and Apt-P-AuNR-CUR were determined using DLS device (174.3 ± 5.95 and 206 ± 52, respectively). NIR (near-infrared)-laser-triggered drug delivery release performance of multifunctional polymersome was demonstrated in both citrate and phosphate buffer saline. According to both in vitro and in vivo studies, NIR-responsive polymersomes possess remarkable therapeutic efficacy for Chemo-PTT in comparison to individual cancer therapy. Furthermore, the diagnostic capability of the designed nanoplatform was confirmed using in vivo CT scan imaging 6 h post-intravenous injection.

Quinoxalineimide-Based Semiconducting Polymer Nanoparticles as an Effective Phototheranostic for the Second Near-Infrared Fluorescence Imaging and Photothermal Therapy.

Multifunctional theranostics play a critical role in improving the efficacy of photothermal therapy and tumor fluorescence imaging; however, they require the integration of complex components into a single theranostic system, and their response in the second near-infrared (NIR-II) region is constrained by wavelengths of a photosensitizer. To address this issue, we herein developed a novel multifunctional thiazole-fused quinoxalineimide semiconducting polymer (named PQIA-BDTT), which exhibits NIR-II fluorescence and photothermal properties. PQIA-BDTT nanoparticles achieved an impressively high photothermal conversion efficiency (72.6%) in laser (1064 nm)-induced photothermal therapy at a safe maximum permissible exposure, demonstrating their capability as an effective photothermal agent. Moreover, PQIA-BDTT nanoparticles can be used as a reference for NIR-II fluorescence imaging under a low laser fluence. The tumor size and location in 4T1 mice intravenously injected with the PQIA-BDTT nanoparticles could be precisely identified through NIR-II fluorescence imaging, which also exhibited remarkable photothermal antitumor efficacy by in vitro and in vivo therapy. Overall, this study demonstrates that introducing a thiazole-fused quinoxalineimide acceptor unit into a donor-acceptor conjugated polymer is an effective strategy for the synthesis of novel multifunctional theranostic systems, which provides a novel platform for designing theranostic agents for biomedical applications.

A multifunctional AIE gold cluster-based theranostic system: tumor-targeted imaging and Fenton reaction-assisted enhanced radiotherapy

BackgroundAs cancer is one of the main leading causes of mortality, a series of monotherapies such as chemotherapy, gene therapy and radiotherapy have been developed to overcome this thorny problem. However, a single treatment approach could not achieve satisfactory effect in many experimental explorations.ResultsIn this study, we report the fabrication of cyclic RGD peptide (cRGD) modified Au4-iron oxide nanoparticle (Au4-IO NP-cRGD) based on aggregation-induced emission (AIE) as a multifunctional theranostic system. Besides Au4 cluster-based fluorescence imaging and enhanced radiotherapy, iron oxide (IO) nanocluster could realize magnetic resonance (MR) imaging and Fenton reaction-based chemotherapy. Abundant toxic reactive oxygen species generated from X-ray irradiation and in situ tumor-specific Fenton reaction under acidic microenvironment leads to the apoptotic and necrotic death of cancer cells. In vivo studies demonstrated good biocompatibility of Au4-IO NP-cRGD and a high tumor suppression rate of 81.1% in the synergistic therapy group.ConclusionsThe successful dual-modal imaging and combined tumor therapy demonstrated AIE as a promising strategy for constructing multifunctional cancer theranostic platform.Graphical

Multifunctional Organic Fluorescent Probe with Aggregation-Induced Emission Characteristics: Ultrafast Tumor Monitoring, Two-Photon Imaging, and Image-Guide Photodynamic Therapy.

The development of multifunctional photosensitizers (PSs) with aggregation-induced emission (AIE) properties plays a critical role in promoting the progress of the photodynamic therapy (PDT). In this work, a multifunctional PS (named DSABBT NPs) with AIE activity has been designed and prepared to carry out ultrafast staining, excellent two-photon bioimaging, and high-efficiency image-guided PDT. Simply, DSABBT with AIE characteristic was synthesized by one-step Schiff reaction of 4-(diethylamino)-salicylaldehyde (DSA) and 4,7-bis(4-aminophenyl)-2,1,3-benzothiadiazole (BBT). Then, DSABBT and DSPE-PEG2000-cRGD generate nanoparticles (NPs) easily in an ultrapure water/tetrahydrofuran mixture through a facile nanoprecipitation at room temperature. We found that DSABBT NPs exhibit bright solid-state fluorescence with large stokes shifts (180 nm) and two-photon absorption cross-section (1700 GM). Importantly, DSABBT NPs exhibited excellent ability of ultrafast staining and two-photon imaging, which can readily label suborganelles by subtly shaking the living cells for 5 s under mild conditions. Moreover, DSABBT NPs displayed high singlet oxygen (1O2) generation capacity and remarkable image-guided PDT efficiency. Therefore, DSABBT NPs can act as the promising candidate for multifunctional PSs, which can destroy cancer cells and block malignant tumor growth via the production of reactive oxygen species upon irradiation conditions. These outcomes provide us with a selectable strategy for developing multifunctional theranostic systems.

Comprehensive Effects of Near-Infrared Multifunctional Liposomes on Cancer Cells.

Multifunctional theranostic systems are a recent important development of medical research. We combined the characteristics of near-infrared luminescent quantum dots and thermosensitive magnetoliposomes to develop a multifunctional nano-diagnostic material. This system is based on near-infrared magnetic thermosensitive liposomes, which encapsulate drugs and can control drug localization and release. After incubating cancer cells with the liposomes, the state of the cells was analyzed in real time by near-infrared imaging. Cell viability was significantly inhibited by heat treatment or alternating magnetic field treatment, which thus improved the anti-cancer properties of the liposomes. In the future, by combining near-infrared imaging technology and an external high-frequency alternating magnetic field, we could not only detect cancer cells noninvasively but also conduct image-guided treatments for cancer.

Self-Assembly Nanoparticles for Overcoming Multidrug Resistance and Imaging-Guided Chemo-Photothermal Synergistic Cancer Therapy.

Background and PurposeThe development of multiple drug resistance (MDR) to chemotherapy and single modal therapy remains unsatisfied for the eradication of tumor, which are major obstacles in cancer therapy. This novel system with excellent characteristics for inhibition of P-glycoprotein (P-gp), and for near-infrared fluorescence (NIRF) imaging-guided chemo-photothermal therapy (PTT), has been identified as a promising way to MDR and achieve synergistic cancer therapy.MethodsIn this study, we successfully synthesized a multifunctional theranostic system, which was developed through FDA-approved self-assembling drugs, which contain anticancer drug doxorubicin (Dox), imaging and high photothermal conversion drug indocyanine green (ICG) and P-gp regulator TPGS (the system named T/Dox-ICG). We studied the characterization of T/Dox-ICG NPs, including the TEM, SEM, DLS, UV-vis-NIR, zeta potential, CLSM, in vitro FL imaging, in vitro photothermal effect, in vitro Dox and ICG release. We used CLSM to verify the location of intracellular distribution of Dox in SCG 7901/VCR cells, Western blot was performed to demonstrate the TPGS-mediated inhibition of P-gp. And, the cytotoxicity of materials against SCG 7901/VCR cells was studied by the MTT assay.ResultsThe TEM showed the T/Dox-ICG NPs had good monodispersity with diameters of 19.03 nm, Dox and ICG could be released constantly from T/Dox-ICG NPs in vitro. In vitro cell experiments demonstrated higher Dox accumulation and retention in the nucleus. Western blot showed TPGS could obviously inhibit the expression of P-gp. In vitro cytotoxicity assay showed more significant cytotoxicity on MDR cells (SCG 7901/VCR) with only 8.75% of cells surviving.ConclusionMDR cancer therapy indicates that it may be important to develop a safer system that can simultaneously inhibit the drug transporters and monitor the delivery of chemotherapeutic agents, and combination therapy have raised widespread concern on tumor treatment.

A DNA/metal cluster-based nano-lantern as an intelligent theranostic device.

We constructed a DNA/metal cluster-based nano-lantern as a multifunctional theranostic system by combining various properties into one ingenious DNA device.

Meet the First Authors.

Meet the First Authors.

Smart Delivery Systems Based on Poly(glycidyl methacrylate)s-Coated Organic/Inorganic Core-Shell Nanohybrids.

Smart delivery systems have gained momentum over the last few decades due to their potential to realize enhanced therapeutic efficacy. Poly(glycidyl methacrylate)s (PGMAs), which spring up like mushrooms, have drawn great attention in the theranostics field, especially in multifunctional theranostic systems. The marriage of PGMAs with functional inorganic cores is expected to integrate diagnosis (e.g., fluorescence, X-ray computed tomography, magnetic resonance, photoacoustic and upconversion luminescence imaging), treatment, or multimodal synergistic therapies (e.g., chemotherapy, gene therapy, photothermal therapy) in one pot for personalized medicine. In this review, recent progress in various PGMA-coated nanohybrids based on the type of integrated inorganic nanoparticle, including silica nanoparticles, magnetic nanoparticles, quantum dots, gold nanoparticles, gold nanorods, metal-organic frameworks, cellulose nanocrystals, and their core-shell nanostructures is systematically reviewed. Future work in this field is anticipated to be devoted to developing efficient real-time-imaging-guided multimodal synergistic therapies.

Carbon Dots for In Vivo Bioimaging and Theranostics.

Carbon dots (CDs), a kind of carbon material discovered accidentally, exhibit unexpected advantages in fluorescence imaging/sensing such as photostability, biocompatibility, and low toxicity. For emerging theranostics, an interdiscipline created by integrating therapy and diagnostics, CDs are good candidates when they are combined with targeted chemo/gene/photodynamic/photothermal therapeutic moieties. Here, the development of CDs in nanomedicine is reviewed from their use as original imaging agents and/or drug carriers to multifunctional theranostic systems. Finally, the challenges and prospects of the next-generation of CD-based theranostics for clinical applications are also discussed.

Excitation Modulation of Upconversion Nanoparticles for Switch-like Control of Ultraviolet Luminescence.

The ability to control ultraviolet (UV) luminescence intensity in a switch-like manner is demonstrated through the use of 980 nm excitation pulse-width modulation in NaYF4:Yb3+,Tm3+ upconversion nanoparticles (UNPs). Varying the ytterbium doping resulted in a single order of magnitude improvement of UV luminescence intensity. The excitation pulse-width modulation technique applied to these optimized UNPs enables 3 orders of magnitude control over UV luminescence intensity while maintaining NIR luminescence emission at 800 nm. Controlled in the switch-like manner, these UNPs can transfer their UV energy to 9,10-diphenylanthracene (DPA). Independent control of NIR luminescence and UV energy transfer through NIR excitation modulation may find applications in the development of multifunctional theranostic systems.

NIR-to-Red Upconversion Nanoparticles with Minimized Heating Effect for Synchronous Multidrug Resistance Tumor Imaging and Therapy

Lanthanide-doped upconversion nanoparticles (UCNPs), especially the 808 nm activated UCNPs, are promising imaging agents for biological applications because of their minimal tissue overheating effects and low autofluorescence background. Optimizing the emission peaks located in the "biological window (600-1100 nm)" is of vital importance to obtain the maximum penetration depth and intense deep tissue imaging. On the other hand, because of the widely existing multidrug resistance (MDR) of tumor cells, traditional tumor chemotherapy often fails to achieve the desired effect. Herein, a new type of 808 nm excited pure red luminescence core-shell Nd3+-sensitized NaY(Mn)F4:Yb/Er@NaYbF4:Nd UCNPs (CSUCNPs) was designed and synthesized for deep tissue imaging and MDR tumor diagnosis with a minimized heating effect. In the meanwhile, d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) coating was introduced to endow CSUCNPs with capabilities of drug loading and overcoming MDR. The in vitro cytotoxicity test revealed that CSUCNPs-TPGS-doxorubicin (D-CSUCT) had excellent MDR cancer cell killing efficacy. The in vivo test showed that D-CSUCT can target the tumor site by enhanced retention effect, and the intense luminescent signals from the tumor site in the deep tissue were detected. Generally, this work shows D-CSUCT can overcome the MDR effect, diagnose the tumor, inhibit tumor growth, and induce tumor cells necrosis and apoptosis, without causing damage to major organs and other side effects. Overall, the study demonstrates the conjugation of red-emitted UCNPs with a minimized heating effect and that the anti-MDR carrier is highly promising for developing multifunctional theranostic system with effective simultaneous diagnosis and for multidrug-resistant tumor treatment.

Pompon-like RuNPs-Based Theranostic Nanocarrier System with Stable Photoacoustic Imaging Characteristic for Accurate Tumor Detection and Efficient Phototherapy Guidance.

Even though numerous therapeutic methods exist for cancer treatment, many fail to achieve ideal outcomes or have severe side effects. Here, we describe a theranostic nanocarrier system with improved tumor vasculature detection and tumor margin quantification that increases the accuracy and guidance efficiency of phototherapy. Novel pompon-like RuNPs with superb photothermal properties and high encapsulation efficiency were first synthesized via the polyol reducing method. Based on these RuNPs, we then developed a multifunctional theranostic system, pRu-pNIPAM@RBT, composed of poly(N-isopropylacrylamide) as the thermal-response switch and of [Ru(bpy)2(tip)]2+ as the photosensitizer of PDT and the contrast agent of biomedical imaging. We demonstrate that the pRu-pNIPAM@RBT can generate intracellular hyperthermia and reactive oxygen species (ROS) for simultaneous photothermal therapy (PTT) and photodynamic therapy (PDT) by laser activation. In contrast to other studies, our work highlights the integration of quantitative analysis of infrared thermal imaging and PA imaging data, which can distinguish between tumor and healthy tissues and guide the destructive but precise phototherapy and decrease nonspecific tissue injury. Considering the excellent in vivo antitumor phototherapeutic effects, this strategy may help preclinical researchers gain insight into theoretical as well as practical aspects of precision cancer therapy.

Biodegradable Core-shell Dual-Metal-Organic-Frameworks Nanotheranostic Agent for Multiple Imaging Guided Combination Cancer Therapy.

Metal-organic-frameworks (MOFs) possess high porosity, large surface area, and tunable functionality are promising candidates for synchronous diagnosis and therapy in cancer treatment. Although large number of MOFs has been discovered, conventional MOF-based nanoplatforms are mainly limited to the sole MOF source with sole functionality. In this study, surfactant modified Prussian blue (PB) core coated by compact ZIF-8 shell (core-shell dual-MOFs, CSD-MOFs) has been reported through a versatile stepwise approach. With Prussian blue as core, CSD-MOFs are able to serve as both magnetic resonance imaging (MRI) and fluorescence optical imaging (FOI) agents. We show that CSD-MOFs crystals loading the anticancer drug doxorubicin (DOX) are efficient pH and near-infrared (NIR) dual-stimuli responsive drug delivery vehicles. After the degradation of ZIF-8, simultaneous NIR irradiation to the inner PB MOFs continuously generate heat that kill cancer cells. Their efficacy on HeLa cancer cell lines is higher compared with the respective single treatment modality, achieving synergistic chemo-thermal therapy efficacy. In vivo results indicate that the anti-tumor efficacy of CSD-MOFs@DOX+NIR was 7.16 and 5.07 times enhanced compared to single chemo-therapy and single thermal-therapy respectively. Our strategy opens new possibilities to construct multifunctional theranostic systems through integration of two different MOFs.

Multifunctional pDNA-Conjugated Polycationic Au Nanorod-Coated Fe3 O4 Hierarchical Nanocomposites for Trimodal Imaging and Combined Photothermal/Gene Therapy.

It is very desirable to design multifunctional nanocomposites for theranostic applications via flexible strategies. The synthesis of one new multifunctional polycationic Au nanorod (NR)-coated Fe3 O4 nanosphere (NS) hierarchical nanocomposite (Au@pDM/Fe3 O4 ) based on the ternary assemblies of negatively charged Fe3 O4 cores (Fe3 O4 -PDA), polycation-modified Au nanorods (Au NR-pDM), and polycations is proposed. For such nanocomposites, the combined near-infrared absorbance properties of Fe3 O4 -PDA and Au NR-pDM are applied to photoacoustic imaging and photothermal therapy. Besides, Fe3 O4 and Au NR components allow the nanocomposites to serve as MRI and CT contrast agents. The prepared positively charged Au@pDM/Fe3 O4 also can complex plasmid DNA into pDNA/Au@pDM/Fe3 O4 and efficiently mediated gene therapy. The multifunctional applications of pDNA/Au@pDM/Fe3 O4 nanocomposites in trimodal imaging and combined photothermal/gene therapy are demonstrated using a xenografted rat glioma nude mouse model. The present study demonstrates that the proper assembly of different inorganic nanoparticles and polycations is an effective strategy to construct new multifunctional theranostic systems.

Quantum dots in nanomedicine: recent trends, advances and unresolved issues

The review addresses the current state of progress in the use of ultra-small nanoparticles from the category of quantum dots (QDs), which presently embraces a widening range of nanomaterials of different nature, including “classical” semiconductor groups III-V and II-VI nanocrystals, along with more recently emerged carbon, silicon, gold and other types of nanoparticles falling into this class of nanomaterials due to their similar physical characteristics such as small size and associated quantum confinement effects. A diverse range of QDs applications in nanomedicine has been extensively summarised previously in numerous publications. Therefore, this review is not intended to provide an all-embracing survey of the well documented QDs uses, but is rather focused on the most recent emerging developments, concepts and outstanding unresolved problematic and sometimes controversial issues. Over 125 publications are overviewed and discussed here in the context of major nanomedicine domains, i.e. medical imaging, diagnostics, therapeutic applications and combination of them in multifunctional theranostic systems.

An efficient nano-based theranostic system for multi-modal imaging-guided photothermal sterilization in gastrointestinal tract

Since understanding the healthy status of gastrointestinal tract (GI tract) is of vital importance, clinical implementation for GI tract-related disease have attracted much more attention along with the rapid development of modern medicine. Here, a multifunctional theranostic system combining X-rays/CT/photothermal/photoacoustic mapping of GI tract and imaging-guided photothermal anti-bacterial treatment is designed and constructed. PEGylated W18O49 nanosheets (PEG-W18O49) are created via a facile solvothermal method and an in situ probe-sonication approach. In terms of excellent colloidal stability, low cytotoxicity, and neglectable hemolysis of PEG-W18O49, we demonstrate the first example of high-performance four-modal imaging of GI tract by using these nanosheets as contrast agents. More importantly, due to their intrinsic absorption of NIR light, glutaraldehyde-modified PEG-W18O49 are successfully applied as fault-free targeted photothermal agents for imaging-guided killing of bacteria on a mouse infection model. Critical to pre-clinical and clinical prospects, long-term toxicity is further investigated after oral administration of these theranostic agents. These kinds of tungsten-based nanomaterials exhibit great potential as multi-modal contrast agents for directed visualization of GI tract and anti-bacterial agents for phothothermal sterilization.

Nanoencapsulated and microencapsulated SERS platforms for biomedical analysis.

The problems of layer-by-layer-based surface enhancement Raman scattering (SERS)-sensor application for pharmaceutical analysis were discussed. Layer-by-layer (LbL) method allows fabrication of encapsulated SERS platforms with high reproducibility of enhancement factor and increased signal/noise ratio of Raman scattering. LbL encapsulation approach opens an avenue to implement a novel type of theranostic systems combining SERS based sensing and drug delivery in one entity. The area of encapsulation development toward smart multifunctional theranostic systems could bring benefits for personalized medicine and should minimize costs and resources at preclinical and clinical study in pharmacology while testing new bioactive compounds.

A continuous tri-phase transition effect for HIFU-mediated intravenous drug delivery

Aiming at substantially enhanced efficacy and biosafety of clinical HIFU therapy, a natural solid medium, L-menthol (LM), characteristic of mild and controllable “solid-liquid-gas” (SLG) tri-phase transition, was adopted, instead of those conventional explosive liquid–gas (LG) bi-phase transitional media, in constructing a multifunctional theranostic system. Owing to the continuous and controllable characteristics of SLG tri-phase transition, such a novel tri-phase transition-based theranostic system has been demonstrated of the repeatedly enhanced HIFU efficacy ex vivo and in vivo under once intravenous injection and the significantly improved treatment precision, controllability and biosafety when comparing to the traditional bi-phase transition medium, perfluorohexane (PFH), thus promising great application potential in clinical HIFU treatment. Moreover, this theranostic system has been demonstrated a long blood-circulation lifetime and continuous accumulation in tumor in 24 h, which is very beneficial for the enhanced tumor ablation in vivo along with SLG tri-phase transition. More importantly, after loading multiple model drugs and real drug, such a theranostic system presents a HIFU-mediated temperature-responsive drug release property, and depending on the versatile miscibility of LM, co-loadings with hydrophobic and hydrophilic drugs are also achieved, which provides the possibility of synergistic treatment combining HIFU therapy and chemotherapy.