Multifunctional Theranostic Platform Research Articles

Macrophage-Capturing Self-Assembly Photosensitizer Nanoparticles Induces Immune Microenvironment Re-Programming and Golgi-Responsive Immunogenic Cell Death in Head and Neck Carcinoma.

Head and neck carcinoma treatment is shifted toward the combination of therapy causing immune checkpoint blockade (ICB) and immunogenic cell death. In this study, a CSFRi-chimeric TAMCSFR+-targeting extracellular vesicle (EV@CSFRi) platform is developed and designed an intracellular protoporphyrin conjugated with RVRR peptide sequence for furin-cleavage to perform Golgi-targeting and generating ROS (GT-RG). The graphical abstract illustrates the self-assembly of GT-RG nanoparticles into nanofiber through the hydrophily of RVRR and hydrophobicity of RG, and the red line indicates the site of furin cleavage. As is shown in the Graphical abstract, the Golgi-targeting Protoporphyrin-RVRR platform is composed with CSFRi-chimeric extracellular vesicles and forms the tumor-responsive TAM-reprogramming bilayers (GT-RGEV@CSFRi). The GT-RGEV@CSFRi acted as a multifunctional theranostic platform, which can induce immunogenic cell death and further help modulate TAM, thus suppressing the HNC xenograft model by combination therapy with anti-PD-1.

Assessment of chitosan-coated zinc cobalt ferrite nanoparticle as a multifunctional theranostic platform facilitating pH-sensitive drug delivery and OCT image contrast enhancement

Colorectal cancer (CC) is one of the most predominant malignancies in the world, with the current treatment regimen consisting of surgery, radiation therapy, and chemotherapy. Chemotherapeutic drugs, such as 5-fluorouracil (5-FU), have gained popularity as first-line antineoplastic agents against CC but have several drawbacks, including variable absorption through the gastrointestinal tract, inconsistent liver metabolism, short half-life, toxicological reactions in several organ systems, and others. Therefore, herein, we develop chitosan-coated zinc-substituted cobalt ferrite nanoparticles (CZCFNPs) for the pH-sensitive (triggered by chitosan degradation within acidic organelles of cells) and sustained delivery of 5-FU in CC cells in vitro. Additionally, the developed nanoplatform served as an excellent exogenous optical coherence tomography (OCT) contrast agent, enabling a significant improvement in the OCT image contrast in a CC tissue phantom model with a biomimetic microvasculature. Further, this study opens up new possibilities for using OCT for the non-invasive monitoring and/or optimization of magnetic targeting capabilities, as well as real-time tracking of magnetic nanoparticle-based therapeutic platforms for biomedical applications. Overall, the current study demonstrates the development of a CZCFNP-based theranostic platform capable of serving as a reliable drug delivery system as well as a superior OCT exogenous contrast agent for tissue imaging.

One Stone, Three Birds: Multifunctional Nanodots as "Pilot Light" for Guiding Surgery, Enhanced Radiotherapy, and Brachytherapy of Tumors.

Surgery, radiotherapy (RT), and brachytherapy are crucial treatments for localized deep tumors. However, imprecise tumor location often leads to issues such as positive surgical margins, extended radiotherapy target volumes, and radiation damage to healthy tissues. Reducing side effects in healthy tissue and enhancing RT efficacy are critical challenges. To address these issues, we developed a multifunctional theranostic platform using Au/Ag nanodots (Au/AgNDs) that act as a "pilot light" for real-time guided surgery, high-efficiency RT, and brachytherapy, achieving a strategy of killing three birds with one stone. First, dual-mode imaging of Au/AgNDs enabled precision RT, minimizing damage to adjacent normal tissue during X-ray irradiation. Au/AgNDs enhanced ionizing radiation energy deposition, increased intracellular reactive oxygen species (ROS) generation, regulated the cell cycle, promoted DNA damage formation, and inhibited DNA repair in tumor cells, significantly improving RT efficacy. Second, in brachytherapy, precise guidance provided by dual-mode imaging addressed challenges related to non-visualization of existing interstitial brachytherapy and multiple adjustments of insertion needle positions. Meanwhile, the effect of brachytherapy was improved. Third, the excellent fluorescence imaging of Au/AgNDs accurately distinguished tumors from normal tissue, facilitating their use as a powerful tool for assisting surgeons during tumor resection. Taken together, our multifunctional theranostic platform offers real-time guidance for surgery and high-efficiency RT, and improves brachytherapy precision, providing a novel strategy and vision for the clinical diagnosis and treatment of cancer.

CeO2@CuS@PDA-FA as targeted near-infrared PTT/CDT therapeutic agents for cancer cells

Single tumor treatment method usually has some defects, which makes it difficult to achieve good therapeutic effect. The ingenious combination of multiple tumor treatment methods on a single nanoplatform to achieve multifunctional treatment can effectively improve the efficiency of treatment. The targeted modification of nanomaterials can augment the precision of nanotherapeutic drugs in tumor treatment. Herein, a multifunctional nanoplatform (CeO2@CuS@PDA-FA) based on cerium dioxide nanoparticles engineered with copper sulfide (CeO2@CuS) has been constructed for synergistic photothermal therapy (PTT) and chemodynamic therapy (CDT). The CeO2@CuS were coated using polydopamine (PDA), and the modification of PDA surface by folic acid, in order to achieve the targeted effect for tumors. The localized hyperthermia induced by PTT can further improve the CDT efficiency of the nanoplatform, leading to a PTT/CDT synergistic effect. The nanoplatform possessed the capability of cancer cell-targeted and achieved better therapeutic efficacy in vitro. This work provided a new strategy for combined multifunctional theranostic platform and shows strong potential in practical applications.

Optical Bioimaging and Therapy

Optical Bioimaging and Therapy

A smart metal-polyphenol-DNAzyme nanoplatform for gene-chemodynamic synergistic tumor therapy

DNAzyme-based gene regulation shows great potential for the therapy of many cancers. However, ineffective delivery and insufficient cofactor supply pose challenges for potent gene therapy. In this study, we constructed a smart metal-polyphenol-DNAzyme nanoplatform (TA-Mn@Dz NPs) with intrinsic stability, effective delivery, and cofactor self-supply ability for gene-chemodynamic synergistic tumor therapy. Tannic acid, a plant-derived polyphenol, acts as an intermediate structural unit to mediate the assembly of Mn2+/DNAzyme and tumor acid environment-responsive nanocarriers. Intracellularly, the acidic environment triggers the decomposition of TA-Mn@Dz NPs to release DNAzyme and Mn2+. The Mn2+ ion not only boosts the catalytic cleavage of surviving mRNA for effective gene therapy but also activates chemodynamic therapy (CDT), generating highly toxic ·OH from endogenous H2O2. When tail intravenously injected into MCF-7 tumor-bearing mice, the TA-Mn@Dz NPs display desirable synergistic gene-chemodynamic antitumor effects, paving the way for developing DNAzyme-based multifunctional theranostic platforms for biomedical applications. Statement of significance1. A smart metal-polyphenol-DNAzyme nanoplatform was constructed for gene-chemodynamic synergistic tumor therapy. 2. Tannic acid act as intermediate structural units to mediate the assembly of Mn2+/DNAzyme and tumor acid environment-responsive nanocarriers. 3. The Mn2+-ion could not only boost the catalytic cleavage of surviving mRNA for effective gene therapy, but also catalyze endogenous H2O2 to form cytotoxic hydroxyl radicals for chemodynamic therapy. 4. Our work paves an extremely simple way to integrate gene therapy with CDT for the dual-catalytic tumor treatment.

Cross-linkage induced fluorescence: Fabrication of fluorescent organic particles via reaction between polyethyleneimine and dopamine-containing copolymers

Dopamine is the most abundant catecholamine neurotransmitter in the brain and has extensive applications in biomedicine and materials science. Here, novel metal-free fluorescent organic particles (FOPs) with excellent biocompatibility and high photostability, namely DA-PEG-PEI, were successfully synthesized through combination of ring-opening reaction and crosslinking reaction between polyethyleneimine (PEI) and dopamine-containing copolymers (DA-PEGDGE). Because of the crosslink-enhanced emission (CEE) effect of PEI and a quantity of functional groups such as catechol and amines on the surface of the particles, DA-PEG-PEI FOPs possessed high water dispersibility and superior optical properties, making them highly potential for biological imaging applications. Moreover, owing to the existence of functional components/groups, such as amines, catechol groups, the resultant DA-PEG-PEI FOPs can be potentially applied for loading or carrying different bioactive molecules, such as anticancer agent bortezomib, siRNA and CPG oligodeoxynucleotide through formation of dynamic bonds or electrostatic interaction. Furthermore, this reaction can occur under ambient environment, room temperature, in the present of oxygen and without catalysts. Therefore, we believe that this work could not only provide a simple and elegant route for preparation of FOPs, but also have great potential for construction of multifunctional theranostic platforms.

Virus-like nanoparticles as a theranostic platform for cancer.

Virus-like nanoparticles (VLPs) are natural polymer-based nanomaterials that mimic viral structures through the hierarchical assembly of viral coat proteins, while lacking viral genomes. VLPs have received enormous attention in a wide range of nanotechnology-based medical diagnostics and therapies, including cancer therapy, imaging, and theranostics. VLPs are biocompatible and biodegradable and have a uniform structure and controllable assembly. They can encapsulate a wide range of therapeutic and diagnostic agents, and can be genetically or chemically modified. These properties have led to sophisticated multifunctional theranostic platforms. This article reviews the current progress in developing and applying engineered VLPs for molecular imaging, drug delivery, and multifunctional theranostics in cancer research.

Copper sulfide engineered covalent organic frameworks for pH-responsive chemo/photothermal/chemodynamic synergistic therapy against cancer

Developing nanomedicines with high-performance is a promising therapeutic strategy for cancer treatment. Herein, a multifunctional nanoplatform (CuS@COFs-BSA-FA/DOX) based on copper sulfide nanoparticles engineered covalent organic frameworks (CuS@COFs) has been established for synergistic photothermal therapy (PTT), chemotherapy and chemodynamic therapy (CDT). The high photothermal effect and excellent Fenton-like catalytic activity enabled CuS@COFs to generate a new minimally invasive PTT/CDT synergistic therapy. Moreover, with the pH-dependent fluorescence behavior and the inherited mesoporous structure, the nanocomposites can also be utilized as fluorescent probes for cancer cell imaging and drug-delivery carriers to encapsulate the chemotherapeutic agent, DOX. The densely coated PEI and BSA-FA layers on the surface of CuS@COFs not only increased the cancer-targeting efficiency but also prevented the nonspecific release of DOX from CuS@COFs. The acid tumor microenvironment and near-infrared light triggered the release of DOX for chemotherapy, which simultaneously augmented the CDT efficiency of CuS@COFs. Notably, the localized hyperthermia induced by PTT can further improve the CDT efficiency of the nanoplatform, leading to a synergistic PTT/chemotherapy/CDT effect. The nanoplatform possessed the capability of cancer cell-targeted imaging and achieved better therapeutic efficacy with negligible systemic toxicity both in vitro and in vivo. Our work opens up a powerful avenue for developing multifunctional COFs-based theranostic platform and shows strong potential in practical applications.

A polydopamine coated nanoscale FeS theranostic platform for the elimination of drug-resistant bacteria via photothermal-enhanced Fenton reaction

Infections caused by drug-resistant bacteria pose a great threat to human health. Non-antibiotic-dependent antibacterial strategies have become the focus of research. Among them, chemical dynamic treatment-based (CDT) therapeutic systems, which catalyze the production of hydroxyl radicals by enzymes, have achieved tremendous success for antibacterial purposes. However, limited kinetics of the Fenton reaction, poor permeability, and short half-life of hydroxyl radicals compromise the antibacterial effects of CDT. In addition, difficulties in the early diagnosis of infection lead to drug abuse and delayed treatment. Herein, a polydopamine coated ferrous sulfide theranostic platform adsorbing a hypochlorite responsive probe with photothermal treatment (PTT) enhanced CDT was synthesized. The probe component was used for the early diagnosis of infection. PTT not only inactivated bacteria by hyperthermia but also accelerated the Fenton reaction to produce more ·OH. In vitro antibacterial experiments demonstrated that the multifunctional theranostic platform has a broad antibacterial spectrum, including methicillin-resistant Staphylococcus aureus (MRSA), drug-resistant Escherichia coli (DR E. coli), and Pseudomonas aeruginosa (P. aeruginosa). In addition, in vivo antibacterial experiments demonstrated that nanoparticles could effectively rescue S. aureus-infected full-thickness skin defects with negligible cytotoxicity. This study proposes an efficient and multifunctional theranostic platform for bacterial infection, providing an effective synergistic antibacterial strategy for the treatment of antibiotic resistance. Statement of significanceAn infection responsive theranostic platform (ClO− probe@FeS@PDA) is prepared. ·CDT is enhanced prominently by PTT at a relative low temperature. · FeS@PDA exhibits good antibacterial performance against drug resistant bacteria in vitro and in vivo.

A novel drug susceptibility testing AIEgen with spatiotemporal resolved progress-reporting characteristic for therapy of drug-resistant tumor

Drug resistance has become the biggest challenge in cancer treatments today. Addressing this problem seems to be an insurmountable challenge due to the underlying immensely complicated mechanisms. Thus, great endeavors have been devoted to solving this issue. Herein, a novel, simple but powerful photosensitizer, called ITPM, with aggregation-induced emission characteristic is developed and demonstrated to hold enormous potential to address drug resistance. This system can achieve fluorescent visual discrimination of living cells and dead cells due to its unique double-targeting ability, thus it can be developed into an ultrafast, precise and reliable drug susceptibility testing platform to report the therapeutic effect of different clinical chemotherapeutic drugs. Moreover, ITPM can exert efficient photodynamic therapy towards drug-resistant tumor, and simultaneously itself can enable real-time and in situ self-reporting to its treatment progress via spatiotemporal resolved fluorescent migration from cell membrane to nucleus. Therefore, such a superb system is expected to be a high-performance multifunctional theranostic platform for clinical application and provides great inspiration for tackling the issue of clinical drug resistance.

Porphyrin NanoMetal-Organic Frameworks as Cancer Theranostic Agents.

Metal-Organic Frameworks (MOFs) are hybrid multifunctional platforms that have found remarkable applications in cancer treatment and diagnostics. Independently, these materials can be employed in cancer treatment as intelligent drug carriers in chemotherapy, photothermal therapy, and photodynamic therapy; conversely, MOFs can further be used as diagnostic tools in fluorescence imaging, magnetic resonance imaging, computed tomography imaging, and photoacoustic imaging. One essential property of these materials is their great ability to fine-tune their composition toward a specific application by way of a judicious choice of the starting building materials (metal nodes and organic ligands). Moreover, many advancements were made concerning the preparation of these materials, including the ability to downsize the crystallites yielding nanoporous porphyrin MOFs (NMOFs) which are of great interest for clinical treatment and diagnostic theranostic tools. The usage of porphyrins as ligands allows a high degree of multifunctionality. Historically these molecules are well known for their reactive oxygen species formation and strong fluorescence characteristics, and both have proved helpful in cancer treatment and diagnostic tools. The anticipation that porphyrins in MOFs could prompt the resulting materials to multifunctional theranostic platforms is a reality nowadays with a series of remarkable and ground-breaking reports available in the literature. This is particularly remarkable in the last five years, when the scientific community witnessed rapid development in porphyrin MOFs theranostic agents through the development of imaging technologies and treatment strategies for cancer. This manuscript reviews the most relevant recent results and achievements in this particular area of interest in MOF chemistry and application.

Controllable synthesis of layered black bismuth oxidechloride nanosheets and their applications in internal tumor ablation.

The recently emerging bismuth oxyhalide (BiOX) nanomaterials are promising indirect band gap photosensitizer for ultraviolet (UV) light-triggered phototherapy due to their unique layered nanosheet structure. However, the low absorption and poor photothermal conversion efficiency have always impeded their further applications in cancer clinical therapy. Herein, BiOCl rich in oxygen vacancies has been reported to have full-spectrum absorption properties, making it possible to achieve photothermal property under near-infrared laser. Under 808 nm irradiation, the photothermal conversion efficiency of black BiOCl nanosheets (BBNs) is up to 40%. BBNs@PEG can effectively clear primary subcutaneous tumors and prevent recurrence, achieving good synergistic treatment effect. These results not only broke the limitation of UV on the BiOCl material and provided a good template for other semiconductor materials, but also represent a promising approach to fabricate BBN@PEG a novel, potent and multifunctional theranostic platform for precise photothermal therapy and prognostic evaluation.

Recent advances in aggregation-induced emission luminogens in photoacoustic imaging.

Photoacoustic imaging (PAI) is a rapidly emerging modality in biomedical research with the advantages of noncontact operation, high optical resolution, and deep penetration. Great efforts and progress in the development of PAI agents with improved imaging resolution and sensitivity have been made over the past 2 decades. Among them, organic agents are the most promising candidates for preclinical/clinical applications due to their outstanding in vivo properties and facile biofunctionalities. Motivated by the unique properties of aggregation-induced emission (AIE) luminogens (AIEgens), various optical probes have been developed for bioanalyte detection, multimodal bioimaging, photodynamic/photothermal therapy, and imaging-guided therapeutics. In particular, AIE-active contrast agents have been demonstrated in PAI applications with excellent performance in imaging resolution and tissue permeability in vivo. This paper presents a brief overview of recent progress in AIE-based agents in the field of photoacoustic imaging. In particular, we focus on the basic concepts, data sorting and comparison, developing trends, and perspectives of photoacoustic imaging. Through numerous typical examples, the way each system realizes the desired photoacoustic performance in various biomedical applications is clearly illustrated. We believe that AIE-based PAI agents would be promising multifunctional theranostic platforms in clinical fields and will facilitate significant advancements in this research topic.

Hybridized double-shell periodic mesoporous organosilica nanotheranostics for ultrasound imaging guided photothermal therapy

Hybridized periodic mesoporous organosilica (PMO) nanoparticles are expected to provide a multifunctional theranostic platform for precision medicine by combining the advantages of different organic and inorganic components. In this work, double-shell-structured PMO nanotheranostics composed of ethane- and thioether-bridged organosilica shells were synthesized. Gold colloids were generated in situ by the thioether groups on the inner shell. The obtained double-shell PMO@Au (DSPA) has uniform size, large surface areas, ordered mesochannels and photothermal conversion capability. After being encapsulated with perfluorohexacene (PFH), DSPA-PFH produced a strong ultrasound signal upon laser irradiation due to the phase transit of PFH during hyperthermia. DSPA-PFH showed enhanced photothermal therapeutic efficacy, great ultrasound contrast, and minimal toxicity both in vitro and in vivo. These results demonstrated the distribution of different organosilica could be delicately adjusted in hybridized PMO nanoparticles. Furthermore, it showed the potential of using hybridized PMO nanoparticles as a theranostic platform for biomedical applications by combining unique characteristics of different organosilica through rational design.

Mesoporous silica coated gold nanorods: a multifunctional theranostic platform for radiotherapy and X-ray imaging

Mesoporous silica coated gold nanorods: a multifunctional theranostic platform for radiotherapy and X-ray imaging

Production of ibuprofen-magnetite nanocomposites by pulsed laser ablation

We investigated the application of pulsed laser ablation (PLA) for the production of magnetic nanoparticles (MNPs)/drug nanocomposites. Magnetic drug delivery vehicles can provide a multifunctional theranostic platform and allow for a combination of diagnostics, monitoring and therapeutics. We applied nanosecond laser pulses at two different wavelengths (Nd:YAG laser, λ 1 = 532 nm/λ 2 = 1064 nm, FWHM = 6 ns) for the ablation of target tablets consisting of a mixture of ibuprofen (as a model drug) and magnetite NPs in various mass ratios. Fourier-transform infrared and Raman spectroscopy investigations of the ablated particles revealed that PLA induced no chemical changes in the pharmaceutical compound. The size distributions of the composite particles were established using a particle size analyzer (scanning mobility particle sizer), and 100–150 nm mean particle size values were obtained. SEM, energy dispersive x-ray spectroscopy and fast photography studies provided morphological and compositional information about the ablated particles. We demonstrated that PLA offers a simple and chemical free method for producing MNPs/drug nanocomposites, and it can be applied for the future development of new theranostic nanosystems.

Ultrasonic Implantation and Imaging of Sound-Sensitive Theranostic Agents for the Treatment of Arterial Inflammation.

For site-specific diseases such as atherosclerosis, it is desirable to noninvasively and locally deliver therapeutics for extended periods of time. High-intensity focused ultrasound (HIFU) provides targeted drug delivery, yet remains unable to sustain delivery beyond the HIFU treatment time. Furthermore, methods to validate HIFU-enhanced drug delivery remain limited. In this study, we report on HIFU-targeted implantation of degradable drug-loaded sound-sensitive multicavity PLGA microparticles (mcPLGA MPs) as a theranostic agent for the treatment of arterial lesions. Once implanted into the targeted tissue, mcPLGA MPs eluted dexamethasone for several days, thereby reducing inflammatory markers linked to oxidized lipid uptake in a foam cell spheroid model. Furthermore, implanted mcPLGA MPs created hyperechoic regions on diagnostic ultrasound images, and thus noninvasively verified that the target region was treated with the theranostic agents. This novel and innovative multifunctional theranostic platform may serve as a promising candidate for noninvasive imaging and treatment for site-specific diseases such as atherosclerosis.

Biomedical applications of Pt(II) metallacycle/metallacage-based agents: From mono-chemotherapy to versatile imaging contrasts and theranostic platforms

Platinum-based coordination chemistry has laid the foundation for the development of numerous metal complexes and provoked their applications in cancer chemotherapy. It is noteworthy that Pt(II) metallacyles/metallacages formed through coordination-driven self-assembly exhibit improved optical properties and superior anticancer efficacies in comparison with their precursors. To this end, the employment of metallacycles/metallacages as chemotherapy agents, imaging contrasts and multifunctional theranostic platforms has attracted tremendous attention. In this context, we provide an insight into the progression of Pt(II) metallacycles/metallacages from mono-chemotherapeutic agents to versatile imaging contrasts and theranostic platforms.

Multifunctional Theranostic Graphene Oxide Nanoflakes as MR Imaging Agents with Enhanced Photothermal and Radiosensitizing Properties.

The integration of multiple therapeutic and diagnostic functions into a single nanoplatform for image-guided cancer therapy has been an emerging trend in nanomedicine. We show here that multifunctional theranostic nanostructures consisting of superparamagnetic iron oxide (SPIO) and gold nanoparticles (AuNPs) scaffolded within graphene oxide nanoflakes (GO-SPIO-Au NFs) can be used for dual photo/radiotherapy by virtue of the near-infrared (NIR) absorbance of GO for photothermal therapy (PTT) and the Z element radiosensitization of AuNPs for enhanced radiation therapy (RT). At the same time, this nanoplatform can also be detected by magnetic resonance (MR) imaging because of the presence of SPIO NPs. Using a mouse carcinoma model, GO-SPIO-Au NF-mediated combined PTT/RT exhibited a 1.85-fold and 1.44-fold higher therapeutic efficacy compared to either NF-mediated PTT or RT alone, respectively, resulting in a complete eradication of tumors. As a sensitive multifunctional theranostic platform, GO-SPIO-Au NFs appear to be a promising nanomaterial for enhanced cancer imaging and therapy.