Theranostic Platform Research Articles

Synthesis of Glutathione-Responsive Cyclomatrix Polyphosphazene for Multimodal Theranostic Nanodrug Delivery

In this work, a multimodal (chemotherapeutic/photodynamic/photothermal) theranostic nanodrug delivery platform was developed based on the synergetic action of self-framed polyphosphazene prodrug and heptamethine cyanine dye IR-780. First, an electronegative glutathione (GSH)-responsive polyphosphazene prodrug abbreviated as HGEH was prepared via multicomponent condensation reaction of genistein (GEN), bis-(4-hydroxyphenyl)-disulfide, and hexachlorocyclotriphosphazene. The particle size of drug (GEN)-containing HGEH nanoparticles is adjustable. Subsequently, cationic near-infrared photosensitizer IR-780 was adsorbed onto the electron-rich HGEH to obtain the multimodal theranostic nanodrug delivery platform HGEH-IR780. The platform was demonstrated to retain high stability in avoiding drug leakage and enable controlled drug release in response to the tumor microenvironment, in which a higher GSH concentration exists. The in vitro experiments show that HGEH-IR780 undergoes photothermal and photodynamic processes to concurrently generate heat and reactive oxygen species for efficiently killing mouse breast cancer cells (4T1) upon exposure to a single-bandwidth near-infrared laser (808 nm). Specifically, HGEH-IR780 inhibits 4T1 cells by up to 80% at a concentration of 100 μg/mL. The as-developed HGEH-IR780 exhibits promising results in GSH-responsive anticancer activity and photodynamic/photothermal therapy, which provides a reference for the construction of the polyphenol flavonoid multimodal therapeutic nanoplatform.

Bio-inspired self-assembled bacteriochlorin nanoparticles for superior visualization and photothermal ablation of tumors

BackgroundAlthough hyperthermia-based photothermal therapy (PTT) has achieved great success in the battle against malignant tumors, various commonly used photothermal sensitizers still suffer from non-selective tumor accumulation, limited photothermal conversion efficiency, potential toxicity and side effects, as well as complex and low cost-effective preparation process. Therefore, novel photothermal sensitizers are urgently required. The well-organized self-assembling of natural bacteriochlorophylls with superior photothermal property may provide an interesting option for the engineering of ideal PTS. MethodsInspired by the self-assembly peripheral light-harvesting antennas of natural bacteriochlorin in microorganisms, a biomimetic light-harvesting nanosystem (Nano-Bc) was developed via bacteriochlorophylls self-arranging in aqueous phase. The characterization of Nano-Bc were measured using DLS, TEM, UV−vis−near-infrared spectroscopy and preclinical PA imaging system. The cytotoxicity of Nano-Bc was quantitatively evaluated via a standard MTT assay using mouse breast cancer 4T1 cells, and the in vivo photothermal eradication of tumor was investigated in the 4T1 breast tumor-bearing mouse model. ResultsThe obtained bacteriochlorin nanoparticles (Nano-Bc) exhibited ultra-high photothermal performance within the biological transparent window, showing superior heating capacity compared to commonly used photothermal sensitizers of organic dye indocyanine green and inorganic gold nanorods. Guiding by the inherent photoacoustic imaging of Nano-Bc, complete tumor elimination in vitro and vivo was evidenced upon laser irradiation. ConclusionThe green and facile preparation, ultra-high photothermal effect in the transparent window, excellent photoacoustic imaging capacity, and great biosafety prompt, the bio-inspired Nano-Bc as a promising theranostic platform against cancer in the areas of healthcare.

An All-In-One Transient Theranostic Platform for Intelligent Management of Hemorrhage.

Developing theranostic devices to detect bleeding and effectively control hemorrhage in the prehospital setting is an unmet medical need. Herein, an all-in-one theranostic platform is presented, which is constructed by sandwiching silk fibroin (SF) between two silver nanowire (AgNW) based conductive electrodes to non-enzymatically diagnose local bleeding and stop the hemorrhage at the wound site. Taking advantage of the hemostatic property of natural SF, the device is composed of a shape-memory SF sponge, facilitating blood clotting, with ≈82% reduction in hemostatic time in vitro as compared with untreated blood. Furthermore, this sandwiched platform serves as a capacitive sensor that can detect bleeding and differentiate between blood and other body fluids (i.e., serum and water) via capacitance change. In addition, the AgNW electrode endows anti-infection efficiency against Escherichia coli and Staphylococcus aureus. Also, the device shows excellent biocompatibility and gradually biodegrades in vivo with no major local or systemic inflammatory responses. More importantly, the theranostic platform presents considerable hemostatic efficacy comparable with a commercial hemostat, Dengen, in rat liver bleeding models. The theranostic platform provides an unexplored strategy for the intelligent management of hemorrhage, with the potential to significantly improve patients' well-being through the integration of diagnostic and therapeutic capabilities.

Ultrastable graphene isolated AuAg nanoalloy for SERS biosensing and photothermal therapy of bacterial infection

Plasmonic metal nanomaterials with intrinsic surface–enhanced Raman scattering (SERS) and photothermal properties, especially AuAg nanoalloys with both the outstanding merits of Au and Ag nanocrystals, show huge application prospects in bacterial theranostics. However, the direct exposure of AuAg nanoalloys in external conditions probably cause undesirable reactions and poisonous metal ion leakage during SERS detection and photothermal antibacterial therapy process, which severely hinder bacterial theranostics applications. Herein, we report an ultrastable graphene–isolated AuAg nanoalloy (GAA) with AuAg core confined in few–layer graphitic shell as a versatile platform for bacterial detection and therapy. The encapsulation of graphene ensures the good stability of AuAg core, that its superior SERS and photothermal properties are therefore further guaranteed. GAA is used for SERS detection of two vital bacterial biomarkers (including corrosive cyanide and pyocyanin), exhibiting good SERS quantitative and multiplexing ability. GAA is further used for photothermal antibacterial therapy application, and ultrahigh antibacterial efficacies for both Gram–negative Escherichia coli and Gram–positive Staphylococcus aureus are achieved under 808 nm laser irradiation. This work proposes a valuable method to develop robust bacterial theranostic platform.

A novel AD theranostic platform with NIR-II laser controlled drug release and real-time monitoring of therapeutic outcomes

There is a long-standing lack of monitoring of Alzheimer's disease (AD) treatment. Imaging-guided dynamic monitoring of neurological disease treatment can provide a basis for sustained treatment, reflecting the outcomes of treatment and guiding the adjustment of therapy strategies. Here, by ingeniously using a second near-infrared (NIR-II) laser twice in tandem, we designed an AD theranostic nanoplatform with real-time monitoring of AD therapeutic outcomes. Upon first being irradiated with a 1064 nm laser, it realizes the light-controlled delivery of nanoparticles for valid antioxidant therapy. Notably, with secondary irradiation, the presence of AβO and Ca2+ triggered the DNA nanomachine, causing the fluorescent signal to recover. Using a two-step series switch based on thermodynamics, the platform can not only differentiate AD mice from wild-type mice but also provide guidance for the treatment of AD via monitoring the degree of intracellular calcium overload in the brain. Results suggest that the degree of calcium overload is negatively correlated with treatment outcome and can be used as a prognostic indicator for precision medicine. This method provides an image-based non-invasive strategy for early prognosis prediction of AD treatment, which is helpful for future precision medicine treatment planning and prognosis stratification.

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.

Photo-Responsive Self-Assembled Polymeric Nanoparticle Probes for 19F MRI Theranostics.

19F magnetic resonance imaging (MRI)-assisted drug delivery provides the possibility to monitor and track drug transportation details in situ. A series of photo-responsive amphiphilic block copolymers consisting of hydrophilic poly(ethylene glycol) and 19F-containing hydrophobic segments, poly(2,2,2-trifluoroethyl acrylate) (PTFEA), with different chain lengths were synthesized by reversible addition-fragmentation chain-transfer polymerization. In particular, the photo-sensitive functional group of o-nitrobenzyl oxygen was introduced to control the photolysis behavior of the copolymers under ultraviolet irradiation. With the extension of the hydrophobic chain length, the drug loading capacity and photoresponsivity were both enhanced, while the chain mobility of PTFEA was suppressed, and the 19F MRI signal was attenuated. When the polymerization degree of PTFEA was about 10, the nanoparticles exhibit detectable 19F MRI signals and sufficient drug loading capacity (loading efficiency = 10%, cumulative release = 49%). These results offer a promising "smart" theranostic platform for 19F MRI.

Recent Bio-medical applications of iron oxide magnetic nanoparticles

In recent times, pronounced consideration has been dedicated to the amalgamation of several magnetic nanoparticles because of their widespread smart and encouraging biological solicitations. The magnetic IONPs, magnetite (Fe3O4 DQG PDJKHPLWH Ȗ-Fe2O3) have shown some remarkable applications in nanomedicines, diagnosis tools, and pharmaceuticals. Iron oxide magnetic nanoparticles (IOMNPs) have been explored for an extensive collection of biomedical and healthcare solicitations built on their surface properties, biocompatibility, and exceptionally, great magnetic susceptibility. In this logic, the magnetic properties of IOMNPs permit their usage in numerous biomedical applications, such as targeted drug delivery, hyperthermia, magnetic tissue engineering, MRI contrast agents, in vitro magnetic bio separation, bio-analysis, magnetic transducers, and theranostic platforms. The functionalized hybrid IOMNPs have also been utilized against fungal infections and numerous pathogenic strains of microorganisms. Iron oxides play a significant role in the field of bio-catalysis, nanotechnology, and bio-medicines; therefore they are the main focus of this review. Keeping in mind the state-of-the-art, this review is intended to report the latest information about IOMNPs from methods of synthesis to modern bio-medical applications. Moreover, in-vivo and in-vitro uses of IOMNPs have conversed in detail. The challenges and restrictions in the biological usage of IOMNPs are also highlighted. This review based on IOMNPs will deliver a convincing vision for the investigators in nano-biotechnology and pharmacy

Surface engineering of hollow gold nanoparticle with mesenchymal stem cell membrane and MUC-1 aptamer for targeted theranostic application against metastatic breast cancer

Mesenchymal stem cell membrane (MSCM)-coated biomimetic doxorubicin-loaded hollow gold nanoparticles were fabricated and decorated with MUC1 aptamer in order to provide smart theranostic platform. The prepared targeted nanoscale biomimetic platform was extensively characterized and evaluated in terms of selective delivery of DOX and CT-scan imaging.The fabricated system illustrated spherical morphology with 118 nm in diameter. Doxorubicin was loaded into the hollow gold nanoparticles through physical absorption technique with encapsulation efficiency and loading content of 77%±10 and 31%±4, respectively. The in vitro release profile demonstrated that the designed platform could respond to acidic environment, pH 5.5 and release 50% of the encapsulated doxorubicin during 48 h, while 14% of the encapsulated doxorubicin was released in physiological condition, pH 7.4 up to 48 h. The in vitro cytotoxicity experiments on 4T1 as MUC1 positive cell line illustrated that the targeted formulation could significantly increase mortality at 0.468 and 0.23 µg/ml of equivalent DOX concentration compared to non-targeted formulation while this cytotoxicity was not observed in CHO as MUC1 negative cell line. Furthermore, in vivo experiments showed high tumor accumulation of the targeted formulation even 24 h after intravenous injection which induced effective tumor growth suppression against 4T1 tumor bearing mice. On the other hand, existence of hollow gold in this platform provided CT scan imaging capability of the tumor tissue in 4T1 tumor bearing mice up to 24 h post-administration. The obtained results indicated that the designed paradigm are promising and safe theranostic system for fighting against metastatic breast cancer.

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.

Grafting of Cyclodextrin to Theranostic Nanoparticles Improves Blood-Brain Barrier Model Crossing.

Core-shell superparamagnetic iron oxide nanoparticles hold great promise as a theranostic platform in biological systems. Herein, we report the biological effect of multifunctional cyclodextrin-appended SPIONs (CySPION) in mutant Npc1-deficient CHO cells compared to their wild type counterparts. CySPIONs show negligible cytotoxicity while they are strongly endocytosed and localized in the lysosomal compartment. Through their bespoke pH-sensitive chemistry, these nanoparticles release appended monomeric cyclodextrins to mobilize over-accumulated cholesterol and eject it outside the cells. CySPIONs show a high rate of transport across blood-brain barrier models, indicating their promise as a therapeutic approach for cholesterol-impaired diseases affecting the brain.

Preclinical evaluation of theranostic strategy using nanoplatform and transferrin to target hyperactivity of cMYC in the context of non-small cell lung cancer

Non-small cell lung cancer affects 1.3 million people annually worldwide. The cMYC pathway regulates a large number of physiological processes and is hyperactivated in many cancers, including lung cancers. Due to the high avidity of cancer cells for iron, transferrin receptor complex (TFRC) has been demonstrated to be overexpressed when the cMYC pathway is hyperactivated. On this basis, there has been extensive interest in targeting TFRC therapeutically and in imaging TFRC expression. Our objective here is to develop a theranostic method targeting the transferrin receptor. We propose to target TFRC through a ligand scaffold based on a peptide able to be radiolabelled with either 18-Fluor (18F) for imaging or with 177-Lutetium (177Lu) for internal radiotherapy. To fully exploit the internal radiotherapy potential, nano-radioenhencer agent (platinum agent) will be used to exalt the irradiation impact. We radiolabelled the anti-TFRC peptide thanks to direct 18F labeling or via the conjugation of a chelate for 177Lu. We carried out in vitro tests to select a cell line overexpressing TFRC (human and murine). We evaluated the ability of the modified peptide to bind to TFRC thanks to binding assays. C57BL/6J mice were implanted with NSCLC (CMT167) or melanoma (B16F10) xenografts to establish the biodistribution of the new theranostic platform and the nanoparticles distribution. The distribution of the nanoparticles was also assessed by PET imaging. We radiolabelled and validated in vitro the functionality of the peptide with specific radiolabelling through a pyridine modified prosthetic group. The affinity of the modified peptide to TFRC remains sufficient to accumulate specifically within the tumor (Kd∼500 nM). We were able to assess the ability of the peptide to bind to TFRC by preclinical PET imaging through pharmacokinetic and biodistribution data. Nanoparticle presents a high tumor uptake (4.5%ID/cc, at 24 h). High liver TFRC expression can limit the performance of such cMYC theranostic platform. The peptide distribution may present some advantages to decreasing liver accumulation. The biodistribution and pharmacokinetics of either the nanoparticles or the peptides offer a promising therapeutic perspective. This novel therapeutic approach will have the potential to redirect the community's effort to ablative reagents that target downstream pathobiology regulated by cMYC.

Design of One-for-All Near-Infrared Aggregation-Induced Emission Nanoaggregates for Boosting Theranostic Efficacy.

Fluorescence-guided phototherapy, including photodynamic and photothermal therapy, is considered an emerging noninvasive strategy for cancer treatments. Organic molecules are promising theranostic agents because of their facile construction, simple modification, and good biocompatibility. Organic systems that integrated multifunctionalities in a single component and achieved high efficiency in both imaging and therapies are rarely reported as the inherently competitive energy relaxation pathways are hard to modulate, and fluorescence quenching occurs upon molecular aggregation. Herein, a versatile theranostic platform with near-infrared emission, high fluorescence quantum yield, robust reactive oxygen species production, and excellent photothermal conversion efficiency was developed based on an aggregation-induced emission luminogen, namely, TPA-TBT. In vivo studies revealed that the TPA-TBT nanoaggregates exhibit outstanding photodynamic and photothermal therapy efficacy to ablate tumors inoculated in a mouse model. This work offers a design strategy to develop one-for-all cancer theranostic agents by modulating and utilizing the relaxation energy of excitons in full.

Biodegradable nanoplatform upregulates tumor microenvironment acidity for enhanced cancer therapy via synergistic induction of apoptosis, ferroptosis, and anti-angiogenesis

Chemodynamic therapy of cancer is limited by insufficient endogenous H2O2 generation and acidity in the tumor microenvironment (TME). Herein, we developed a biodegradable theranostic platform (pLMOFePt-TGO) involving composite of dendritic organosilica and FePt alloy, loaded with tamoxifen (TAM) and glucose oxidase (GOx), and encapsulated by platelet-derived growth factor-B (PDGFB)-labeled liposomes, that effectively uses the synergy among chemotherapy, enhanced chemodynamic therapy (CDT), and anti-angiogenesis. The increased concentration of glutathione (GSH) present in the cancer cells induces the disintegration of pLMOFePt-TGO, releasing FePt, GOx, and TAM. The synergistic action of GOx and TAM significantly enhanced the acidity and H2O2 level in the TME by aerobiotic glucose consumption and hypoxic glycolysis pathways, respectively. The combined effect of GSH depletion, acidity enhancement, and H2O2 supplementation dramatically promotes the Fenton-catalytic behavior of FePt alloys, which, in combination with tumor starvation caused by GOx and TAM-mediated chemotherapy, significantly increases the anticancer efficacy of this treatment. In addition, T2-shortening caused by FePt alloys released in TME significantly enhances contrast in the MRI signal of tumor, enabling a more accurate diagnosis. Results of in vitro and in vivo experiments suggest that pLMOFePt-TGO can effectively suppress tumor growth and angiogenesis, thus providing an exciting potential strategy for developing satisfactory tumor theranostics.

Orally Administrable H2 S-Scavenging Metal-Organic Framework Prepared by Co-Flow Microfluidics for Comprehensive Restoration of Intestinal Milieu.

Intestinal milieu disorders are strongly related to the occurrence of inflammatory bowel diseases (IBDs), which results from mucosa destruction, epithelium disruption, and tight junction (TJ) proteins loss. Excess of H2 S in the intestinal milieu produced by thesulfate-reducing bacteria metabolism contributes todevelopment ofIBDs via epithelial barrier breakdown. Conventional interventions, such as surgery and anti-inflammatory medications, are considered not completely effective because of frequent recurrence and other complications. Herein, a novel oral delivery system, a hydroxypropyl methylcellulose acetate succinate (HPMCAS)-based polymer-coated Zr-based metal-organic framework (UiO-66) with a Cux -rhodamine B (CR) probe (hereinafter referred to as HUR), is produced viaaco-flow microfluidic approach with the ability to reduce H2 S levels, thus restoring the intestinal lumen milieu. HPMCAS serves as an enteric coating that exposes UiO-66@CR at the pH of the intestine but not the acidic pH of the stomach. The synthesized HUR exhibits notable therapeutic efficacy, including mucosa recovery, epithelium integrity restoration, and TJ proteins upregulation via H2 S scavenging to protect against intestinal barrier damage and microbiome dysbiosis. Thus, HUR is verified to be a promising theranostic platform able to decrease the H2 S content for intestinal milieu disorder treatment. The presented study therefore opens the door for further exploitation for IBDs therapy.

Facile and Green Synthesis of Novel Fluorescent Carbon Quantum Dots and Their Silver Heterostructure: An In Vitro Anticancer Activity and Imaging on Colorectal Carcinoma.

Carbon dots (CQDs) have been widely investigated as prime candidates for developing a tumor theranostic platform due to their tunable fluorescence emission and excitation, high water solubility, good photostability, and biocompatibility. Among the CQDs, natural CQDs are an emerging class of nanomaterials in the carbon family. Herein, highly fluorescent carbon quantum dots (CQDs) were synthesized from orange juice using a one-step hydrothermal method and characterized by different techniques. After that, CQD/Ag heterostructures were synthesized by the reduction of silver salt, in particular silver nitrate (AgNO3) solution using sodium borohydride (NaBH4) in different ratios. The photostability and characterization of CQD/Ag heterostructures were investigated. At last, a comparative cellular toxicity measurement was done to select the superior CQD/Ag heterostructure in the human colorectal carcinoma (HCT 116) cell line along with the imaging property. The detailed cell death signaling was also observed in the HCT 116 cell line via the ROS-dependent mitochondrial-mediated pathway, where Akt (RAC-α serine/threonine-protein kinase) played a important role.

Orally Administrable Aggregation-Induced Emission-Based Bionic Probe for Imaging and Ameliorating Dextran Sulfate Sodium-Induced Inflammatory Bowel Diseases.

As macrophage infiltration is significantly related to the progression of inflammatory bowel disease (IBD), monitoring the macrophages is a valuable strategy for IBD diagnosis. However, owing to the harsh physiological environment of the gastrointestinal tract and enzymatic degradation, the development of orally administrable imaging probes for tracking macrophages remains a considerable challenge. Accordingly, herein, an orally administrable aggregation-induced emission biomimetic probe (HBTTPIP/β-glucan particles [GPs]) is developed for tracing macrophages; HBTTPIP/GPs can diagnose and alleviate dextran sulfate sodium (DSS)-induced colonic inflammation and self-report the treatment efficiency. The fluorophore HBTTPIP can effectively aggregate in GPs, restricting intramolecular rotation and activating the fluorescence of HBTTPIP. After being orally administrated, HBTTPIP/GPs are phagocytosed by intestinal macrophages, which then migrate to colonic lesions, enabling non-invasive monitoring of the severity of IBD via in vivo fluorescence imaging. Notably, oral HBTTPIP/GPs ameliorate DSS-induced IBD by inhibiting the expressions of pro-inflammatory factors and improving colonic mucosal barrier function. Furthermore, these HBTTPIP/GPs realize self-feedback of the therapeutic effects of GPs on DSS-induced colitis. The oral biomimetic probe HBTTPIP/GPs reported herein provide a novel theranostic platform for IBD, integrating non-invasive diagnosis of IBD in situ and the corresponding treatment.

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.

Engineered Nonviral Protein Cages Modified for MR Imaging.

Diagnostic medical imaging utilizes magnetic resonance (MR) to provide anatomical, functional, and molecular information in a single scan. Nanoparticles are often labeled with Gd(III) complexes to amplify the MR signal of contrast agents (CAs) with large payloads and high proton relaxation efficiencies (relaxivity, r1). This study examined the MR performance of two structurally unique cages, AaLS-13 and OP, labeled with Gd(III). The cages have characteristics relevant for the development of theranostic platforms, including (i) well-defined structure, symmetry, and size; (ii) the amenability to extensive engineering; (iii) the adjustable loading of therapeutically relevant cargo molecules; (iv) high physical stability; and (v) facile manufacturing by microbial fermentation. The resulting conjugates showed significantly enhanced proton relaxivity (r1 = 11-18 mM-1 s-1 at 1.4 T) compared to the Gd(III) complex alone (r1 = 4 mM-1 s-1). Serum phantom images revealed 107% and 57% contrast enhancements for Gd(III)-labeled AaLS-13 and OP cages, respectively. Moreover, proton nuclear magnetic relaxation dispersion (1H NMRD) profiles showed maximum relaxivity values of 50 mM-1 s-1. Best-fit analyses of the 1H NMRD profiles attributed the high relaxivity of the Gd(III)-labeled cages to the slow molecular tumbling of the conjugates and restricted local motion of the conjugated Gd(III) complex.