Theranostic Nanomedicine Research Articles

Designed fabrication of mesoporous silica-templated self-assembled theranostic nanomedicines

Theranostic nanosystems that integrate diagnosis and therapy have garnered increasing attention for personalized medicine. The integration of the versatile nanoparticles to fabricate self-assembled theranostic nanomedicines becomes increasingly important in current medical research. Mesoporous silica nanoparticles (MSN) with their highly attractive physicochemical properties and favorable morphological attributes represent ideal templates for the controlled assembly and integration of functional nanomaterials to fabricate self-assembled theranostic nanomedicines The rationally designed combination strategy and heterostructure will improve the overall bioavailability and preserve the unique property of each nanocomponent. In this review, the cutting-edge strategies for the designed fabrication of MSN-templated self-assembled nanomedicines are summarized. We categorize MSN-based nanomedicines by their unique heterostructures, including core-shell, yolk-shell, core-satellite, heterodimer and core-shell-satellite structures, and discuss the controlled assembly approaches as well as the intriguing applications for disease theranostics. Finally, a perspective on the challenges in the clinical translation of self-assembled theranostic nanomedicines is highlighted.

Theranostic Nanomedicine for Synergistic Chemodynamic Therapy and Chemotherapy of Orthotopic Glioma.

Glioma is a common primary brain malignancy with a poor prognosis. Chemotherapy is the first‐line treatment for brain tumors but low efficiency of drugs in crossing the blood–brain barrier (BBB) and drug resistance related to tumor hypoxia thwart its efficacy. Herein, a theranostic nanodrug (iRPPA@TMZ/MnO) is developed by incorporating oleic acid‐modified manganese oxide (MnO) and temozolomide (TMZ) into a polyethylene glycol‐poly(2‐(diisopropylamino)ethyl methacrylate‐based polymeric micelle containing internalizing arginine‐glycine‐aspartic acid (iRGD). The presence of iRGD provides the nanodrug with a high capacity of crossing the BBB and penetrating the tumor tissue. After accumulation in glioma, the nanodrug responds to the tumor microenvironment to simultaneously release TMZ, Mn2+, and O2. The released TMZ induces tumor cell apoptosis and the released Mn2+ causes intracellular oxidative stress that kill tumor cells via a Fenton‐like reaction. The O2 produced in situ alleviates tumor hypoxia and enhances the chemotherapy/chemodynamic therapeutic effects against glioma. The Mn2+ can also serve as a magnetic resonance imaging (MRI) contrast agent for tumor imaging during therapy. The study demonstrates the great potential of this multifunctional nanodrug for MRI‐visible therapy of brain glioma.

Mesoporous Silica Nanoparticles as Theranostic Antitumoral Nanomedicines.

Nanoparticles have become a powerful tool in oncology not only as carrier of the highly toxic chemotherapeutic drugs but also as imaging contrast agents that provide valuable information about the state of the disease and its progression. The enhanced permeation and retention effect for loaded nanocarriers in tumors allow substantial improvement of selectivity and safety of anticancer nanomedicines. Additionally, the possibility to design stimuli-responsive nanocarriers able to release their payload in response to specific stimuli provide an excellent control on the administered dosage. The aim of this review is not to present a comprehensive revision of the different theranostic mesoporous silica nanoparticles (MSN) which have been published in the recent years but just to describe a few selected examples to offer a panoramic view to the reader about the suitability and effectiveness of these nanocarriers in the oncology field.

A novel multi-stimuli-responsive theranostic nanomedicine based on Fe3O4@Au nanoparticles against cancer

A novel multi-stimuli-responsive theranostic nanomedicine was designed and fabricated by the conjugation of a thiol end-capped poly(N-isopropylacrylamide-block-acrylic acid) (HS-PNIPAAm-b-PAA) onto Fe3O4@Au nanoparticles (NPs) followed by physical loading of doxorubicin hydrochloride (Dox) as a general anticancer drug. For this purpose, Fe3O4@Au NPs were fabricated through small Au nanolayer grown on larger magnetic NPs. A HS-PNIPAAm-b-PAA was synthesized through an atom transfer radical polymerization (ATRP) approach, and then conjugated with as-synthesized Fe3O4@Au NPs by Au-S bonding. The Dox loading capacity of the synthesized Fe3O4@Au/Polymer theranostic NPs was calculated to be 81%. The theranostic nanomedicine exhibited excellent in vitro drug release behavior under pH and thermal stimuli. The anticancer activity evaluation using MTT assay (against MCF7 cells) revealed that the fabricated Fe3O4@Au/Polymer has high potential as theranostic nanomedicine for cancer therapy of solid tumors. This nanosystem can also applied in photothermal therapy, hyperthermia therapy, and their combination with chemotherapy due to presence of gold and Fe3O4 nanomaterials in its structure.

Self-assembled nanogels of luminescent thiolated silver nanoclusters and chitosan as bactericidal agent and bacterial sensor

Multifunctional theranostic agents with the features of good biocompatibility, long-term antibacterial efficacy, and rapid bacterial detection are the desired future medicine for infectious diseases, but which poses huge challenges on the design of such multifunctional nanocomposites in a single entity. Herein, self-assembled nanogels of thiolated silver nanoclusters (Ag NCs) and chitosan was designed and synthesized, which combines the desirable biocompatible, targeting specific, luminescent properties. This nanogel displays an amplified luminescence via strong matrix-ligand coordination between thiolate ligands and chitosan matrix to rigidify the molecular structure on the surface of Ag NCs. Concomitantly, this nanogel exhibits exceptional bactericidal activity, with approximately >10-fold stronger activity compared to its counterpart Ag NCs. Furthermore, a bacterial detection system was developed based on the bacterial binding on the fluorescent nanogels. This work provides a new strategy in designing multifunctional theranostic agents and this new composite Ag NC nanogel holds great promise for practical applications as the theranostic nanomedicines.

Illuminating Platinum Transportation while Maximizing Therapeutic Efficacy by Gold Nanoclusters via Simultaneous Near-Infrared-I/II Imaging and Glutathione Scavenging.

Killing tumor cells with a visualized system is a promising strategy in tumor therapy to achieve minimal side effects and high efficiency. Herein, a theranostic nanomedicine (AuNCs-Pt) is developed based on nanocarrier gold nanoclusters (AuNCs) with bifunctions of both NIR-I/NIR-II imaging and glutathione-scavenging abilities. AuNCs-Pt possesses NIR-II imaging capability on a fatal high-grade serous ovarian cancer (HGSOC) model in the deep abdomen, thus facilitating it to be a promising tool for monitoring platinum transportation. Meanwhile, AuNCs-Pt depletes intracellular glutathione to minimize platinum detoxification, effectively maximizing the chemotherapeutic efficacy of platinum. AuNCs-Pt is used to eradicate the tumor burden in this study on a HGSOC model and a patient-derived tumor xenograft model of hepatocellular carcinoma, suggesting great potential for clinical visualized therapy and platinum drug sensitization.

Designing Magnetic NanoMOFs for Biomedicine: Current Trends and Applications

Metal–organic frameworks (MOFs) have shown a great potential in biomedicine due to their promising applications in different fields, including drug delivery, thermometry, theranostics etc. In this context, the development of magnetic sub-micrometric or nanometric MOFs through miniaturization approaches of magnetic MOFs up to the nanoscale still represents a crucial step to fabricate biomedical probes, especially in the field of theranostic nanomedicine. Miniaturization processes have to be properly designed to tailor the size and shape of particles and to retain magnetic properties and high porosity in the same material, fundamental prerequisites to develop smart nanocarriers integrating simultaneously therapeutic and contrast agents for targeted chemotherapy or other specific clinical use. An overview of current trends on the design of magnetic nanoMOFs in the field of biomedicine, with particular emphasis on theranostics and bioimaging, is herein envisioned.

Cathepsin B-responsive and gadolinium-labeled branched glycopolymer-PTX conjugate-derived nanotheranostics for cancer treatment

Multi-modal therapeutics are emerging for simultaneous diagnosis and treatment of cancer. Polymeric carriers are often employed for loading multiple drugs due to their versatility and controlled release of these drugs in response to a tumor specific microenvironment. A theranostic nanomedicine was designed and prepared by complexing a small gadolinium chelate, conjugating a chemotherapeutic drug PTX through a cathepsin B-responsive linker and covalently bonding a fluorescent probe pheophorbide a (Ppa) with a branched glycopolymer. The branched prodrug-based nanosystem was degradable in the tumor microenvironment with overexpressed cathepsin B, and PTX was simultaneously released to exert its therapeutic effect. The theranostic nanomedicine, branched glycopolymer-PTX-DOTA-Gd, had an extended circulation time, enhanced accumulation in tumors, and excellent biocompatibility with significantly reduced gadolinium ion (Gd3+) retention after 96 h post-injection. Enhanced imaging contrast up to 24 h post-injection and excellent antitumor efficacy with a tumor inhibition rate more than 90% were achieved from glycopolymer-PTX-DOTA-Gd without obvious systematic toxicity. This branched polymeric prodrug-based nanomedicine is very promising for safe and effective diagnosis and treatment of cancer.

All-in-One Theranostic Nanomedicine with Ultrabright Second Near-Infrared Emission for Tumor-Modulated Bioimaging and Chemodynamic/Photodynamic Therapy.

Reactive oxygen species (ROS)-based therapeutic modalities including chemodynamic therapy (CDT) and photodynamic therapy (PDT) hold great promise for conquering malignant tumors. However, these two methods tend to be restricted by the overexpressed glutathione (GSH) and hypoxia in the tumor microenvironment (TME). Here, we develop biodegradable copper/manganese silicate nanosphere (CMSN)-coated lanthanide-doped nanoparticles (LDNPs) for trimodal imaging-guided CDT/PDT synergistic therapy. The tridoped Yb3+/Er3+/Tm3+ in the ultrasmall core and the optimal Yb3+/Ce3+ doping in the shell enable the ultrabright dual-mode upconversion (UC) and downconversion (DC) emissions of LDNPs under near-infrared (NIR) laser excitation. The luminescence in the second near-infrared (NIR-II, 1000-1700 nm) window offers deep-tissue penetration, high spatial resolution, and reduced autofluorescence when used for optical imaging. Significantly, the CMSNs are capable of relieving the hypoxic TME through decomposing H2O2 to produce O2, which can react with the sample to generate 1O2 upon excitation of UC photons (PDT). The GSH-triggered degradation of CMSNs results in the release of Fenton-like Mn2+ and Cu+ ions for •OH generation (CDT); simultaneously, the released Mn2+ ions couple with NIR-II luminescence imaging, computed tomography (CT) imaging, and magnetic resonance (MR) imaging of LDNPs, performing a TME-amplified trimodal effect. In such a nanomedicine, the TME modulation, bimetallic silicate photosensitizer, Fenton-like nanocatalyst, and NIR-II/MR/CT contrast agent were achieved "one for all", thereby realizing highly efficient tumor theranostics.

Self-Assembling PCL-PAMAM Linear Dendritic Block Copolymers (LDBCs) for Bioimaging and Phototherapeutic Applications.

This study represents a successful approach toward employing polycaprolactone-polyamidoamine (PCL-PAMAM) linear dendritic block copolymer (LDBC) nanoparticles as small-molecule carriers in NIR imaging and photothermal therapy. A feasible and robust synthetic strategy was used to synthesize a library of amphiphilic LDBCs with well-controlled hydrophobic-to-hydrophilic weight ratios. Systems with a hydrophobic weight ratio higher than 70% formed nanoparticles in aqueous media, which show hydrodynamic diameters of 51.6 and 96.4 nm. These nanoparticles exhibited loading efficiencies up to 21% for a hydrophobic molecule and 64% for a hydrophilic molecule. Furthermore, successful cellular uptake was observed via trafficking into endosomal and lysosomal compartments with an encapsulated NIR theranostic agent (C3) without inducing cell death. A preliminary photothermal assessment resulted in cell death after treating the cells with encapsulated C3 and exposing them to NIR light. The results of this work confirm the potential of these polymeric materials as promising candidates in theranostic nanomedicine.

Targeting Neutrophils for Enhanced Cancer Theranostics.

Improving tumor accumulation and delivery efficiency is an important goal of nanomedicine. Neutrophils play a vital role in both chemically mediating inflammatory response through myeloperoxidase (MPO) and biologically promoting metastasis during inflammation triggered by the primary tumor or environmental stimuli. Herein, a novel theranostic nanomedicine that targets both the chemical and biological functions of neutrophils in tumor is designed, facilitating the enhanced retention and sustained release of drug cargos for improved cancer theranostics. 5-hydroxytryptamine (5-HT) is equipped onto nanoparticles (NPs) loaded with photosensitizers and Zileuton (a leukotriene inhibitor) to obtain MPO and neutrophil targeting NPs, denoted as HZ-5 NPs. The MPO targeting property of 5-HT modified NPs is confirmed by noninvasive positron emission tomography imaging studies. Furthermore, photodynamic therapy is used to initiate the inflammatory response which further mediated the accumulation and retention of neutrophil targeting NPs in a breast cancer model. This design renders a greatly improved theranostic nanomedicine for efficient tumor suppression, and more importantly, inhibition of neutrophil-mediated lung metastasis via the sustained release of Zileuton. This work presents a novel strategy of targeting neutrophils for improved tumor theranostics, which may open up new avenues in designing nanomedicine through exploiting the tumor microenvironment.

Multifunctional hydroxyapatite with potential for application in theranostic nanomedicine

Although several materials are being studied for the development of theranostic systems, factors such as high costs, low yield, stability of nanoparticles (NPs) and toxicity-related issues hinder their application in medicine. Thus, this paper introduces the synthesis of a theranostic system composed of hydroxyapatite (HAp) functionalized with europium (Eu3+) and zinc oxide (ZnO) NPs, resulting in a low-cost material that presents biocompatibility, luminescence, antibacterial activity and whose synthesis method is simple. The Eu3+-doped HAp was obtained through the precipitation method and the functionalization with ZnO occurred in the subsequent stage through the solid-state reaction method. The resulting material, [Ca9.5Eu0.5(PO4)6(OH)2@ZnO], was characterized by several techniques where the photoluminescence spectrum exhibited sharp peaks at the 4fN→4fN transitions typical of Eu3+ ions, while tests with bacteria proved its antibacterial property. The crystal structure obtained by X-ray diffraction confirmed HAp as the major phase. The multifunctional HAp (HAp:Eu@ZnO) was considered as hemocompatible, exhibiting an in vitro hemolysis ratio of 1.85 (±0.2) %, and its loading potential, tested for two antitumor drugs, showed an adsorption capacity of 43.0±3.6% for 5-Fluorouracil and 84.0±4.0% for curcumin. The cytotoxicity of the system as well as its use as a support for drugs was analyzed through in vitro assays with tumor cells from sarcoma 180 in mice. The results confirmed that HAp:Eu@ZnO is non-toxic to cells and its potential for antineoplastic vectorization is increased by cell internalization due to endocytosis, with up to 39.0% of cancer cell deaths having been observed at the concentrations and period evaluated.

99mTc-doxorubicin-loaded gallic acid-gold nanoparticles (99mTc-DOX-loaded GA-Au NPs) as a multifunctional theranostic agent.

The development of cancer theranostic nanomedicines is recommended to concurrently achieve and evaluate the therapeutic benefit and progress. The current work aims to develop gallic acid-gold nanoparticles (GA-Au NPs) as a theranostic probe for 99mTc-Doxorubicin (99mTc-DOX) based on the spatiotemporal release pattern induced intra-tumoral (IT) delivery. DOX-loaded GA-Au NPs were developed and identified via UV-Vis spectroscopy. The system was characterized for drug loading efficiency%, particle size, zeta potential, topography, in vitro DOX release and anti-proliferative activity against the MCF-7 cell-line. The factors influencing radiolabeling efficiency of DOX with 99mTc (DOX concentration, stannous chloride concentration, reaction time and pH) were optimized. The in vitro stability in mice serum and in vivo distribution studies in mice of 99mTc-DOX-loaded GA-Au NPs were investigated following IV and IT administration. Dox-loaded GA-Au NPs had a loading efficiency of 91%, a small particle size (≈50nm), a promising zeta potential (-20mV) and a sustained drug release profile at pH 5.3. GA-Au NPs exhibited increased anti-proliferative activity, with approximately a four-fold lower IC50 value (0.15μg/ml) than free DOX. The optimized radiolabeling efficiency of 99mTc-DOX was ≈93%. It showed good physiological stability in mice serum for at least 8h. The IT delivery of 99mTc-DOX-loaded GA-Au NPs in tumor-induced mice showed dramatic tumor accumulation. A maximum magnitude of 86.73%ID/g was achieved, at 15min post-injection, with a target/non-target ratio of ≈56. 99mTc-DOX-loaded GA-Au NPs could be used for the selective IT delivery of a chemotherapeutic agent and an imaging agent to a target organ.

Programmed Self-Assembly of Protein-Coated AIE-Featured Nanoparticles with Dual Imaging and Targeted Therapy to Cancer Cells.

Modifying different functional moieties into one platform is a conventional strategy for constructing theranostic systems. However, this strategy usually suffers from the unsatisfied efficiency of each individual function. Herein, a programmed self-assembly strategy is presented to fabricate theranostic nanoparticles, which significantly exhibit a dual-modality imaging function involving fluorescence imaging and magnetic resource imaging (MRI), and an efficient targeted therapy to cancer cells. Fluorescent vesicles are first self-assembled by aggregation-induced emission (AIE)-active molecules. Gd3+, serving as an MRI agent, is subsequently bound to the vesicles to provide highly positive charges, which have been realized to be anticancer active. Thereafter, transferrin (Tf) protein is introduced onto the surface of Gd3+ coordinated vesicles, shielding the positive charges and making the nanoparticles nontoxic to cells. With the assistance of Tf protein, the constructed nanoparticles are specifically targeted to cancer cells. Moreover, Tf proteins further peel off from nanoparticles in lysosomes due to their charge reversion, resulting in highly positive charges and heavy toxicity of nanoparticles to kill cancer cells. In the nanoparticles, each of the functional components acts as double-sided adhesive tape to glue the next layer, so that the abilities of functional components are not compromised. This strategy holds great potential for theranostic nanomedicine.

Graphene oxide activated by 980 nm laser for cascading two-photon photodynamic therapy and photothermal therapy against breast cancer

Combinational applying photodynamic therapy (PDT) and photothermal therapy (PTT) have been extensively studied, while simultaneously exciting with a single wavelength NIR laser remains challenges. In this study, PEGylated nano graphene oxide co-loaded with photosensitizers (PS) and two-photon compound was developed as a theranostic nanomedicine GO-PEG(TP) against cancer. Two-photon compound could convert near-infrared laser into visible light for exciting PS thus achieved deeper therapeutic depth. The size, morphology and drug release profile of GO-PEG(TP) were characterized. The photoactivity of PS and two-photon compound get quenched on the graphene sheet, whereas activated quickly after releasing from carrier. Such combined therapy shows blasting of 4T1 murine breast cancer cells and induced large population of apoptosis. Ex vivo distribution and in vivo thermographic images were analyzed by using GO-PEG(TP) as probe, on subcutaneously 4T1 tumor bearing mice. Combinational therapy and histology examination reveal the antitumor property and biosafety of GO-PEG(TP).

Hyaluronic Acid-Based Theranostic Nanomedicines for Targeted Cancer Therapy.

Hyaluronic acid (HA) is a natural mucopolysaccharide and has many useful advantages, including biocompatibility, non-immunogenicity, chemical versatility, non-toxicity, biodegradability, and high hydrophilicity. Numerous tumor cells overexpress several receptors that have a high binding affinity for HA, while these receptors are poorly expressed in normal body cells. HA-based drug delivery carriers can offer improved solubility and stability of anticancer drugs in biological environments and allow for the targeting of cancer treatments. Based on these benefits, HA has been widely investigated as a promising material for developing the advanced clinical cancer therapies in various formulations, including nanoparticles, micelles, liposomes, and hydrogels, combined with other materials. We describe various approaches and findings showing the feasibility of improvement in theragnosis probes through the application of HA.

Chemically Nano-Engineered Theranostics for Phytoconstituents as Healthcare Application

Background: Nanomedicines are capable of disease diagnosis, drug delivery, and in monitoring the therapeutic result to provide appropriate tasks towards research goals. The best therapeutic pattern can be achieved by developing a theranostic nanomedicine, which is an emerging field. It has the advantage of loading phytoconstituents as drugs and is useful for both imaging and therapeutic function. Methods: Nowadays, the design of a novel drug delivery system of the herbal constituent is usually done through the nanotechnology approach. This technique increases the biological activity and counters the puzzles associated with plant medicines. Traditional medicine integration with nanocarriers as an NDDS is very essential in the management of chronic diseases such as hypertension, diabetes, and cancer. Results: The nanotechnology combination with plant science is a green revolution with a practical approach for decreasing the therapeutic side effects. The object of the study is to review herbal nanomedicine with an enhanced therapeutic profile and less toxicity. Conclusion: The development of herbal theranostic nanoformulation is very useful for the treatment of different diseases.

DNA biodots based targeted theranostic nanomedicine for the imaging and treatment of non-small cell lung cancer

The light absorption and emission characteristics of DNA biodots (DNA-BD), along with biocompatibility, give them a high potential for use in various medical applications, particularly in diagnostic purpose. DNA, under high pressure and temperature, condenses to form luminescent biodots. The objective of this research is to develop DNA-biodots (BD) loaded and cetuximab conjugated targeted theranostic liposomes of etoposide for lung cancer imaging and therapy. Theranostic liposomes were prepared by using the solvent injection method and characterized for their particle size, polydispersity, zeta potential, encapsulation efficiency, and pH-dependent in-vitro release, SEM, TEM AFM, EDX, and XRD. The t50% (time at which 50% of the drug releases from the preparation) of the formulations was pH-dependent, with a significant increase in the release at lower pH (5.5). To kill A549 adenocarcinoma cells, the etoposide (control) required significantly (p < 0.05) higher drug concentrations in comparison to non-targeted and; the non-targeted formulation required more concentrations in comparison to targeted liposomes. The in-vivo results demonstrated that CTX-TPGS decorated theranostic liposomes could be a promising carrier for lung theranostics due to their nano-size and selectivity towards EGFR overexpressed cells which provided an improved NSCLC targeted delivery of ETP in comparison to the non-targeted and control formulations.

Design of a Novel Theranostic Nanomedicine (III): Synthesis and Physicochemical Properties of Tumor-Targeting Cisplatin Conjugated to a Hydrophilic Polyphosphazene.

PurposeA new theranostic nanomedicine involving anticancer-active cisplatin moiety was designed to study its tumor-targeting properties as well as its drug efficacy and toxicity.MethodsA cisplatin carrier polymer was prepared by grafting equimolar polyethylene glycol of a molecular weight of 550 (PEG550) and aminoethanol to the poly(dichlorophosphazene) backbone. Cisplatin was conjugated to the carrier polymer using cis-aconitic acid as a linker.ResultsThe cisplatin-loaded polyphosphazene, named “Polycisplatin” was found to be amphiphilic in aqueous solution and self-assembled into nanoparticles with an average particle size of 18.6 nm in diameter. The time-dependent organ distribution study of Cy5.5-labeled Polycisplatin in the A549-tumor-bearing mice exhibited a high tumor selectivity of Polycisplatin by EPR effect despite the relatively small particle size. In order to compare the in vivo efficacy of Polycisplatin and cisplatin, their xenograft trials were performed using nude mice against the human gastric cell line MKN-28. Polycisplatin exhibited slightly less tumor suppression effect compared with cisplatin at the same dose of 1.95 mg Pt/kg, which is the maximum tolerate dose of cisplatin, but at the higher double dose of 3.9 mg Pt/kg, Polycisplatin exhibited a little better efficacy than cisplatin. Furthermore, mice treated with cisplatin at the dose of 1.95 mg Pt/kg exhibited severe body weight decrease by about 25%, while mice treated with Polycisplatin did not show serious body weight decrease even at its double dose of 3.9 mg Pt/kg. Furthermore, kidney indicators including kidney index, BUN, and creatinine values measured displayed that Polycisplatin is much less nephrotoxic than cisplatin.ConclusionNanoparticular Polycisplatin was successfully prepared by conjugating cisplatin to a hydrophilic polyphosphazene carrier polymer using the acid-cleavable cis-aconitic acid. Polycisplatin nanoparticles exhibit excellent tumor-targeting properties by EPR effect. The xenograft trials exhibited excellent antitumor efficacy and reduced systemic toxicity of Polycisplatin.

A de novo theranostic nanomedicine composed of PEGylated graphene oxide and gold nanoparticles for cancer therapy

Abstract