Silica–Polymer Hybrid with Self‐Assembled PEG Corona Excreted Rapidly via a Hepatobiliary Route

Nanotechnology‐based diagnostics and therapeutics usually suffer from long‐term retention of nanosized devices in the major organs, which may cause unwanted side effects. Herein, we describe the development of ultra‐small silica‐polymer hybrid dots (Sdots) through the self‐assembly between a polyethylene oxide‐poly(propylene oxide)‐polyethylene oxide (PEO‐PPO‐PEO) triblock copolymer and a silica precursor. Sdots feature a silica particle size of 4.2 nm and a hydrated size of 14 nm. The larger hydrated size is related to their polyethylene glycol (PEG) surface ligands, which evolve from the PEO blocks in the copolymer. The densely packed PEG corona can effectively shield the hybrid from reticuloendothelial uptake, which gives rise to rapid and thorough hepatobiliary clearance. In vivo experiments demonstrated that, upon intravenous injection, almost complete clearance of Sdots from mouse bodies could be realized through hepatobiliary excretion within only 5 days. Compared to renal clearable nanoparticles with short blood‐circulation times, the proposed Sdots have a prolonged blood‐circulation half‐life of 19 h, so that the Sdots could effectively accumulate at a subcutaneous transplanted tumor through enhanced penetration and retention. As the PPO core of the Sdots can be utilized to accommodate hydrophobic guest molecules, such as anticancer drugs, these Sdots can prospectively serve as fast‐clearable drug carriers for targeted cancer treatment.     

High‐Drug‐Loading Mesoporous Silica Nanorods with Reduced Toxicity for Precise Cancer Therapy against Nasopharyngeal Carcinoma

Nanorod‐based drug delivery systems have attracted great interest because of their enhanced cell internalization capacity and improved drug loading property. Herein, novel mesoporous silica nanorods (MSNRs) with different lengths are synthesized and used as nanocarriers to achieve higher drug loading and anticancer activity. As expected, MSNRs‐based drug delivery systems can effectively enhance the loading capacity of drugs and penetrate into tumor cells more rapidly than spherical nanoparticles due to their greater surface area and trans‐membrane transporting rates. Interestingly, these tailored MSNRs also enhance the cellular uptake of doxorubicin (DOX) in cancer cells, thus significantly enhancing its anticancer efficacy for hundreds of times by inducing of cell apoptosis. Internalized MSNRs‐DOX triggers intracellular reactive oxygen species (ROS) overproduction, which subsequently activates p53 and mitogen‐activated protein kinases (MAPKs) pathways to promote cell apoptosis. MSNRs‐DOX nanosystem also shows prolonged blood circulation time in vivo. In addition, MSNRs‐DOX significantly inhibits in vivo tumor growth in nude mice model and effectively reduced its in vivo toxicity. Therefore, this study provides an effective and safe strategy for designing chemotherapeutic agents for precise cancer therapy.     

A New Single 808 nm NIR Light‐Induced Imaging‐Guided Multifunctional Cancer Therapy Platform

The NIR light‐induced imaging‐guided cancer therapy is a promising route in the targeting cancer therapy field. However, up to now, the existing single‐modality light‐induced imaging effects are not enough to meet the higher diagnosis requirement. Thus, the multifunctional cancer therapy platform with multimode light‐induced imaging effects is highly desirable. In this work, captopril stabilized‐Au nanoclusters Au₂₅(Capt)₁₈?(Au₂₅) are assembled into the mesoporous silica shell coating outside of Nd³⁺‐sensitized upconversion nanoparticles (UCNPs) for the first time. The newly formed Au₂₅ shell exhibits considerable photothermal effects, bringing about the photothermal imaging and photoacoustic imaging properties, which couple with the upconversion luminescence imaging. More importantly, the three light‐induced imaging effects can be simultaneously achieved by exciting with a single NIR light (808 nm), which is also the triggering factor for the photothermal and photodynamic cancer therapy. Besides, the nanoparticles can also present the magnetic resonance and computer tomography imaging effects due to the Gd³⁺ and Yb³⁺ ions in the UCNPs. Furthermore, due to the photodynamic and the photothermal effects, the nanoparticles possess efficient in vivo tumor growth inhibition under the single irradiation of 808 nm light. The multifunctional cancer therapy platform with multimode imaging effects realizes a true sense of light‐induced imaging‐guided cancer therapy.     

Near‐Infrared Fluorescent Silica/Porphyrin Hybrid Nanorings for In Vivo Cancer Imaging

Ring‐shaped silica nanoparticles are synthesized with a high tetrakis(4‐carboxyphenyl)porphyrin (TCPP) content or silica/TCPP hybrid nanorings (HNRs) using a one‐pot sol‐gel reaction with a TCPP‐binding silica precursor for fluorescence imaging of tumor. The shape of the HNRs is a reflection of abundant ring‐shaped TCPP aggregates in the silica matrix. The HNRs are of a size that makes them susceptible to the enhanced permeability and retention effect. For comparison, the TCPP‐doped silica nanoparticles are synthesized using a conventional method. The nanoparticles are spherical in shape because little TCPP is contained in the silica matrix and are designated as TCPP‐containing silica nanospheres (NSs). The absorption bands of the HNRs shift by about 20 nm toward longer wavelengths compared with the TCPP bands. This redshift leads the excitation wavelength of the HNRs into the near‐infrared (NIR) region. Therefore, the HNRs are excited by NIR light to emit strong fluorescence, although the NSs emit no fluorescence. The PEGylated HNRs (PEG‐HNRs) are uncharged and possess a significantly longer blood circulation time than PEG‐NSs. The PEG‐HNRs accumulate in tumor through multiple factors including their size, uncharged surface, unique shape, and long circulation time in blood, resulting in the acquisition of clear images of tumor.     

Renal‐Clearable PEGylated Porphyrin Nanoparticles for Image‐Guided Photodynamic Cancer Therapy

Nanomaterials with renal clearance from the body within a reasonable timescale have shown great promises in the area of nanomedicine recently. However, the integration of theranostic and renal clearance properties into a single ultrasmall nanostructure remains a great challenge. Herein, meso‐tetra(4‐carboxyphenyl)porphyrin (TCPP) structure is utilized as a model, for the first time using noninvasive dynamic positron emission tomography (PET) imaging to investigate the balance of the renal clearance and tumor uptake behaviors of polyethylene glycol (PEG)‐modified porphyrin nanoparticles (TCPP‐PEG) with various molecular weights. This study finds that TCPP‐PEG nanoparticles with larger molecular weight show higher tumor uptake due to the enhanced permeability and retention effect, while the lower ones tend to be better for renal clearance. Based on dynamic PET and fluorescence dual‐modal imaging modalities, the TCPP‐PEG_10K nanoparticles seem to be an excellent choice for the balance of renal clearance and tumor retention. In vitro and in vivo photodynamic therapy confirms an excellent therapeutic efficacy. Therefore, this work presents a simplified approach to fabricate and select biocompatible multifunctional TCPP‐PEG‐based theranostic agents with renal clearance behavior, which highlights the clinical application potential of TCPP‐PEG nanoparticles as theranostic probes for imaging‐guided cancer therapy.     

Tumor Microenvironment‐Responsive Mesoporous MnO2‐Coated Upconversion Nanoplatform for Self‐Enhanced Tumor Theranostics

The insufficient blood flow and oxygen supply in solid tumor cause hypoxia, which leads to low sensitivity of tumorous cells and thus causing poor treatment outcome. Here, mesoporous manganese dioxide (mMnO₂) with ultrasensitive biodegradability in a tumor microenvironment (TME) is grown on upconversion photodynamic nanoparticles for not only TME‐enhanced bioimaging and drug release, but also for relieving tumor hypoxia, thereby markedly improving photodynamic therapy (PDT). In this nanoplatform, mesoporous silica coated upconversion nanoparticles (UCNPs@mSiO₂) with covalently loaded chlorin e6 are obtained as near‐infrared light mediated PDT agents, and then a mMnO₂ shell is grown via a facile ultrasonic way. Because of its unique mesoporous structure, the obtained nanoplatform postmodified with polyethylene glycol can load the chemotherapeutic drug of doxorubicin (DOX). When used for antitumor application, the mMnO₂ degrades rapidly within the TME, releasing Mn²⁺ ions, which couple with trimodal (upconversion luminescence, computed tomography (CT), and magnetic resonance imaging) imaging of UCNPs to perform a self‐enhanced imaging. Significantly, the degradation of mMnO₂ shell brings an efficient DOX release, and relieve tumor hypoxia by simultaneously inducing decomposition of tumor endogenous H₂O₂ and reduction of glutathione, thus achieving a highly potent chemo‐photodynamic therapy.     

Ultrasmall Confined Iron Oxide Nanoparticle MSNs as a pH‐Responsive Theranostic Platform

A unique mesoporous silica nanoparticles (MSNs)‐based theranostic platform with ultrasmall iron oxide nanoparticles (NPs) confined within mesopore network has been developed by a facile but efficient physical‐vapor‐infiltration (PVI) method. The highly dispersed Fe species within mesopore channels can synchronously function as the non‐toxic contrast agents for highly efficient T₁‐weighted MR imaging, and as anchoring sites for anti‐cancer drug molecule loading and pH‐responsive release based on the special metal‐ligand coordination bonding between the Fe species and drug molecules. Moreover, the obtained Fe‐MSNs exhibit favorable biocompatibility, enhanced chemotherapeutic efficacy and concurrently diminished side effects due to the non‐specific attack of chemotherapeutic drugs, as well as the capability in circumventing the multidrug resistance (MDR) of cancer cells and suppressing the metastasis of tumor cells in vitro and in vivo. This pH‐resoponsive theranostic agent provides a new promising MSNs‐based anti‐cancer nanomedicine for future biomedical application.     

Porous Porphyrin‐Based Organosilica Nanoparticles for NIR Two‐Photon Photodynamic Therapy and Gene Delivery in Zebrafish

Periodic mesoporous organosilica nanoparticles emerge as promising vectors for nanomedicine applications. Their properties are very different from those of well‐known mesoporous silica nanoparticles as there is no silica source for their synthesis. So far, they have only been synthesized from small bis‐silylated organic precursors. However, no studies employing large stimuli‐responsive precursors have been reported on such hybrid systems yet. Here, the synthesis of porphyrin‐based organosilica nanoparticles from a large octasilylated metalated porphyrin precursor is described for applications in near‐infrared two‐photon‐triggered spatiotemporal theranostics. The nanoparticles display unique interconnected large cavities of 10–80 nm. The framework of the nanoparticles is constituted with J‐aggregates of porphyrins, which endows them with two‐photon sensitivity. The nanoparticle efficiency for intracellular tracking is first demonstrated by the in vitro near‐infrared imaging of breast cancer cells. After functionalization of the nanoparticles with aminopropyltriethoxysilane, two‐photon‐excited photodynamic therapy in zebrafish is successfully achieved. Two‐photon photochemical internalization in cancer cells of the nanoparticles loaded with siRNA is also performed for the first time. Furthermore, siRNA targeting green fluorescent protein complexed with the nanoparticles is delivered in vivo in zebrafish embryos, which demonstrates the versatility of the nanovectors for biomedical applications.     

Highly Scalable,Closed‐Loop Synthesis of Drug‐Loaded,Layer‐by‐Layer Nanoparticles

Layer‐by‐layer (LbL) self‐assembly is a versatile technique from which multi­component and stimuli‐responsive nanoscale drug‐carriers can be constructed. Despite the benefits of LbL assembly, the conventional synthetic approach for fabricating LbL nanoparticles requires numerous purification steps that limit scale, yield, efficiency, and potential for clinical translation. In this report, a generalizable method for increasing throughput with LbL assembly is described by using highly scalable, closed‐loop diafiltration to manage intermediate purification steps. This method facilitates highly controlled fabrication of diverse nanoscale LbL formulations smaller than 150 nm composed from solid‐polymer, mesoporous silica, and liposomal vesicles. The technique allows for the deposition of a broad range of polyelectrolytes that included native polysaccharides, linear polypeptides, and synthetic polymers. The cytotoxicity, shelf life, and long‐term storage of LbL nanoparticles produced using this approach are explored. It is found that LbL coated systems can be reliably and rapidly produced: specifically, LbL‐modified liposomes could be lyophilized, stored at room temperature, and reconstituted without compromising drug encapsulation or particle stability, thereby facilitating large scale applications. Overall, this report describes an accessible approach that significantly improves the throughput of nanoscale LbL drug‐carriers that show low toxicity and are amenable to clinically relevant storage conditions.     

Versatile Prodrug Nanoparticles for Acid‐Triggered Precise Imaging and Organelle‐Specific Combination Cancer Therapy

Integration of chemotherapy with photodynamic therapy (PDT) has been emerging as a novel strategy for treatment of triple negative breast cancer (TNBC). However, the clinical translation of this approach is hindered by the unwanted dark toxicity due to the “always‐on” model and low tumor specificity of currently approved photosensitizer (PS). Here, the design of a multifunctional prodrug nanoparticle (NP) is described for precise imaging and organelle‐specific combination cancer therapy. The prodrug NP is composed of a newly synthesized oxaliplatin prodrug, hexadecyl‐oxaliplatin‐trimethyleneamine (HOT), an acid‐activatable PS, derivative of Chlorin e6 (AC), and functionalized with a targeting ligand iRGD for tumor homing and penetration. HOT displays much higher antitumor efficiency than oxaliplatin by simultaneously inducing mitochondria depolarizing and DNA cross‐linking. AC is specifically activated in the orthotopic or metastatic TNBC tumor for fluorescence imaging and PDT, while it remains inert in blood circulation to minimize the dark toxicity. Under the guide of acid‐activatable fluorescence imaging, PDT and chemotherapy can be synergistically performed for highly efficient regression of TNBC. Taken together, this versatile prodrug nanoplatform could achieve tumor‐specific imaging and organelle‐specific combination therapy, which can provide an alternative option for cancer theranostic.     

MAPK‐Targeted Drug Delivered by a pH‐Sensitive MSNP Nanocarrier Synergizes with PD‐1 Blockade in Melanoma without T‐Cell Suppression

The combination of BRAF/MEK‐targeted therapy with immune checkpoint blockade is regarded as a promising regimen for patients with metastatic melanoma due to their complementary advantages. However, MEK‐inhibitor‐induced T‐cell toxicity impedes effective cooperation. In this experiment, a pH‐responsive on‐demand controlled release mesoporous silica nanoparticles (MSNPs) system is designed. Fluorescein‐isothiocyanate‐loaded MSNP can be specifically delivered into tumor cells rather than T‐cells. MEK‐inhibitor‐loaded MSNP avoids proliferative and functional inhibitions of T‐cells, while preserving growth suppression of tumor cells in vitro. In an in vivo model, MSNP encapsulation reverses the MEK‐inhibitor‐induced suppression of activated CD8⁺ T‐cells, and enhances the secretion of INF‐γ and IL‐2. The combination of BRAF inhibitor plus MSNP‐loaded MEK inhibitor and anti‐PD‐1 antibody synergistically inhibits tumor growth via promoting robust immune‐related antitumor response. This work provides a novel and generalized framework for combining T‐cell‐impaired targeted therapy and immune checkpoint blockade by using a nanoparticle‐based delivery system.     

A Drug‐Self‐Gated Mesoporous Antitumor Nanoplatform Based on pH‐Sensitive Dynamic Covalent Bond

To achieve on‐demand drug release, mesoporous silica nanocarriers as antitumor platforms generally need to be gated with stimuli‐responsive capping agents. Herein, a “smart” mesoporous nanocarrier that is gated by the drug itself through a pH‐sensitive dynamic benzoic–imine covalent bond is demonstrated. The new system, which tactfully bypasses the use of auxiliary capping agents, could also exhibit desirable drug release at tumor tissues/cells and enhanced tumor inhibition. Moreover, a facile dynamic PEGylation via benzoic–imine bond further endows the drug‐self‐gated nanocarrier with tumor extracellular pH‐triggered cell uptake and improves therapeutic efficiency in vivo. In short, the paradigm shift in capping agents here will simplify mesoporous nanomaterials as intelligent drug carriers for cancer therapy. Moreover, the self‐gated strategy in this work also shows general potential for self‐controlled delivery of natural biomolecules, for example, DNA/RNA, peptides, and proteins, due to their intrinsic amino groups.     

iRGD Modified Chemo‐immunotherapeutic Nanoparticles for Enhanced Immunotherapy against Glioblastoma

Glioblastoma is the most common primary brain tumor in adults and still remains incurable, due to the limited accumulation of drugs in the tumor area. Herein, iRGD‐modified nanoparticles, DOX@MSN‐SS‐iRGD&1MT, are developed for simultaneous delivery of chemotherapeutic agents (doxorubicin, DOX) and immune checkpoint inhibitor (1‐methyltryptophan, 1MT) into orthotopic glioma. The nanoparticles are comprised of mesoporous silica nanoparticles loaded with DOX, combined with Asp‐Glu‐Val‐Asp (DEVD) connected 1MT, and finally modified by iRGD. These nanoparticles show the capability of penetrating through blood brain barrier into the tumor area, and significantly improve accumulation of drugs in orthotopic brain tumors with minimal side effects. The nanoparticles also activate cytotoxic CD8⁺ T lymphocytes and inhibit CD4⁺ T cells in both GL261 cells cocultured with splenocytes in vitro and GL261‐luc orthotopic tumors in vivo. Moreover, the expression of antitumor cytokines IFNα/β, IFN‐γ, TNF, IL‐17, STING, and GrzB is upregulated while protumor proteins p‐STAT3 and IL‐10 are downregulated in the brain tumor area. This study demonstrates the advantages of chemo‐immunotherapeutic nanoparticles accumulated in the brain tumor area and their effectively inhibiting tumor proliferation, which establishes a delivery platform to promote antitumor immunity against glioblastoma.     

Noncovalent Polymer‐Gatekeeper in Mesoporous Silica Nanoparticles as a Targeted Drug Delivery Platform

Selective targeting of tumor cells and release of drug molecules inside the tumor microenvironment can reduce the adverse side effects of traditional chemotherapeutics because of the lower dosages required. This can be achieved by using stimuli‐responsive targeted drug delivery systems. In the present work, a robust and simple one‐pot route is developed to synthesize polymer‐gatekeeper mesoporous silica nanoparticles by noncovalent capping of the pores of drug‐loaded nanocontainers with disulfide cross‐linkable polymers. The method offers very high loading efficiency because chemical modification of the mesoporous nanoparticles is not required; thus, the large empty pore volume of pristine mesoporous silica nanoparticles is entirely available to encapsulate drug molecules. Furthermore, the polymer shell can be easily decorated with a targeting ligand for selective delivery to specific cancer cells by subsequent addition of the thiol‐containing ligand molecule. The drug molecules loaded in the nanocontainers can be released by the degradation of the polymer shell in the intracellular reducing microenvironment, which consequentially induces cell death.     

Biocompatible,Uniform, and Redispersible Mesoporous Silica Nanoparticles for Cancer‐Targeted Drug Delivery In Vivo

Engineering multifunctional nanocarriers for targeted drug delivery shows promising potentials to revolutionize the cancer chemotherapy. Simple methods to optimize physicochemical characteristics and surface composition of the drug nanocarriers need to be developed in order to tackle major challenges for smooth translation of suitable nanocarriers to clinical applications. Here, rational development and utilization of multifunctional mesoporous silica nanoparticles (MSNPs) for targeting MDA‐MB‐231 xenograft model breast cancer in vivo are reported. Uniform and redispersible poly(ethylene glycol)‐incorporated MSNPs with three different sizes (48, 72, 100 nm) are synthesized. They are then functionalized with amino‐β‐cyclodextrin bridged by cleavable disulfide bonds, where amino‐β‐cyclodextrin blocks drugs inside the mesopores. The incorporation of active folate targeting ligand onto 48 nm of multifunctional MSNPs (PEG‐MSNPs48‐CD‐PEG‐FA) leads to improved and selective uptake of the nanoparticles into tumor. Targeted drug delivery capability of PEG‐MSNPs48‐CD‐PEG‐FA is demonstrated by significant inhibition of the tumor growth in mice treated with doxorubicin‐loaded nanoparticles, where doxorubicin is released triggered by intracellular acidic pH and glutathione. Doxorubicin‐loaded PEG‐MSNPs48‐CD‐PEG‐FA exhibits better in vivo therapeutic efficacy as compared with free doxorubicin and non‐targeted nanoparticles. Current study presents successful utilization of multifunctional MSNP‐based drug nanocarriers for targeted cancer therapy in vivo.     

A Mesoporous,Silica‐Immobilized‐Nanoparticle Colorimetric Chemosensor for the Detection of Nerve Agents

A new and an easy‐to‐make colorimetric azo‐pyridine, 1, and its recyclable mesoporous silica‐immobilized nanoparticles for nerve‐agent detection are synthesized. The binding site, comprising an azo‐pyridine moiety, is capable of selectively sensing diethylchlorophosphate (DCP), one of the nerve‐agent mimics of chemical‐warfare agents, over a series of other phosphate compounds. Compound 1 shows ratiometric changes in absorption spectroscopy to the extent of a 60 nm red‐shift upon the addition of DCP, mainly due to a change in the intramolecular charge transfer (ICT) in 1 . The color change of receptor 1 from yellow to red in the concentration region ≈1.0 × 10^?6 M is sufficient for the selective detection of the DCP nerve‐agent mimic by the naked eye. With regards to solid‐phase application, mesoporous silica nanoparticles using 1 ( MSIAP ) are also prepared using a sol‐gel grafting reaction. The color of the MSIAP also changes from red to yellow when dipped into an aqueous DCP solution, and turns back to red when treated with NaOH solution, with nontoxic diethylphosphoric acid being given off. The absorption changes of MSIAP in the presence of DCP are consistent within the 3–9 pH range.     

Actively Targeted Deep Tissue Imaging and Photothermal‐Chemo Therapy of Breast Cancer by Antibody‐Functionalized Drug‐Loaded X‐Ray‐Responsive Bismuth Sulfide@Mesoporous Silica Core–Shell Nanoparticles

A theranostic platform combining synergistic therapy and real‐time imaging attracts enormous attention but still faces great challenges, such as tedious modifications and lack of efficient accumulation in tumor. Here, a novel type of theranostic agent, bismuth sulfide@mesoporous silica (Bi₂S₃@mPS) core‐shell nanoparticles (NPs), for targeted image‐guided therapy of human epidermal growth factor receptor‐2 (HER‐2) positive breast cancer is developed. To generate such NPs, polyvinylpyrrolidone decorated rod‐like Bi₂S₃ NPs are chemically encapsulated with a mesoporous silica (mPS) layer and loaded with an anticancer drug, doxorubicin. The resultant NPs are then chemically conjugated with trastuzumab (Tam, a monoclonal antibody targeting HER‐2 overexpressed breast cancer cells) to form Tam‐Bi₂S₃@mPS NPs. By in vitro and in vivo studies, it is demonstrated that the Tam‐Bi₂S₃@mPS bear multiple desired features for cancer theranostics, including good biocompatibility and drug loading ability as well as precise and active tumor targeting and accumulation (with a bismuth content in tumor being ≈16 times that of nontargeted group). They can simultaneously serve both as an excellent contrast enhancement probe (due to the presence of strong X‐ray‐attenuating bismuth element) for computed tomography deep tissue tumor imaging and as a therapeutic agent to destruct tumors and prevent metastasis by synergistic photothermal‐chemo therapy.     

A Bio‐Inspired Rod‐Shaped Nanoplatform for Strongly Infecting Tumor Cells and Enhancing the Delivery Efficiency of Anticancer Drugs

The rapid clearance of circulating nanocarriers in blood during systemic drug delivery remains a challenging hurdle in cancer chemotherapy. Here, inspired by the unique features of bacterial pathogens, an original biodegradable polymer micellar system with a rod‐like shape similar to the morphology of bacterial pathogens is developed. These novel nanocarriers have excellent features such as a great capacity of overcoming the rapid clearance of reticuloendothelial system (RES) with long blood circulation, high cellular internalization, and enhanced therapeutic efficacy against cancers. In vivo pharmacokinetic studies in mice reveal that the rod‐like micelles of ≈40 nm in diameter and 600 nm in length possess a minimal uptake by the RES and excellent blood circulation half‐lives (t_1/2β = 24.23 ± 2.87 h) for carrying doxorubicin in contrast to spheres (t_1/2β = 8.39 ± 0.53 h). The antitumor activity of the rod‐shaped micelles in Balb/c mice bearing H22 tumor xenograft models reveals that they are promptly internalized by tumor cells, resulting in their superior potency and efficacy against artificial solid tumors. These findings suggest that the bio‐inspired nanocarriers as an emerging drug delivery platform may have considerable benefits for enhancing the delivery efficiency of anticancer drugs and in turn enhancing cancer therapy in future clinical applications.     

“All‐in‐One” Nanoparticles for Trimodality Imaging‐Guided Intracellular Photo‐magnetic Hyperthermia Therapy under Intravenous Administration

Great efforts have been devoted so far to combine nano‐magnetic hyperthermia and nano‐photothermal therapy to achieve encouraging additive therapeutic performance in vitro and in vivo with limitation to direct intratumoral injection and no guidance of multimodality molecular imaging. In this study, a novel multifunctional theranostic nanoplatform (MNP@PES‐Cy7/2‐DG) consisting of magnetic nanoparticles (MNPs), poly(3,4‐ethylenedioxythiophene):poly(4‐styrenesulfonate) (PES), Cyanine7 (Cy7), and 2‐deoxyglucose (2‐DG)‐polyethylene glycol is developed. They are then applied to combined photo‐magnetic hyperthermia therapy under intravenous administration that is simultaneously guided by trimodality molecular imaging. Remarkably, nanoparticles are found aggregated mainly in the cytoplasm of tumor cells in vitro and in vivo, and exhibit stealth‐like behavior with a long second‐phase blood circulation half‐life of 20.38 ± 4.18 h. Under the guidance of photoacoustic/near‐infrared fluorescence/magnetic resonance trimodality imaging, tumors can be completely eliminated under intracellular photo‐magnetic hyperthermia therapy with additive therapeutic effect due to precise hyperthermia. This study may promote a further exploration of such a platform for clinical applications.     

Smart Tumor Microenvironment‐Responsive Nanotheranostic Agent for Effective Cancer Therapy

The tumor microenvironment (TME), which includes acidic and hypoxic conditions, severely impedes the therapeutic efficacy of antitumor agents. Herein, MnO₂‐loaded, bovine serum albumin, and PEG co‐modified mesoporous CaSiO₃ nanoparticles (CaM‐PB NPs) are developed as a nanoplatform with sequential theranostic functions for the engineering of TME. The MnO₂ NPs generate O₂ in situ by reacting with endogenous H₂O₂, relieving the hypoxic state of the TME that further modulates the cancer cell cycle status to S phase, which improves the potency of co‐loaded S phase‐sensitive chemotherapeutic drugs. After the hypoxia relief, CaM‐PB can sustainably release drugs due to the enlarged pores of mesoporous CaSiO₃ in the acidic TME, preventing the drug pre‐leakage into the blood circulation and insufficient drug accumulation at tumor sites. Moreover, the Mn²⁺ released from the MnO₂ NPs at tumor sites can potentially serve as a diagnostic agent, enabling the identification of tumor regions by T₁‐weighted magnetic resonance imaging during therapy. In vivo pharmacodynamics results demonstrate that these synergetic effects caused by CaM‐PB NPs significantly contribute to the inhibition of tumor progression. Therefore, the CaM‐PB NPs with sequential theranostic functions are a promising system for effective cancer therapy.