Targeted Lymphoma Therapy Using a Gold Nanoframework-Based Drug Delivery System.

Precision nanomedicine can be employed as an alternative to chemo- or radiotherapy to overcome challenges associated with the often narrow therapeutic window of traditional treatment approaches, while safely inducing effective, targeted antitumor responses. Herein, we report the formulation of a therapeutic nanocomposite comprising a hyaluronic acid (HA)-coated gold nanoframework (AuNF) delivery system and encapsulated IT848, a small molecule with potent antilymphoma and -myeloma properties that targets the transcriptional activity of nuclear factor kappa B (NF-κB). The porous AuNFs fabricated via a liposome-templated approach were loaded with IT848 and surface-functionalized with HA to formulate the nanotherapeutics that were able to efficiently deliver the payload with high specificity to myeloma and lymphoma cell lines in vitro. In vivo studies characterized biodistribution, pharmacokinetics, and safety of HA-AuNFs, and we demonstrated superior efficacy of HA-AuNF-formulated IT848 vs free IT848 in lymphoma mouse models. Both in vitro and in vivo results affirm that the AuNF system can be adopted for targeted cancer therapy, improving the drug safety profile, and enhancing its efficacy with minimal dosing. HA-AuNF-formulated IT848 therefore has strong potential for clinical translation.

A Porous Bimetallic Au@Pt Core-Shell Oxygen Generator to Enhance Hypoxia-Dampened Tumor Chemotherapy Synergized with NIR-II Photothermal Therapy.

The characteristic hypoxia of solid tumors and inadequate oxygen supply become a key causation of the resistance to chemotherapy in cancer treatment. Herein, a bimetallic oxygen nanogenerator, i.e., porous Au@Pt core-shell nanostructures, is particularly developed to reduce the multidrug resistance by oxygenating the tumor along with synergistic chemo-photothermal therapy for efficient tumor eradication. The porous platinum (Pt) shell was able to catalyze oxygen generation from endogenous hydrogen peroxide in the tumor, reducing the exocytosis of doxorubicin (DOX) via suppressed expression of hypoxia-inducible factor-1α, multidrug resistance gene 1, and P-glycoprotein. The strong absorbance of Au@Pt nanostructures in NIR window II enabled NIR-II photothermal therapy. Further incorporation of DOX into the mesopores of Au@Pt nanostructures with the assistance of phase change materials (PCM) led to the formulation of Au@Pt-DOX-PCM-PEG nanotherapeutics for NIR-II-activated chemotherapy. This work presents an efficient H2O2-driven oxygenerator for enhanced hypoxia-dampened chemotherapy and NIR-II photothermal therapy.

Recent advances in porous nanostructures for cancer theranostics.

Porous nanomaterials with high surface area, tunable porosity, and large mesopores have recently received particular attention in cancer therapy and imaging. Introduction of additional pores to nanostructures not only endows the tunability of optoelectronic and optical features optimal for tumor treatment, but also modulates the loading capacity and controlled release of therapeutic agents. In recognition, increasing efforts have been made to fabricate various porous nanomaterials and explore their potentials in oncology applications. Thus, a systematic and comprehensive summary is necessary to overview the recent progress, especially in last ten years, on the development of various mesoporous nanomaterials for cancer treatment as theranostic agents. While outlining their individual synthetic mechanisms after a brief introduction of the structures and properties of porous nanomaterials, the current review highlighted the representative applications of three main categories of porous nanostructures (organic, inorganic, and organic-inorganic nanomaterials). In each category, the synthesis, representative examples, and interactions with tumors were further detailed. The review was concluded with deliberations on the key challenges and future outlooks of porous nanostructures in cancer theranostics.

Camouflaged Gold Nanodendrites Enable Synergistic Photodynamic Therapy and NIR Biowindow II Photothermal Therapy and Multimodal Imaging.

Gold nanodendrite (AuND)-based nanotheranostic agents with versatile capabilities were fabricated by optimizing the geometrical configurations (dendrite length and density) of AuND to achieve localized surface plasmon resonance (LSPR) in near-infrared biowindow II (NIR-II), and then subsequently functionalizing with a mitochondria-targeting compound (triphenylphosphonium, TPP), loading with an NIR-photosensitizer (indocyanine green, ICG) and coating with the macrophage cell membrane (MCM) to trap ICG within AuND and selectively interact with MDA-MB-231 cells. The novel AuND-TPP-ICG@MCM system enabled the integration of multimodal fluorescence/photoacoustic/surface-enhanced Raman imaging with synergistic therapies of NIR-II photothermal therapy and NIR-I photodynamic therapy for cancer treatment. Enhanced hyperthermia and elevated production of reactive oxygen species within the tumors via MCM coating and mitochondria targeting afforded a synergistic efficacy for tumor eradication with limited side effects. The demonstrated biocompatibility, multi-imaging capability, and high therapeutic efficiency under NIR laser irradiation indicate the potentials of this multifunctional nanotheranostic platform for clinical utility in cancer therapy.

A Porous Au@Rh Bimetallic Core-Shell Nanostructure as an H2 O2 -Driven Oxygenerator to Alleviate Tumor Hypoxia for Simultaneous Bimodal Imaging and Enhanced Photodynamic Therapy.

In treatment of hypoxic tumors, oxygen-dependent photodynamic therapy (PDT) is considerably limited. Herein, a new bimetallic and biphasic Rh-based core-shell nanosystem (Au@Rh-ICG-CM) is developed to address tumor hypoxia while achieving high PDT efficacy. Such porous Au@Rh core-shell nanostructures are expected to exhibit catalase-like activity to efficiently catalyze oxygen generation from endogenous hydrogen peroxide in tumors. Coating Au@Rh nanostructures with tumor cell membrane (CM) enables tumor targeting via homologous binding. As a result of the large pores of Rh shells and the trapping ability of CM, the photosensitizer indocyanine green (ICG) is successfully loaded and retained in the cavity of Au@Rh-CM. Au@Rh-ICG-CM shows good biocompatibility, high tumor accumulation, and superior fluorescence and photoacoustic imaging properties. Both in vitro and in vivo results demonstrate that Au@Rh-ICG-CM is able to effectively convert endogenous hydrogen peroxide into oxygen and then elevate the production of tumor-toxic singlet oxygen to significantly enhance PDT. As noted, the mild photothermal effect of Au@Rh-ICG-CM also improves PDT efficacy. By integrating the superiorities of hypoxia regulation function, tumor accumulation capacity, bimodal imaging, and moderate photothermal effect into a single nanosystem, Au@Rh-ICG-CM can readily serve as a promising nanoplatform for enhanced cancer PDT.

Gold Nanoframeworks with Mesopores for Raman-Photoacoustic Imaging and Photo-Chemo Tumor Therapy in the Second Near-Infrared Biowindow.

Gold-based nanostructures with tunable wavelength of localized surface plasmon resonance (LSPR) in the second near-infrared (NIR-II) biowindow receive increasing attention in phototheranostics. In view of limited progress on NIR-II gold nanostructures, a particular liposome template-guided route is explored to synthesize novel gold nanoframeworks (AuNFs) with large mesopores (≈40 nm) for multimodal imaging along with therapeutic robustness. The synthesized AuNFs exhibit strong absorbance in NIR-II region, affording their capacity of NIR-II photothermal therapy (PTT) and photoacoustic (PA) imaging for deep tumors. Functionalization of AuNFs with hyaluronic acid (HA) endows the targeting capacity for CD44-overexpressed tumor cells while gatekeeping doxorubicin (DOX) loaded into mesopores. Conjugation of Raman reporter 4-aminothiophenol (4-ATP) onto AuNFs yields a surface-enhanced Raman scattering (SERS) fingerprint for Raman spectroscopy/imaging. In vivo evaluation of HA-4-ATP-AuNFs-DOX on tumor-bearing xenografts demonstrates its high efficacy in eradication of solid tumors in NIR-II under PA-Raman dual image-guided photo-chemotherapy. Thus, current AuNFs offer versatile capabilities for phototheranostics.

Nanomedicine-Enabled Modulation of Tumor Hypoxic Microenvironment for Enhanced Cancer Therapy.

Hypoxia is a common condition of solid tumors that is mainly caused by enhanced tumor proliferative activity and dysfunctional vasculature. In the treatment of hypoxic human solid tumors, many conventional therapeutic approaches (e.g., oxygen-dependent photodynamic therapy, anticancer drug-based chemotherapy or X-ray induced radiotherapy) become considerably less effective or ineffective. In recent years, various strategies have been explored to deliver or generate oxygen inside solid tumors to overcome tumorous hypoxia and show promising evidence to improve the antitumor efficiency. In this review, the extrinsic regulation of tumor hypoxia via nanomaterial delivery is discussed followed by a summary of the mechanisms through which the modulated tumor hypoxic microenvironment improves therapeutic efficacy. The review concludes with future perspectives, to specifically address the translation of nanomaterial-based therapeutic strategies for clinical applications.

Micelle-Coated, Hierarchically Structured Nanofibers with Dual-Release Capability for Accelerated Wound Healing and Infection Control.

Tailoring nanofibrous matrices-a material with much promise for wound healing applications-to simultaneously mitigate bacterial colonization and stimulate wound closure of infected wounds is highly desirable. To that end, a dual-releasing, multiscale system of biodegradable electrospun nanofibers coated with biocompatible micellar nanocarriers is reported. For wound healing, transforming growth factor-ß1 is incorporated into polycaprolactone/collagen (PCL/Coll) nanofibers via electrospinning and the myofibroblastic differentiation of human dermal fibroblasts is locally stimulated. To prevent infection, biocompatible nanocarriers of polypeptide-based block copolymer micelles are deposited onto the surfaces of PCL/Coll nanofibers using tannic acid as a binding partner. Micelle-modified fibrous scaffolds are favorable for wound healing, not only supporting the attachment and spreading of fibroblasts comparable to those on noncoated nanofibers, but also significantly enhancing fibroblast migration. Micellar coatings can be loaded with gentamicin or clindamycin and exhibit antibacterial activity as measured by Petrifilm and zone of inhibition assays as well as time-dependent reduction of cellular counts of Staphylococcus aureus cultures. Moreover, delivery time of antibiotic dosage is tunable through the application of a novel modular approach. Altogether, this system holds great promise as an infection-mitigating, cell-stimulating, biodegradable skin graft for wound management and tissue engineering.

Enzyme responsive mesoporous silica nanoparticles for targeted tumor therapy in vitro and in vivo.

This study reports a biocompatible controlled drug release system based on mesoporous silica nanoparticles (MSNs) for tumor microenvironment responsive drug delivery. It was fabricated by grafting phenylboronic acid conjugated human serum albumin (PBA-HSA) onto the surfaces of MSNs as a sealing agent, via an intermediate linker of a functional polypeptide, which was composed of two functional units: the polycation cell penetrating peptide (CPP) polyarginine, and matrix metalloproteinase 2 (MMP-2) substrate peptide. A series of characterizations confirmed that the system had been successfully constructed. In vitro tests proved that the anticancer drug loading system could efficiently induce cell apoptosis in vitro. More importantly, the in vivo tumor experiments confirmed that the anticancer loading system could efficiently inhibit tumor growth with minimal side effects.

Cytochrome c end-capped mesoporous silica nanoparticles as redox-responsive drug delivery vehicles for liver tumor-targeted triplex therapy in vitro and in vivo.

To develop carriers for efficient anti-cancer drug delivery with reduced side effects, a biocompatible and redox-responsive nanocontainer based on mesoporous silica nanoparticles (MSNs) for tumor-targeted triplex therapy was reported in this study. The nanocontainer was fabricated by immobilizing cytochrome c (CytC) onto the MSNs as sealing agent via intermediate linkers of disulfide bonds for redox-responsive intracellular drug delivery. AS1411 aptamer was further tailored onto MSNs for cell/tumor targeting. The successful construction of redox- responsive MSNs was confirmed by BET/BJH analysis, transmission electron microscopy, Fourier transform infrared spectroscopy, fluorescence spectroscopy and thermogravimetric analysis (TGA), respectively. Detailed investigations demonstrated that anticancer drug of doxorubicin (DOX) loaded nanocontainer could be triggered by reductant (e.g. glutathione) within cellular microenvironment and release DOX to induce tumor cell apoptosis in vitro. More importantly, the nanocontainer displayed great potential for tumor targeting and achieved triplex therapy effects on the tumor inhibition in vivo through the loading DOX, gatekeeper of CytC and AS1411 aptamer, which were reflected by the change of tumor size, TUNEL staining and HE staining assays.

Intracellular redox-activated anticancer drug delivery by functionalized hollow mesoporous silica nanoreservoirs with tumor specificity.

In this study, a type of intracellular redox-triggered hollow mesoporous silica nanoreservoirs (HMSNs) with tumor specificity was developed in order to deliver anticancer drug (i.e., doxorubicin (DOX)) to the target tumor cells with high therapeutic efficiency and reduced side effects. Firstly, adamantanamine was grafted onto the orifices of HMSNs using a redox-cleavable disulfide bond as an intermediate linker. Subsequently, a synthetic functional molecule, lactobionic acid-grafted-ß-cyclodextrin (ß-CD-LA), was immobilized on the surface of HMSNs through specific complexation with the adamantyl group, where ß-CD served as an end-capper to keep the loaded drug within HMSNs. ß-CD-LA on HMSNs could also act as a targeting agent towards tumor cells (i.e., HepG2 cells), since the lactose group in ß-CD-LA is a specific ligand binding with the asialoglycoprotein receptor (ASGP-R) on HepG2 cells. In vitro studies demonstrated that DOX-loaded nanoreservoirs could be selectively endocytosed by HepG2 cells, releasing therapeutic DOX into cytoplasm and efficiently inducing the apoptosis and cell death. In vivo investigations further confirmed that DOX-loaded nanoreservoirs could permeate into the tumor sites and actively interact with tumor cells, which inhibited the tumor growth with the minimized side effect. On the whole, this drug delivery system exhibits a great potential as an efficient carrier for targeted tumor therapy in vitro and in vivo.

Redox-responsive nanocarrier based on heparin end-capped mesoporous silica nanoparticles for targeted tumor therapy in vitro and in vivo.

This study reports a smart controlled drug release system based on mesoporous silica nanoparticles (MSNs) for targeted drug delivery. The system was fabricated by employing heparin as an end-capping agent to seal the mesopores of MSNs via disulfide bonds as intermediate linkers for intracellular glutathione triggered drug release. Lactobionic acid molecules were then coupled to heparin end-capped MSNs that serve as targeting motifs for facilitating the uptake of doxorubicin (DOX) loaded MSNs by HepG2 cells and tumors, respectively. Detailed investigations demonstrated that the fabricated drug delivery systems could deliver DOX to cancer cells to induce cell apoptosis in vitro and tumor tissue for the inhibition of tumor growth in vivo with minimal side effects. The study affords a promising nanocarrier for redox-responsive cargo delivery with high curative efficiency for cancer therapy.

Hydrazone-bearing PMMA-functionalized magnetic nanocubes as pH-responsive drug carriers for remotely targeted cancer therapy in vitro and in vivo.

To develop vehicles for efficient chemotherapeutic cancer therapy, we report a remotely triggered drug delivery system based on magnetic nanocubes. The synthesized magnetic nanocubes with average edge length of around 30 nm acted as cores, whereas poly(methyl methacrylate) (PMMA) was employed as an intermediate coating layer. Hydrazide was then tailored onto PMMA both for doxorubicin (DOX) loading and pH responsive drug delivery via the breakage of hydrazine bonds. The successful fabrication of the pH responsive drug carrier was confirmed by transmission electron microscopy, Fourier transform infrared spectroscopy, thermogravimetric analysis, and magnetic hysteresis loops, respectively. The carrier was stable at neutral environment and doxorubicin released at pH of 5.0. Cell viability assay and confocal laser scanning microscopy observations demonstrated that the loaded DOX could be efficiently released after cellular endocytosis and induced cancer cells apoptosis thereby. More importantly, the carrier could be guided to the tumor tissue site with an external magnetic field and led to efficient tumor inhibition with low side effects, which were reflected by magnetic resonance imaging (MRI), change of tumor size, TUNEL staining, and H&E staining assays, respectively. All results suggest that hydrazide-tailoring PMMA-coated magnetic nanocube would be a promising pH-responsive drug carrier for remotely targeted cancer therapy in vitro and in vivo.

Surface functionalized mesoporous silica nanoparticles with natural proteins for reduced immunotoxicity.

Mesoporous silica nanoparticles (MSNs) present themselves as one of the most promising nano-carriers for drug delivery. To reduce their immunotoxicities, in this study, natural proteins of gelatin (Gel), bovine serum albumin (BSA), and lysozyme (Lys) were employed as end-caps of MSNs by using succinic anhydride as an intermediate linker, thus leading to fabrication of MSNs/protein nanocomposites, respectively. Furthermore, combined techniques of SEM, TEM, FTIR, and zeta potential instruments were utilized to monitor the construction processes of MSNs/protein nanocomposites, respectively. Finally, the immunotoxicities of those nanocomposites to macrophage cells (RAW264.7 cells) were investigated in detail, i.e., cell morphology, cell viability, nitric oxide (NO) production, reactive oxygen species (ROS), and acid phosphatase activity (ACP) as well as inflammation cytokine expressions (tumor necrosis factor-α and interleukin-1ß). All results suggest that macrophages were activated after uptaking nanoparticles of SiO2 and MSNs, which subsequently induced severe inflammation responses in vitro. In contrast, the inflammation responses of MSNs nanocomposites were reduced dramatically after end-capping with those natural proteins. Overall, this study accumulates knowledge for the development of MSNs-based drug delivery systems with reduced immunotoxicity.

Engineering a hollow nanocontainer platform with multifunctional molecular machines for tumor-targeted therapy in vitro and in vivo.

In order to selectively target malignant cells and eliminate severe side effects of conventional chemotherapy, biocompatible and redox-responsive hollow nanocontainers with tumor specificity were fabricated. The mechanized nanocontainers were achieved by anchoring mechanically interlocked molecules, i.e., [2]rotaxanes, onto the orifices of hollow mesoporous silica nanoparticles via disulfide bonds as intermediate linkers for intracellular glutathione-triggered drug release. The [2]rotaxane employed was mainly composed of U.S. Food and Drug Administration approved tetraethylene glycol chains, α-cyclodextrin, and folic acid. In this study, folate groups on the mechanized hollow nanocontainers act as both the tumor-targeting agents and stoppers of the [2]rotaxanes. Detailed investigations showed that anticancer drug doxorubicin loaded mechanized nanocontainers could selectively induce the apoptosis and death of tumor cells. The drug-loaded nanocontainers enhanced the targeting capability to tumor tissues in vitro and inhibited the tumor growth with minimal side effects in vivo. The present controlled and targeted drug delivery system paves the way for developing the next generation of nanotherapeutics toward efficient cancer treatment.

Cell-specific intracellular anticancer drug delivery from mesoporous silica nanoparticles with pH sensitivity.

A nanoreservoir for efficient intracellular anticancer drug delivery based on mesoporous silica nanoparticles end-capped with lactobionic acid-grafted bovine serum albumin is fabricated. It demonstrates great potential for both cell-specific endocytosis and intracellular pH-responsive controlled release of drugs. A possible endocytosis pathway/mechanism of the smart controlled drug release system is proposed.

Redox-responsive molecular nanoreservoirs for controlled intracellular anticancer drug delivery based on magnetic nanoparticles.

A novel redox responsive controlled drug release system based on magnetic nanoparticles for efficient intracellular anticancer drug delivery is fabricated. Disulfide bonds are employed as intermediate linkers to immobilize PEI/ß-CD molecules as nanoreservoirs for drug loading onto magnetic nanoparticles. The endocytotic pathway and endosomal escape of the smart controlled drug release system is proposed.