A smart magnetic nanosystem for sequential extracellular and intracellular release of proteins for cancer therapy.

Protein therapy, an innovative therapeutic strategy, has been extensively used in the treatment of cancer in recent years. However, the sequential delivery of multiple proteins acting separately intracellular and extracellular to their sites of action remains a challenge. Here, we construct a nanosystem (PEI-PEG-TRAIL@IONP-GOx) to sequentially release tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) extracellularly and glucose oxidase (GOx) intracellularly for synergistic cancer treatment. The nanosystem is built as a core-shell structure. The core is a pH responsive nanoassembly of boronic acid modified iron oxide nanoparticles (FPBA-IONPs) and polyphenol decorated GOx. The shell is a PEGylated polyethyleneimine (PEI-PEG) polymer on which TRAIL was coupled by a matrix metalloproteinase-2 (MMP-2) responsive peptide. Once the nanosystems were magnetically guided to the tumor site, TRAIL was quickly released by the extracellular MMP-2 to induce tumor apoptosis and enhanced the cellular uptake of the cores. After cytosolic delivery, FPBA-IONPs and GOx were disassembled intracellularly to trigger a cascade reaction to generate free radicals for tumor inhibition. Both in vitro and in vivo experiments proved the separate delivery of TRAIL and GOx and their remarkable synergistic anti-cancer effect. We believe that this nanosystem can offer a new approach for the multistage delivery of proteins and accomplish the objective of protein cooperation for cancer treatment.

Prodrug-based strategy with a two-in-one liposome for Cerenkov-induced photodynamic therapy and chemotherapy.

Cerenkov radiation induced photodynamic therapy (CR-PDT) can tackle the tissue penetration limitation of traditional PDT. However, co-delivery of radionuclides and photosensitizer may cause continuous phototoxicity in normal tissues during the circulation. 5-aminolevulinic acid (ALA) which can intracellularly transform into photosensitive protoporphyrin IX (PpIX) is a cancer-selective photosensitizer with negligible side effect. However, the hydrophilic nature of ALA and the further conversion of PpIX to photoinactive Heme severely hinder the therapeutic benefits of ALA-based PDT. Herein, we developed an 89Zr-labeled, pH responsive ALA and artemisinin (ART) co-loaded liposome (89Zr-ALA-Liposome-ART) for highly selective cancer therapy. 89Zr can serve as the internal excitation source to self-activate PpIX for CR-PDT, and the photoinactive Heme can activate the chemotherapeutic effect of ART. The 89Zr-ALA-Liposome-ART exhibited excellent tumor inhibition capability in subcutaneous 4T1-tumor-bearing Balb/c mice via CR-PDT and chemotherapy. Combined with anti-PD-L1, the 89Zr-ALA-Liposome-ART elicited strong antitumor immunity to against tumor recurrence.

Catechol-metal coordination-mediated nanocomposite hydrogels for on-demand drug delivery and efficacious combination therapy.

Hydrogels have drawn considerable attention in the field of drug delivery, yet their poor mechanical strength and uncontrollable drug release behavior have hindered further applications in clinical practice. Taking utility of metal-ligand coordination for structurally reinforcing the hydrogel network, we report design and synthesis of magnetic nanocomposite hydrogels (HA-DOPA·MNPs) that are crosslinked by DOPA-Fe(III) coordination existing between dopamine-conjugated hyaluronan (HA-DOPA) and iron oxide magnetic nanoparticles (MNPs). The MNPs in the nanocomposite hydrogel not only serve as structural crosslinkers, but also facilitate magnetic hyperthermia and on-demand release of doxorubicin (DOX) in HA-DOPA·MNPs/DOX hydrogels, for release rate of DOX accelerates when external alternating magnetic field (AMF) is ON, and it restores to a slow pace when AMF is OFF. Importantly, HA-DOPA·MNPs/DOX hydrogel shows a longer retention time than HA-DOPA/DOX gel or DOX solution in vivo. Further experiments confirm the efficacious anticancer potency of HA-DOPA·MNPs/DOX in vitro and in vivo, that is mediated by a combination therapy consisting of chemotherapy (DOX) and hyperthermia (MNPs). In contrast, single-modality treatment (DOX or hyperthermia only) fails to show an equivalent efficacy at the same dose. STATEMENT OF SIGNIFICANCE: This study reports the design of a class of magnetic nanocomposite hydrogel (HA-DOPA·MNPs) that was structurally reinforced by DOPA-Fe (III) coordination between HA-DOPA and iron oxide MNPs. On one hand, MNPs served as crosslinking centers for structurally reinforcing the nanocomposite hydrogel; on the other hand, MNPs facilitated temperature rise under an external MNPs, which prompted on-demand drug release as well as a combination therapy. Comparing to single modality treatment (chemotherapy or hyperthermia alone), the HA-DOPA·MNPs/DOX formulation with AMF demonstrated better efficacy against proliferation of tumor cells (A375) both in vitro and in vivo. We believe that design of HA-DOPA·MNPs/DOX hydrogel in this report provides a general approach to fabricate structurally-reinforced nanocomposite hydrogels for on-demand drug delivery and efficacious combination therapy.

Magnetic liposomal emodin composite with enhanced killing efficiency against breast cancer.

As an active natural ingredient extracted from the plant Rheum palmatum, emodin exhibits various pharmacological activities, especially the inhibition of tumor growth and migration. However, the anticancer activity of emodin is limited mainly due to its poor solubility and the lack of specific targeting. Herein, we employed liposome to load emodin into the lipid bilayer, and high-performance ferromagnetic iron oxide nanocubes were simultaneously encapsulated in the hydrophilic bilayer. The optimized magnetic liposomal emodin nanocomposite (MLE) exhibited a 24.1% increase in the efficiency of killing MCF-7 cancer cells at a low concentration of 16 µg mL-1 compared with that of the hydrophobic free emodin. A further 8.67% enhancement of the killing efficiency was obtained by magnetic targeting. Benefitting from the high ferromagnetism, the transverse relaxivity (r2) of MLE was measured to be as high as 392.9 mM-1 s-1. With guidance from the external magnetic field, the effective accumulation of this magnetic liposome in the tumor region of a 4T1 breast tumor bearing mouse was observed by both MR tracking and fluorescence imaging, which should be beneficial for decreasing the required therapeutic dose of emodin. Hemolysis, cytotoxicity and biochemistry assays confirmed the excellent biocompatibility of this magnetic liposomal carrier. The anti-tumor therapeutic effect of MLE was further investigated in vivo, and the tumor in the therapeutic group was almost eliminated, indicating that this magnetic liposomal emodin could serve as a novel magnetically guided theranostic nanoagent.

Ceria nanocrystals decorated mesoporous silica nanoparticle based ROS-scavenging tissue adhesive for highly efficient regenerative wound healing.

Restoration of tissue integrity and tissue function of wounded skin are both essential for wound repair and regeneration, while synergistic promotion of the two remains elusive. Since elevated reactive oxygen species (ROS) production in the injured site has been implicated in triggering a set of deleterious effects such as cellular senescence, fibrotic scarring, and inflammation, it is speculated that alleviating oxidative stress in the microenvironment of injured site would be beneficial to promote regenerative wound healing. In this study, a highly versatile ROS-scavenging tissue adhesive nanocomposite is synthesized by immobilizing ultrasmall ceria nanocrystals onto the surface of uniform mesoporous silica nanoparticles (MSN). The ceria nanocrystals decorated MSN (MSN-Ceria) not only has strong tissue adhesion strength, but also significantly restricts ROS exacerbation mediated deleterious effects, which efficiently accelerates the wound healing process, and more importantly, the wound area exhibits an unexpected regenerative healing characteristic featured by marked skin appendage morphogenesis and limited scar formation. This strategy can also be adapted to other wound repair where both ROS-scavenging activity and tissue adhesive ability matter.

Preparation of Magnetic Nanoparticles for Biomedical Applications.

Magnetic nanoparticles have obtained great attention in the field of biomedicine in recent years owing to their excellent biocompatibility, unique magnetic properties, and ease of functionalization. Potential applications for functionalized magnetic nanoparticles span biomedical imaging, treatment via magnetic hyperthermia, drug delivery, and biosensing. This chapter provides detailed procedures for the synthesis, PEGylation, and bioconjugation of monodispersed Fe3O4 nanoparticles, hollow Fe3O4 nanoparticles, porous hollow Fe3O4 nanoparticles, and dumbbell-like Au-Fe3O4 nanoparticles. We hope this article can help readers design and reproducibly prepare high-quality magnetic nanoparticles with their specific goals in mind.

Croconaine nanoparticles with enhanced tumor accumulation for multimodality cancer theranostics.

A novel nanoparticle self-assembled by polyethylene glycol (PEG) modified croconaine dye (CR780) is presented for photoacoustic (PA)/near-infrared (NIR) fluorescence imaging-guided photothermal therapy (PTT). The simple PEGylation made CR780 amphiphilic, and led to their self-assembly into well-defined and uniform nanostructures with size tunable by controlling the assembly conditions. The CR780-PEG5K not only displayed the strength of small molecules (including rapid distribution to different organs, fast renal clearance and minimal accumulation to normal tissues), but also demonstrated the advantages of nanomaterials (including high physiological stability, multimodal theranostic ability, high tumor accumulation and retention). These facilely synthesized molecular nanoprobes showed great clinical translation potential as a versatile theranostic agent.

Improved Tumor Uptake by Optimizing Liposome Based RES Blockade Strategy.

Minimizing the sequestration of nanomaterials (NMs) by the reticuloendothelial system (RES) can enhance the circulation time of NMs, and thus increase their tumor-specific accumulation. Liposomes are generally regarded as safe (GRAS) agents that can block the RES reversibly and temporarily. With the help of positron emission tomography (PET), we monitored the in vivo tissue distribution of 64Cu-labeled 40 × 10 nm gold nanorods (Au NRs) after pretreatment with liposomes. We systematically studied the effectiveness of liposome administration by comparing (1) differently charged liposomes; (2) different liposome doses; and (3) varying time intervals between liposome dose and NR dose. By pre-injecting 400 µmol/kg positively charged liposomes into mice 5 h before the Au NRs, the liver and spleen uptakes of Au NRs decreased by 30% and 53%, respectively. Significantly, U87MG tumor uptake of Au NRs increased from 11.5 ± 1.1 %ID/g to 16.1 ± 1.3 %ID/g at 27 h post-injection. Quantitative PET imaging is a valuable tool to understand the fate of NMs in vivo and cationic liposomal pretreatment is a viable approach to reduce RES clearance, prolong circulation, and improve tumor uptake.

Ultrasmall Gold Nanorod Vesicles with Enhanced Tumor Accumulation and Fast Excretion from the Body for Cancer Therapy.

A new kind of ultrasmall dissociable AuNR@PEG/PLGA vesicles (≈60 nm) (AuNR = gold nanorod; PEG = poly(ethylene glycol); PLGA = poly(lactic-co-glycolic acid)) assembled from small AuNRs (dimension: ≈8 nm × 2 nm) is reported. They exhibit several striking features: prolonged circulation and prominent tumor accumulation; rapid excretion from the body as AuNR@PEG after therapy; enhanced photoacoustic and photo thermal properties; and high photothermal cancer therapy efficacy.

Chelator-free (64)Cu-integrated gold nanomaterials for positron emission tomography imaging guided photothermal cancer therapy.

Using positron emission tomography (PET) imaging to monitor and quantitatively analyze the delivery and localization of Au nanomaterials (NMs), a widely used photothermal agent, is essential to optimize therapeutic protocols to achieve individualized medicine and avoid side effects. Coupling radiometals to Au NMs via a chelator faces the challenges of possible detachment of the radiometals as well as surface property changes of the NMs. In this study, we reported a simple and general chelator-free (64)Cu radiolabeling method by chemically reducing (64)Cu on the surface of polyethylene glycol (PEG)-stabilized Au NMs regardless of their shape and size. Our (64)Cu-integrated NMs are proved to be radiochemically stable and can provide an accurate and sensitive localization of NMs through noninvasive PET imaging. We further integrated (64)Cu onto arginine-glycine-aspartic acid (RGD) peptide modified Au nanorods (NRs) for tumor theranostic application. These NRs showed high tumor targeting ability in a U87MG glioblastoma xenograft model and were successfully used for PET image-guided photothermal therapy.

Monodisperse gold-palladium alloy nanoparticles and their composition-controlled catalysis in formic acid dehydrogenation under mild conditions.

Monodisperse 4 nm AuPd alloy nanoparticles with controlled composition were synthesized by co-reduction of hydrogen tetrachloroaurate(III) hydrate and palladium(II) acetylacetonate with a borane-morpholine complex in oleylamine. These NPs showed high activity (TOF = 230 h(-1)) and stability in catalyzing formic acid dehydrogenation and hydrogen production in water at 50 °C without any additives.

Magnetic Fe3O4 nanoparticles coupled with a fluorescent Eu complex for dual imaging applications.

Magnetic 8 nm Fe(3)O(4) nanoparticles (NPs) were synthesized and modified with dopamine (DPA) and polyethylene glycol (PEG) diacid. The water soluble Fe(3)O(4)-DPA-PEG NPs were then conjugated with the fluorescent Eu(iii) complex of tris(dibenzoylmethane)-5-amino-1,10-phenanthroline (BMAP), giving an Fe(3)O(4)-DPA-PEG-BMAP-Eu NP conjugate. The conjugate was both colloidally and chemically stable in phosphate buffered solutions and could be used as a probe for magnetic resonance and fluorescent imaging.

Polyaspartic acid coated manganese oxide nanoparticles for efficient liver MRI.

We report in this communication a simple, facile surface modification strategy to transfer hydrophobic manganese oxide nanoparticles (MONPs) into water by using polyaspartic acid (PASP). We systematically investigated the effect of the size of PASP-MONPs on MRI of normal liver and found that the particles with a core size of 10 nm exhibited greater enhancement than those with larger core sizes.