Enzyme‐Responsive Multifunctional Magnetic Nanoparticles for Tumor Intracellular Drug Delivery and Imaging

Enzyme‐responsive, hybrid, magnetic silica nanoparticles have been employed for multifunctional applications in selective drug delivery and intracellular tumor imaging. In this study, doxorubicin (Dox)‐conjugated, enzyme‐cleavable peptide precursors were covalently tethered onto the surface of uniform silica‐coated magnetic nanoparticles through click chemistry. This enzyme‐responsive nanoparticle conjugate demonstrated highly efficient Dox release upon specific enzyme interactions in vitro. It also exhibits multiple functions in selective tumor intracellular drug delivery and imaging in the tumor cells with high cathepsin B expression, whereas it exhibited lower cytotoxicity towards other cells without enzyme expression.     

Highly Stable Water‐Soluble Platinum Nanoparticles Stabilized by Hydrophilic N‐Heterocyclic Carbenes

Controlling the synthesis of stable metal nanoparticles in water is a current challenge in nanochemistry. The strategy presented herein uses sulfonated N‐heterocyclic carbene (NHC) ligands to stabilize platinum nanoparticles (PtNPs) in water, under air, for an indefinite time period. The particles were prepared by thermal decomposition of a preformed molecular Pt complex containing the NHC ligand and were then purified by dialysis and characterized by TEM, high‐resolution TEM, and spectroscopic techniques. Solid‐state NMR studies showed coordination of the carbene ligands to the nanoparticle surface and allowed the determination of a ¹³C–¹⁹⁵Pt coupling constant for the first time in a nanosystem (940 Hz). Additionally, in one case a novel structure was formed in which platinum(II) NHC complexes form a second coordination sphere around the nanoparticle.     

Cross‐Platform Comparison of Therapeutic Delivery from Multilamellar Lipid‐Coated Polymer Nanoparticles

Significant efforts have been invested in finding a delivery system that can encapsulate and deliver therapeutics. Core–shell polymer‐lipid hybrid nanoparticles have been studied as a promising platform because of their mechanical stability, narrow size distribution, biocompatibility, and ability to co‐deliver diverse drugs. Here, novel core–shell nanoparticles based on a poly(lactic‐co‐glycolic acid) (PLGA) core and multilamellar lipid shell are designed, where the lipid bilayers are crosslinked between the two adjacent bilayers (PLGA‐ICMVs). The cross‐platform performance of the nanoparticles to other polymer‐lipid hybrid platforms is examined, including physicochemical characteristics, ability to encapsulate a variety of therapeutics, biocompatibility, and functionality as a vaccine delivery platform. Differential abilities of nanoparticle systems to encapsulate distinct pharmaceutics are observed, which suggest careful consideration of the platform chosen depending on the therapeutic agent and desired function. The novel PLGA‐ICMV platform herein demonstrates great potential in stably encapsulating water‐soluble agents and therefore is an attractive platform for therapeutic delivery.     

Controlled Multi‐functionalization Facilitates Targeted Delivery of Nanoparticles to Cancer Cells

A major objective of nanomedicine is to combine in a controlled manner multiple functional entities into a single nanoscale device to target particles with great spatial precision, thereby increasing the selectivity and potency of therapeutic drugs. A multifunctional nanoparticle is described for controlled conjugation of a cytotoxic drug, a cancer cell targeting ligand, and an imaging moiety. The approach is based on the chemical synthesis of polyethylene glycol that at one end is modified by a thioctic acid for controlled attachment to a gold core. The other end of the PEG polymers is modified by a hydrazine, amine, or dibenzocyclooctynol moiety for conjugation with functional entities having a ketone, activated ester, or azide moiety, respectively. The conjugation approach allowed the controlled attachment of doxorubicin through an acid‐labile hydrazone linkage, an Alexa Fluor dye through an amide bond, and a glycan‐based ligand for the cell surface receptor CD22 of B‐cells using strain promoted azide‐alkyne cycloaddition. The incorporation of the ligand for CD22 led to rapid entry of the nanoparticle by receptor‐mediated endocytosis. Covalent attachment of doxorubicin via hydrazone linkage caused pH‐responsive intracellular release of doxorubicin and significantly enhanced the cytotoxicity of nanoparticles. A remarkable 60‐fold enhancement in cytotoxicity of CD22 (+) lymphoma cells was observed compared to non‐ targeted nanoparticles.     

All‐in‐One Target‐Cell‐Specific Magnetic Nanoparticles for Simultaneous Molecular Imaging and siRNA Delivery

Cancer‐cell‐targeted gene silencing was observed with a magnetic‐nanoparticle platform (MEIO, magnetism‐engineered iron oxide) on which a fluorescent dye, siRNA, and a RGD‐peptide targeting moiety were attached (see picture). The different functionalities enable the macroscopic (magnetic resonance) and microscopic (fluorescence) imaging of target cells. This system may be suitable for concurrent diagnostic and therapeutic applications.

     

Upconverting Nanoparticles with a Mesoporous TiO2 Shell for Near‐Infrared‐Triggered Drug Delivery and Synergistic Targeted Cancer Therapy

Malignant tumors remain a major health burden throughout the world and effective therapeutic strategies are urgently needed. Herein, we report the synthesis of upconverting nanoparticles with a mesoporous TiO₂ (mTiO₂) shell for near‐infrared (NIR)‐triggered drug delivery and synergistic targeted cancer therapy. The NaGdF₄:Yb,Tm could convert NIR light to UV light, which activated the mTiO₂ to produce reactive oxygen species for photodynamic therapy (PDT). Due to the large surface area and porous structure, the mTiO₂ shell endowed the nanoplatform with another functionality of anticancer drug loading for chemotherapy. The hyaluronic acid modified on the surface not only promised controlled drug release but also conferred targeted ability of the system toward cluster determinant 44 overexpressed cancer cells. More importantly, cytotoxicity experiments demonstrated that combined therapy mediated the highest rate of death of breast carcinoma cells compared with that of single chemotherapy or PDT.     

Facile Solvothermal Synthesis of Mesostructured Fe3O4/Chitosan Nanoparticles as Delivery Vehicles for pH‐Responsive Drug Delivery and Magnetic Resonance Imaging Contrast Agents

We report a facile fabrication of a host–metal–guest coordination‐bonding system in a mesostructured Fe₃O₄/chitosan nanoparticle that can act as a pH‐responsive drug‐delivery system. The mesostructured Fe₃O₄/chitosan was synthesized by a solvothermal approach with iron(III) chloride hexahydrate as a precursor, ethylene glycol as a reducing agent, ammonium acetate as a porogen, and chitosan as a surface‐modification agent. Subsequently, doxorubicin (DOX), acting as a model drug (guest), was loaded onto the mesostructured Fe₃O₄/chitosan nanoparticles, with chitosan acting as a host molecule to form the NH₂? Zn^II? DOX coordination architecture. The release of DOX can be achieved through the cleavage of coordination bonds that are sensitive to variations in external pH under weakly acidic conditions. The pH‐responsive nature of the nanoparticles was confirmed by in vitro releases and cell assay tests. Furthermore, the relaxation efficiency of the nanoparticles as high‐performance magnetic resonance imaging contrast agents was also investigated. Experimental results confirm that the synthesized mesostructured Fe₃O₄/chitosan is a smart nanovehicle for drug delivery owing to both its pH‐responsive nature and relaxation efficiency.     

Dual‐Targeted Selenium Nanoparticles for Synergistic Photothermal Therapy and Chemotherapy of Tumors

A combination of chemo‐ and photothermal therapy has emerged as a promising tactic for cancer therapy. However, the intricacy of accurate delivery and the ability to initiate drug release in specific tumor sites remains a challenging puzzle. Hence, to assure that the chemotherapeutic drug and photothermal agent are synchronously delivered to a tumor area for their synergistic effect, dual‐target (RC‐12 and PG‐6 peptides) functionalized selenium nanoparticles loaded with both doxorubicin (DOX) and indocyanine green (ICG) were designed and successfully synthesized. The as‐synthesized nanoparticles exhibited good monodispersity, size stability, and consistent spectral characteristics compared with those of ICG or DOX alone. The nanoparticles underwent self‐immolated cleavage under irradiation from a near‐IR laser and released the loaded drug owing to sufficient hyperthermia. Moreover, the internalized nanoparticles triggered the overproduction of intracellular reactive oxygen species to induce cell apoptosis. Taken together, this study provides a sequentially triggered nanosystem to achieve precise drug delivery by chemo‐photothermal combination.     

Bioresponsive Hyaluronic Acid‐Capped Mesoporous Silica Nanoparticles for Targeted Drug Delivery

In this paper, we present a facile strategy to synthesize hyaluronic acid (HA) conjugated mesoporous silica nanoparticles (MSP) for targeted enzyme responsive drug delivery, in which the anchored HA polysaccharides not only act as capping agents but also as targeting ligands without the need of additional modification. The nanoconjugates possess many attractive features including chemical simplicity, high colloidal stability, good biocompatibility, cell‐targeting ability, and precise cargo release, making them promising agents for biomedical applications. As a proof‐of‐concept demonstration, the nanoconjugates are shown to release cargoes from the interior pores of MSPs upon HA degradation in response to hyaluronidase‐1 (Hyal‐1). Moreover, after receptor‐mediated endocytosis into cancer cells, the anchored HA was degraded into small fragments, facilitating the release of drugs to kill the cancer cells. Overall, we envision that this system might open the door to a new generation of carrier system for site‐selective, controlled‐release delivery of anticancer drugs.     

Synthesis and Cytotoxicity of Dendritic Platinum Nanoparticles with HEK‐293 Cells

Dendritic platinum nanoparticles (DPNs) have been synthesized from l ‐ascorbic acid and an amphiphilic non‐ionic surfactant (Brij‐58) via a sonochemical method. The particle size and shape of the DPNs could be tuned by changing the reduction temperature, resulting in a uniform DPN with a size of 23 nm or 60 nm. The facets of DPNs have been studied by high‐resolution transmission electron microscopy. The cytotoxicity of DPNs has been investigated using human embryonic kidney cells (HEK‐293), and the biological adaptability exhibited by DPNs has opened a pathway to biomedical applications such as drug‐delivery systems, photothermal treatment, and biosensors.     

Human Serum Albumin Conjugated Nanoparticles for pH and Redox‐Responsive Delivery of a Prodrug of Cisplatin

Platinum anticancer drugs are particularly in need of controlled drug delivery because of their severe side effects. Platinum(IV) agents are designed as prodrugs to reduce the side effects of platinum(II) drugs; however, premature reduction could limit the effect as a prodrug. In this work, a highly biocompatible, pH and redox dual‐responsive delivery system is prepared by using hybrid nanoparticles of human serum albumin (HSA) and calcium phosphate (CaP) for the Pt^IV prodrug of cisplatin. This conjugate is very stable under extracellular conditions, so that it protects the platinum(IV) prodrug in HSA. Upon reaching the acidic and hypoxic environment, the platinum drug is released in its active form and is able to bind to the target DNA. The Pt–HSA/CaP hybrid inhibits the proliferation of various cancer cells more efficiently than cisplatin. Different cell cycle arrests suggest different cellular responses of the Pt^IV prodrug in the CaP nanocarrier. Interestingly, this delivery system demonstrates enhanced cytotoxicity to tumor cells, but not to normal cells.     

Popcorn‐Shaped Magnetic Core–Plasmonic Shell Multifunctional Nanoparticles for the Targeted Magnetic Separation and Enrichment,Label‐Free SERS Imaging,and Photothermal Destruction of Multidrug‐Resistant Bacteria

Over the last few years, one of the most important and complex problems facing our society is treating infectious diseases caused by multidrug‐resistant bacteria (MDRB), by using current market‐existing antibiotics. Driven by this need, we report for the first time the development of the multifunctional popcorn‐shaped iron magnetic core–gold plasmonic shell nanotechnology‐driven approach for targeted magnetic separation and enrichment, label‐free surface‐enhanced Raman spectroscopy (SERS) detection, and the selective photothermal destruction of MDR Salmonella DT104. Due to the presence of the “lightning‐rod effect”, the core–shell popcorn‐shaped gold‐nanoparticle tips provided a huge field of SERS enhancement. The experimental data show that the M3038 antibody‐conjugated nanoparticles can be used for targeted separation and SERS imaging of MDR Salmonella DT104. A targeted photothermal‐lysis experiment, by using 670 nm light at 1.5 W cm^?2 for 10 min, results in selective and irreparable cellular‐damage to MDR Salmonella. We discuss the possible mechanism and operating principle for the targeted separation, label‐free SERS imaging, and photothermal destruction of MDRB by using the popcorn‐shaped magnetic/plasmonic nanotechnology.     

Inorganic Metal Hydroxide Nanoparticles for Targeted Cellular Uptake Through Clathrin‐Mediated Endocytosis

Layered double hydroxides (LDHs) are biocompatible materials which can be used as drug‐delivery nanovehicles. In order to define the optimum size of LDH nanoparticles for efficient cellular uptake and drug‐delivery pathway, we prepared different sized LDH nanoparticles with narrow size distribution by modulating the crystal growth rate, and labelled each LDH particle with a fluorophore using a silane coupling reaction. The cellular uptake rate of LDHs was found to be highly dependent on particle size (50>200≥100>350 nm), whose range of 50 to 200 nm was selectively internalized into cells through clathrin‐mediated endocytosis with enhanced permeability and retention. Our study clearly shows that not only the particle size plays an important role in the endocytic pathway and processing, but also the size control of LDH nanoparticles results in their targeted uptake to site‐specific clathrin‐mediated endocytosis. This result provides a new perspective for the design of LDH nanoparticles with maximum ability towards targeted drug delivery.     

Near‐Infrared Light‐Mediated Photoactivation of a Platinum Antitumor Prodrug and Simultaneous Cellular Apoptosis Imaging by Upconversion‐Luminescent Nanoparticles

Platinum‐based drugs are among the most active antitumor reagents in clinical practice; their application is limited by side effects and drug resistance. A novel and personalized near‐infrared (NIR) light‐activated nanoplatform is obtained by combining a photoactivatable platinum(IV) prodrug and a caspase imaging peptide conjugated with silica‐coated upconversion‐luminescent nanoparticles (UCNPs) for the remote control of antitumor platinum prodrug activation, and simultaneously for real‐time imaging of apoptosis induced by activated cytotoxicity. Upon NIR light illumination, the Pt^IV prodrug complex is activated at the surface of the nanoparticle and active components are selectively released which display cytotoxicity against human ovarian carcinoma A2780 cells and its cisplatin‐resistant variant A2780cis cells. More importantly, the caspases enzymes triggered by cytotoxicity would effectively cleave the probe peptide, thereby allowing the direct imaging of apoptosis in living cells.     

Enhanced Targeted Delivery of Cyclodextrin‐Based Supermolecules by Core–Shell Nanocapsules for Magnetothermal Chemotherapy

In this study, double‐emulsion capsules (DECs) capable of concealing drug‐incorporated targeted‐supermolecules are developed to achieve “on‐demand” supermolecule release and enhanced sequential targeting for magneto‐chemotherapy. These water‐in‐oil‐in‐water DECs less than 200 nm in diameter are synthesized using a single component of PVA (polyvinyl alcohol) polymer and the magnetic nanoparticles, which are capable of encapsulating large quantities of targeted supermolecules composed of palitaxel‐incorporated beta‐cyclodextrin decorated by hyaluronic acid (HA, a CD44‐targeting ligand) in the watery core. The release profiles (slow, sustained and burst release) of the targeted supermolecules can be directly controlled by regulating the high‐frequency magnetic field (HFMF) and polymer conformation without sacrificing the targeting ability. Through an intravenous injection, the positive targeting of the supermolecules exhibited a 20‐fold increase in tumor accumulation via the passive targeting and delivery of DECs followed by positive targeting of the supermolecules. Moreover, this dual‐targeting drug‐incorporated supermolecular delivery vehicle at the tumor site combined with magneto‐thermal therapy suppressed the cancer growth more efficiently than treatment with either drug or supermolecule alone.

     

General Route to Multifunctional Uniform Yolk/Mesoporous Silica Shell Nanocapsules: A Platform for Simultaneous Cancer‐Targeted Imaging and Magnetically Guided Drug Delivery

Hollow mesoporous SiO₂ (mSiO₂) nanostructures with movable nanoparticles (NPs) as cores, so‐called yolk‐shell nanocapsules (NCs), have attracted great research interest. However, a highly efficient, simple and general way to produce yolk‐mSiO₂ shell NCs with tunable functional cores and shell compositions is still a great challenge. A facile, general and reproducible strategy has been developed for fabricating discrete, monodisperse and highly uniform yolk‐shell NCs under mild conditions, composed of mSiO₂ shells and diverse functional NP cores with different compositions and shapes. These NPs can be Fe₃O₄ NPs, gold nanorods (GNRs), and rare‐earth upconversion NRs, endowing the yolk‐mSiO₂ shell NCs with magnetic, plasmonic, and upconversion fluorescent properties. In addition, multifunctional yolk‐shell NCs with tunable interior hollow spaces and mSiO₂ shell thickness can be precisely controlled. More importantly, fluorescent‐magnetic‐biotargeting multifunctional polyethyleneimine (PEI)‐modified fluorescent Fe₃O₄@mSiO₂ yolk‐shell nanobioprobes as an example for simultaneous targeted fluorescence imaging and magnetically guided drug delivery to liver cancer cells is also demonstrated. This synthetic approach can be easily extended to the fabrication of multifunctional yolk@mSiO₂ shell nanostructures that encapsulate various functional movable NP cores, which construct a potential platform for the simultaneous targeted delivery of drug/gene/DNA/siRNA and bio‐imaging.