Photoacoustic Imaging Quantifies Drug Release from Nanocarriers via Redox Chemistry of Dye-Labeled Cargo

We report a new approach to monitor drug release from nanocarriers via a paclitaxel–methylene blue conjugate (PTX-MB) with redox activity. This construct is in a photoacoustically silent reduced state inside poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PTX-MB@PLGA NPs). During release, PTX-MB is spontaneously oxidized to produce a concentration-dependent photoacoustic signal. An in vitro drug-release study showed an initial burst release (25 %) between 0–24 h and a sustained release between 24–120 h with a cumulative release of 40.6 % and a 670-fold increase in photoacoustic signal. An in vivo murine drug release showed a photoacoustic signal enhancement of up to 649 % after 10 hours. PTX-MB@PLGA NPs showed an IC₅₀ of 78 μg mL⁻¹ and 44.7±4.8 % decrease of tumor burden in an orthotopic model of colon cancer via luciferase-positive CT26 cells.     

Self‐Assembly of Amphiphilic Drug–Dye Conjugates into Nanoparticles for Imaging and Chemotherapy

An amphiphilic drug–dye conjugate ( PTX‐Pt‐BDP ) was designed and synthesized with a platinum compound as the hydrophilic head. The precursor of PTX‐Pt‐BDP was obtained under mild conditions by means of a three‐component Passerini reaction. PTX‐Pt‐BDP could self‐assemble into nanoparticles ( PTX‐Pt‐BDP NPs) in aqueous solution via a nanoprecipitation method. The obtained nanoparticles exhibited favorable structural stability in both water and physiological environment. PTX‐Pt‐BDP NPs could be endocytosed by cancer cells as revealed by confocal laser scanning microscopy and exert potent cytotoxicity. This work highlights the potential of nanomedicines from amphiphilic drug–dye conjugates for cancer cell imaging and chemotherapy.     

One‐Step Synthesis of Small‐Sized and Water‐Soluble NaREF4 Upconversion Nanoparticles for In Vitro Cell Imaging and Drug Delivery

Small (2–28 nm) NaREF₄ (rare earth (RE)=Nd–Lu, Y) nanoparticles (NPs) were prepared by an oil/water two‐phase approach. Meanwhile, hydrophilic NPs can be obtained through a successful phase‐transition process by introducing the amphiphilic surfactant sodium dodecylsulfate (SDS) into the same reaction system. Hollow‐structured NaREF₄ (RE=Y, Yb, Lu) NPs can be fabricated in situ by electron‐beam lithography on solid NPs. The MTT assay indicates that these hydrophilic NPs with hollow structures exhibit good biocompatibility. The as‐prepared hollow‐structured NPs can be used as anti‐cancer drug carriers for drug storage/release investigations. Doxorubicin hydrochloride (DOX) was taken as model drug. The release of DOX from hollow α‐NaLuF₄:20 % Yb³⁺, 2 % Er³⁺ exhibits a pH‐sensitive release patterns. Confocal microscopy observations indicate that the NPs can be taken up by HeLa cells and show obvious anti‐cancer efficacy. Furthermore, α‐NaLuF₄:20 % Yb³⁺, 2 % Er³⁺ NPs show bright‐red emission under IR excitation, making both the excitation and emission light fall within the “optical window” of biological tissues. The application of α‐NaLuF₄:20 % Yb³⁺, 2 % Er³⁺ in the luminescence imaging of cells was also investigated, which shows a bright‐red emission without background noise.     

Influence of the polymer structure over self‐assembly and thermo‐responsive properties: The case of PEG‐b‐PCL grafted copolymers via a combination of RAFT and ROP

During the last years, the field of drug delivery has experienced a growing interest toward the so‐called thermo‐responsive polymers: synthetic materials that, due to the specific hydrophilic–lipophilic balance of their repeating units, exhibit a lower critical solution temperature (LCST) in water associated to a characteristic coil–globule transition. In this work, thermo‐responsive amphiphilic block copolymers are synthesized via reversible addition‐fragmentation transfer (RAFT) polymerization starting from thermo‐responsive monomers and a hydrophobic biodegradable macromonomer, oligo(caprolactone)methacrylate (CL₃MA), produced via ring opening polymerization (ROP). The obtained copolymers exhibit an interesting self‐assembly behavior leading to nanoparticles (NPs) as long as temperature is kept below the LCST. Otherwise, once this value is overcome, the destabilization of the NPs causes the formation of hydrophobic superstructures that enhance the release of an entrapped lipophilic drug. This characteristic behavior has been systematically studied and related to the copolymer structure. In particular, the self‐assembly behavior as well as temperature‐triggered NP destabilization have been related to the relative length of the two blocks constituting the copolymers and to their hydrophilic–lipophilic balance (HLB). Finally, the efficacy of the thermo‐responsive triggered drug release has been tested in the case of Paclitaxel (PTX). © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 2919–2931     

Self‐Assembly of Porphyrin–Paclitaxel Conjugates Into Nanomedicines: Enhanced Cytotoxicity due to Endosomal Escape

Nanomedicines assembled directly from drug molecules possess several advantages, including precise molecular structure and high content of drugs. Herein, porphyrin–paclitaxel conjugates (Py‐s‐s‐PTX) were synthesized by using a disulfide bond as a linker. The Py‐s‐s‐PTX could self‐assemble into nanoparticles (Py‐s‐s‐PTX NPs) with a size of about 100 nm via disulfide‐induced assembly. Py‐s‐s‐PTX NPs are highly stable under biological conditions and could be destroyed in the presence of reducing agents as revealed by dynamic light scattering. The obtained Py‐s‐s‐PTX NPs could be internalized by cancer cells via endocytosis and disassociated in the reducing cytoplasm, thus releasing PTX in cancer cells. Endosomal escape triggered upon irradiation could enhance the cytotoxicity of paclitaxel, and Py‐s‐s‐PTX NPs possess cytotoxicity comparable to that of free PTX. We believe that this disulfide‐assembled nanomedicine represents a new and important development for chemotherapy in cancer therapy.     

Paclitaxel‐Loaded β‐Cyclodextrin‐Modified Poly(Acrylic Acid) Nanoparticles through Multivalent Inclusion for Anticancer Therapy

A nanoassembled drug delivery system for anticancer treatment, formed by the host–guest interactions between paclitaxel (PTX) and β‐cyclodextrin (β‐CD) modified poly(acrylic acid) (PCDAA), is successfully prepared. After such design, the aqueous solubility of PTX is greatly increased from 0.34 to 36.02 μg mL^?1, and the obtained PCDAA‐PTX nanoparticles (PCDAA‐PTX NPs) exhibit a sustained PTX release behavior in vitro. In vitro cytotoxicity finds that PCDAA‐PTX NPs can accumulate significantly in tumor cells and remain the pharmacological activity of PTX. The in vivo real‐time biodistribution of PCDAA‐PTX NPs is investigated using near‐infrared fluorescence imaging, indicating that the PCDAA‐PTX NPs can effectively target to the tumor site by the enhanced permeability and retention effect in H22 tumor‐bearing mice. Through in vivo antitumor examination, PCDAA‐PTX NPs exhibit superior efficacy in impeding the tumor growth compared to the commercially available Taxol®.

     

Chemical synthesis of MnFe2O4/chitosan nanocomposites for controlled release of ofloxacin drug

In this study, we synthesized ofloxacin‐loaded MnFe₂O₄ nanoparticles (NPs) surface modified with chitosan (CS‐MnFe₂O₄) for prolonged antibiotic release in a controlled manner. It was found that the synthesized CS‐MnFe₂O₄ was spherical in shape with an average size of 30–50 nm, low aggregation, and good magnetic responsibility. An in vitro drug loading and release kinetics study reveals that the drug delivery system can take 86% of drug load and can release ofloxacin over a sustained period of 3 days. The release kinetics study reveals that the drug follows zero order kinetics and the mechanism of drug release is diffusion‐controlled type. These results indicated that CS‐MnFe₂O₄ NPs with pH‐sensitive properties can be used as candidates for intestinal targeted drug delivery through oral administration by avoiding the drug release in the highly acidic gastric fluid region of the stomach.     

Preparation of amphiphilic copolymers for covalent loading of paclitaxel for drug delivery system

A novel drug‐polymer conjugate was prepared by the copper‐catalyzed azide–alkyne cycloaddition reaction between an azide‐functional diblock copolymer and an alkyne‐functional paclitaxel (PTX). The well‐defined azide‐functional diblock copolymer, poly(ethylene glycol) (PEG)‐b‐P(OEGEEMA‐co‐AzPMA), was synthesized via the atom transfer radical polymerization of oligo(ethylene glycol) ethyl ether methacrylate (OEGEEMA) and 3‐azidopropyl methacrylate (AzPMA), using PEG‐Br as macroinitiator and CuBr/PMDETA as a catalytic system. The alkyne‐functional PTX was covalently linked to the copolymer via a click reaction, and the loading content of PTX could be easily tuned by varying the feeding ratio. Transmission electron microscopy and dynamic light scattering results indicated that the drug loaded copolymers could self‐assemble into micelles in aqueous solution. Moreover, the drug release behavior of PEG‐b‐P(OEGEEMA‐co‐AzPMA‐PTX) was pH dependent, and the cumulative release amount of PTX were 50.0% at pH 5.5, which is about two times higher than that at pH 7.4. The in vitro cytotoxicity experimental results showed that the diblock copolymer was biocompatible, with no obvious cytotoxicity, whereas the PTX‐polymer conjugate could efficiently deliver PTX into HeLa and SKOV‐3 cells, leading to excellent antitumor activity. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 366–374     

Magneto‐Plasmonic Janus Vesicles for Magnetic Field‐Enhanced Photoacoustic and Magnetic Resonance Imaging of Tumors

Magneto‐plasmonic Janus vesicles (JVs) integrated with gold nanoparticles (AuNPs) and magnetic NPs (MNPs) were prepared asymmetrically in the membrane for in vivo cancer imaging. The hybrid JVs were produced by coassembling a mixture of hydrophobic MNPs, free amphiphilic block copolymers (BCPs), and AuNPs tethered with amphiphilic BCPs. Depending on the size and content of NPs, the JVs acquired spherical or hemispherical shapes. Among them, hemispherical JVs containing 50 nm AuNPs and 15 nm MNPs showed a strong absorption in the near‐infrared (NIR) window and enhanced the transverse relaxation (T₂) contrast effect, as a result of the ordering and dense packing of AuNPs and MNPs in the membrane. The magneto‐plasmonic JVs were used as drug delivery vehicles, from which the release of a payload can be triggered by NIR light and the release rate can be modulated by a magnetic field. Moreover, the JVs were applied as imaging agents for in vivo bimodal photoacoustic (PA) and magnetic resonance (MR) imaging of tumors by intravenous injection. With an external magnetic field, the accumulation of the JVs in tumors was significantly increased, leading to a signal enhancement of approximately 2–3 times in the PA and MR imaging, compared with control groups without a magnetic field.     

In situ fabrication of paclitaxel‐loaded core‐crosslinked micelles via thiol‐ene “click” chemistry for reduction‐responsive drug release

In this study, a facile method to fabricate reduction‐responsive core‐crosslinked micelles via in situ thiol‐ene “click” reaction was reported. A series of biodegradable poly(ether‐ester)s with multiple pendent mercapto groups were first synthesized by melt polycondensation of diol poly(ethylene glycol), 1,4‐butanediol, and mercaptosuccinic acid using scandium trifluoromethanesulfonate [Sc(OTf)₃] as the catalyst. Then paclitaxel (PTX)‐loaded core‐crosslinked (CCL) micelles were successfully prepared by in situ crosslinking hydrophobic polyester blocks in aqueous media via thiol‐ene “click” chemistry using 2,2′‐dithiodiethanol diacrylate as the crosslinker. These PTX‐loaded CCL micelles with disulfide bonds exhibited reduction‐responsive behaviors in the presence of dithiothreitol (DTT). The drug release profile of the PTX‐loaded CCL micelles revealed that only a small amount of loaded PTX was released slowly in phosphate buffer solution (PBS) without DTT, while quick release was observed in the presence of 10.0 mM DTT. Cell count kit (CCK‐8) assays revealed that the reduction‐sensitive PTX‐loaded CCL micelles showed high antitumor activity toward HeLa cells, which was significantly higher than that of reduction‐insensitive counterparts and free PTX. This kind of biodegradable and biocompatible CCL micelles could serve as a bioreducible nanocarrier for the controlled antitumor drug release. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 99–107     

Mussel‐Inspired Protein Nanoparticles Containing Iron(III)–DOPA Complexes for pH‐Responsive Drug Delivery

A novel bioinspired strategy for protein nanoparticle (NP) synthesis to achieve pH‐responsive drug release exploits the pH‐dependent changes in the coordination stoichiometry of iron(III)–3,4‐dihydroxyphenylalanine (DOPA) complexes, which play a major cross‐linking role in mussel byssal threads. Doxorubicin‐loaded polymeric NPs that are based on Fe^III–DOPA complexation were thus synthesized with a DOPA‐modified recombinant mussel adhesive protein through a co‐electrospraying process. The release of doxorubicin was found to be predominantly governed by a change in the structure of the Fe^III–DOPA complexes induced by an acidic pH value. It was also demonstrated that the fabricated NPs exhibited effective cytotoxicity towards cancer cells through efficient cellular uptake and cytosolic release. Therefore, it is anticipated that Fe^III–DOPA complexation can be successfully utilized as a new design principle for pH‐responsive NPs for diverse controlled drug‐delivery applications.     

Acetazolamide‐Loaded pH‐Responsive Nanoparticles Alleviating Tumor Acidosis to Enhance Chemotherapy Effects

Carbonic anhydrase IX (CA IX), over‐expressed on cancer cells, catalyzes CO₂ to bicarbonate and protons, contributing to the acidic extracellular pH (pHe), which enhances the multidrug resistance of tumor cells. Therefore, alleviating tumor acidosis would greatly improve the outcome of chemotherapy. This work fabricates acetazolamide (ACE)‐loaded pH‐responsive nanoparticles (ACE‐NPs), which are quickly disintegrated in an acidic solution (pH 6.8), resulting in a quick release of ACE from these NPs to inhibit the expression of CA IX, thus up‐regulating the pHe value. These ACE‐NPs have no obvious in vitro cytotoxicity and in vivo studies confirm the accumulation of ACE‐NPs in tumor tissue. In addition, mice treated with ACE and paclitaxel (PTX) co‐loaded NPs show a smaller tumor size and a higher survival rate when compared to that of mice treated with ACE‐ or PTX‐loaded NPs. This work reveals that simultaneous delivery of ACE and chemotherapy agents to tumor tissue can up‐regulate the acidic pHe value, consequently enhancing the anti‐tumor ability of chemotherapy medicine. These findings open a new window for enhancing the anti‐tumor ability of traditional chemotherapy in clinic.     

In vitro curcumin delivery and antibacterial activity of RuS2 and RuO2 nanoparticles loaded chitosan biopolymer

In this work, RuS₂ and RuO₂ nanoparticles loaded chitosan (Chitosan was extracted from Lobsters shells of Persian Gulf, IR. Iran) was prepared and characterized via FE‐SEM, EDS and FT‐IR analysis. FESEM showed the formation of spherical nanoparticles in size ranging of 20 to 100 mm. Subsequently, the role of these new materials as curcumin drug carrier and in vitro release of curcumin in simulated body fluid (SBF) solution (pH 7.4) were studied. RuS₂‐NPs‐CS than to RuO₂‐NPs‐CS showed higher drug loading efficiency (>91%) and rapid (<90 min) curcumin drug release in SBF solution. Also, antibacterial activity of RuS₂‐NPs‐CS and RuO₂‐NPs‐CS in presens and absence of Rosemary extracts against the gram negative bacteria Pseudomonas aeruginosa (PAO 1) was evaluated by detection of minimal inhibition concentration (MIC) and minimal bactericidal concentration (MBC). MIC of RuS₂‐NPs‐CS, RuO₂‐NPs‐CS and Rosemary extracts on Pseudomonas aeruginosa strains were found to be 50 mg/ml, 50 mg/ml and 1250 mg/ml, respectively. The synergistic effect of these materials for inhibition of PAO 1 growth showed that mixture of RuS₂‐NPs‐CS and Rosemary extracts has a better efficiency than to other mixture materials.     

Preparation and in vitro properties of redox-responsive polymeric nanoparticles for paclitaxel delivery

Rice-like polymeric nanoparticles (NPs) composed of a new redox-responsive polymer, poly(ethylene glycol)-b-poly(lactic acid) (MPEG-SS-PLA), were prepared to carry paclitaxel (PTX) for glutathione (GSH)-regulated drug delivery. The PTX-loaded MPEG-SS-PLA NPs were fabricated using an optimized oil-in-water emulsion/solvent evaporation method. The size and morphology of the prepared NPs were characterized by scanning electron microscopy (SEM). The SEM results demonstrate that the NPs were dispersed as individual particles and were rice-shaped. The PTX loading efficiency, in vitro release, and stability of the NPs were analyzed by high-performance liquid chromatography (HPLC). The HPLC results revealed that the NPs released almost 90% PTX within 96 h when GSH presented at intracellular concentrations, whereas only a very small PTX amount was released at plasma GSH levels. The in vitro cytotoxicities of the NPs against A549, MCF-7, and HeLa carcinoma cells were assessed using a standard methyl thiazolyl tetrazoliun (MTT) assay. The MTT assay results show that the NPs caused concentration- and time-dependent changes in cell viability. To investigate the cellular uptake of the PTX-loaded NPs, visual endocytosis assay was performed using the fluorescent dye coumarin-6 as a model drug. The endocytosis assay results reveal rapid penetration and intracellular accumulation of coumarin-6-loaded NPs, as well as rapid coumarin-6 dispersion from the NPs. Overall, these findings establish that the NPs containing the synthesized redox-responsive polymer MPEG-SS-PLA can be used as potential carrier systems for antitumor drug delivery.     

Stem cell membrane vesicle–coated nanoparticles for efficient tumor‐targeted therapy of orthotopic breast cancer

Nanoparticles‐based drug delivery strategies have been widely researched for cancer therapy. However, most of them are expected to accumulate in tumor sites via the enhanced permeability and retention (EPR) effect, which is insufficient to deliver the loaded drug into tumors. Cell membrane–camouflaged nanoparticles have obtained much attention for their excellent stability and long blood circulation and reduced the macrophage cells uptake in drug delivery. Herein, bone marrow–derived mesenchymal stem cell membrane vesicle (SCV)–coated paclitaxel (PTX)–loaded poly (lactide‐co‐glycolide) (PLGA) nanoparticles (SCV/PLGA/PTX) were fabricated as the efficient orthotopic breast cancer–targeted drug delivery system. The SCV/PLGA/PTX showed excellent stability, more controlled PTX release, and more effective antitumor effect in vitro. After administration in vivo, SCV/PLGA/PTX exhibited the long‐term retention and enhanced accumulation at tumor sites due to the immune escape and mesenchymal stem cell–mimicking cancer‐targeting capacity. As expected, the SCV/PLGA/PTX could significantly suppress the primary tumor growth by increased apoptosis and necrosis areas within tumor tissues and attenuated the toxic side effects of PTX in 4T1 orthotopic breast cancer model. The study indicated the mesenchymal stem cell membrane coating strategy was highly efficient for targeted drug delivery, which provided a new insight for precise and effective breast cancer treatment.     

Model‐Based Nanoengineered Pharmacokinetics of Iron‐Doped Copper Oxide for Nanomedical Applications

The progress in nanomedicine (NM) using nanoparticles (NPs) is mainly based on drug carriers for the delivery of classical chemotherapeutics. As low NM delivery rates limit therapeutic efficacy, an entirely different approach was investigated. A homologous series of engineered CuO NPs was designed for dual purposes (carrier and drug) with a direct chemical composition–biological functionality relationship. Model‐based dissolution kinetics of CuO NPs in the cellular interior at post‐exposure conditions were controlled through Fe‐doping for intra/extra cellular Cu²⁺ and biological outcome. Through controlled ion release and reactions taking place in the cellular interior, tumors could be treated selectively, in vitro and in vivo. Locally administered NPs enabled tumor cells apoptosis and stimulated systemic anti‐cancer immune responses. We clearly show therapeutic effects without tumor cells relapse post‐treatment with 6 % Fe‐doped CuO NPs combined with myeloid‐derived suppressor cell silencing.     

Direct Synthesis of N-Heterocyclic Carbene-Stabilized Copper Nanoparticles from an N-Heterocyclic Carbene–Borane

N-Heterocyclic carbene (NHC)-stabilized copper nanoparticles (NPs) were synthesized from an NHC–borane adduct and mesitylcopper(I) under thermal conditions (refluxing toluene for 2.5 h). NPs with a size distribution of 11.6±1.8 nm were obtained. The interaction between Cu NPs and NHC ligands was probed by X-ray photoelectron spectroscopy, which showed covalent binding of the NHC to the surface of the NPs. Mechanistic studies suggested that NHC–borane plays two roles: contributing to the reduction of [CuMes]₂ to release Cu⁰ species and providing NHC ligands to stabilize the copper NPs.     

Fluorinated PLGA Nanoparticles for Enhanced Drug Encapsulation and 19F NMR Detection

In the continuous search for multimodal systems with combined diagnostic and therapeutic functions, several efforts have been made to develop multifunctional drug delivery systems. In this work, through a covalent approach, a new class of fluorinated poly(lactic-co-glycolic acid) co-polymers (F-PLGA) were designed that contain an increasing number of magnetically equivalent fluorine atoms. In particular, two novel compounds, F₃-PLGA and F₉-PLGA, were synthesized and their chemical structure and thermal stability were analyzed by solution NMR, DSC, and TGA. The obtained F-PLGA compounds were proven to form in aqueous solution colloidal stable nanoparticles (NPs) displaying a strong ¹⁹F NMR signal. The fluorinated NPs also showed an enhanced ability to load hydrophobic drugs containing fluorine atoms compared to analogous pristine PLGA NPs. Preliminary in vitro studies showed high cell viability and the NP ability to intracellularly deliver and release a functioning drug.     

Metallogel Template Fabrication of pH‐Responsive Copolymer Nanowires Loaded with Silver Nanoparticles and Their Photocatalytic Degradation of Methylene Blue

Poly(N,N′‐methylenebisacrylamide–4‐vinylpyridine) (P(MBA‐4VP)) nanowires loaded with silver nanoparticles (Ag NPs) have been fabricated by silver metallogel template copolymerization, and subsequently, silver ions are reduced instead of the template being removed. Ag NPs with a diameter of 5–15 nm were dispersed throughout the core of P(MBA‐4VP) nanowires. The size and distribution of the formed Ag NPs could be finely controlled by reduction time. The pH sensitivity of P(MBA‐4VP) nanowires offers the possibility of Ag NP release from the nanowires under acidic conditions. The photocatalytic performance of the P(MBA‐4VP) nanowires loaded with Ag NPs was evaluated for the degradation of methylene blue (MB) under UV light irradiation. Their rate of degradation is dependent on the content and size of the Ag NPs, as well as the pH values of the MB solution. Moreover, the P(MBA‐4VP) nanowires loaded with Ag NPs exhibited high photostability, and the photocatalytic efficiency reduced by only 1.81 % after being used three times.