Cuproptosis: Mechanism and Application in Lymphoma.

The cell death field has profited from the increasing attention of the scientific community and has been shown to lie at the very basis of cancer initiation and progression. Cuproptosis is a recently proposed method of cell death in 2022, and it is different from any previously reported method. The principle is that copper ions lead to aggregation and instability of intracellular proteins. An increasing number of researchers are dedicated to enriching the mechanism of cuproptosis and exploring its relationship with cancer. Studies have found that intracellular copper levels have an impact on the occurrence and development of lymphoma. The complexity of lymphoma and the limitations of treatment necessitate in-depth studies of the disease. We will review the mechanism of cuproptosis and its potential in lymphoma therapy.

Targeted pH-responsive biomimetic nanoparticle-mediated starvation-enhanced chemodynamic therapy combined with chemotherapy for ovarian cancer treatment.

In recent years, the use of arsenic trioxide (ATO) in the context of ovarian cancer chemotherapy has attracted significant attention. However, ATO's limited biocompatibility and the occurrence of severe toxic side effects hinder its clinical application. A nanoparticle (NP) drug delivery system using ATO as a therapeutic agent is reported in this study. Achieving a synergistic effect by combining starvation therapy, chemodynamic therapy, and chemotherapy for the treatment of ovarian cancer was the ultimate goal of this system. This nanotechnology-based drug delivery system (NDDS) introduced arsenic-manganese complexes into cancer cells, leading to the subsequent release of lethal arsenic ions (As3+) and manganese ions (Mn2+). The acidic microenvironment of the tumor facilitated this process, and MR imaging offered real-time monitoring of the ATO dose distribution. Simultaneously, to produce reactive oxygen species that induced cell death through a Fenton-like reaction, Mn2+ exploited the surplus of hydrogen peroxide (H2O2) within tumor cells. Glucose oxidase-based starvation therapy further supported this mechanism, which restored H2O2 and lowered the cellular acidity. Consequently, this approach achieved self-enhanced chemodynamic therapy. Homologous targeting of the NPs was facilitated through the use of SKOV3 cell membranes that encapsulated the NPs. Hence, the use of a multimodal NDDS that integrated ATO delivery, therapy, and monitoring exhibited superior efficacy and biocompatibility compared with the nonspecific administration of ATO. This approach presents a novel concept for the diagnosis and treatment of ovarian cancer.

A copper-loaded self-assembled nanoparticle for disturbing the tumor redox balance and triple anti-tumor therapy.

Both chemodynamic therapy and photodynamic therapy, based on the production of reactive oxygen (ROS), have excellent potential in cancer therapy. However, the abnormal redox homeostasis in tumor cells, especially the overexpressed glutathione (GSH) could scavenge ROS and reduce the anti-tumor efficiency. Therefore, it is essential to develop a simple and effective tumor-specific drug delivery system for modulating the tumor microenvironment (TME) and achieving synergistic therapy at the tumor site. In this study, self-assembled nanoparticles (named CDZP NPs) were developed using copper ion (Cu2+), doxorubicin (Dox), zinc phthalocyanine (ZnPc) and a trace amount of poly(2-(di-methylamino)ethylmethacrylate)-poly[(R)-3-hydroxybutyrate]-poly(2-(dimethylamino)ethylmethacrylate) (PDMAEMA-PHB-PDMAEMA) through chelation, π-π stacking and hydrophobic interaction. These triple factor-responsive (pH, laser and GSH) nanoparticles demonstrated unique advantages through the synergistic effect. Highly controllable drug release ensured its effectiveness at the tumor site, Dox-induced chemotherapy and ZnPc-mediated fluorescence (FL) imaging exhibited the distribution of nanoparticles. Meanwhile, Cu2+-mediated GSH-consumption not only reduced the intracellular ROS elimination but also produced Cu+ to catalyze hydrogen peroxide (H2O2) and generated hydroxyl radicals (˙OH), thereby enhancing the chemodynamic and photodynamic therapy. Herein, this study provides a green and relatively simple method for preparing multifunctional nanoparticles that can effectively modulate the TME and improve synergetic cancer therapy.

Peptide-Mediated Nanocarriers for Targeted Drug Delivery: Developments and Strategies.

Effective drug delivery is essential for cancer treatment. Drug delivery systems, which can be tailored to targeted transport and integrated tumor therapy, are vital in improving the efficiency of cancer treatment. Peptides play a significant role in various biological and physiological functions and offer high design flexibility, excellent biocompatibility, adjustable morphology, and biodegradability, making them promising candidates for drug delivery. This paper reviews peptide-mediated drug delivery systems, focusing on self-assembled peptides and peptide-drug conjugates. It discusses the mechanisms and structural control of self-assembled peptides, the varieties and roles of peptide-drug conjugates, and strategies to augment peptide stability. The review concludes by addressing challenges and future directions.

2D MOF based-heterostructure with hierarchical architecture as antibacterial wound dressing.

Bacterial infections pose a huge threat to human health due to the inevitable emergency of drug resistance. Metal-organic frameworks (MOFs) consisting of metal ions and organic linkers, as emerging efficient antibacterial material, have the merits of structural flexibility and adjustable physicochemical property. With assistance of photosensitive agents as organic linkers, MOFs have great potential in antibacterial application through photocatalytic therapy by the generation of reactive oxygen species (ROS). However, the limited light use efficiency and short lifespan of ROS are two obstacles for their applications. Inspired by the semiconductor heterostructure in photocatalysis, we rationally design and precisely synthesize MOFs based heterostructures, in which the TiO2 nanoclusters are filled into the pores of Cu-TCPP nanosheets (i.e. TiO2 NCs@Cu-TCPP HSs). And the composite materials possess three-dimensional (3D) hierarchical architectures, which have advantages of large surface area, excellent light-absorbing ability and photocatalytic efficiency. Significantly, this novel material displays >99.99 % antibacterial efficiency against E. coli and S. aureus within 30 min and preserves the excellent antibacterial ability during reusing three times, which is superior to recently reported photocatalystic-based antibacterial materials. Our study provides new insights into the energy band engineering for enhanced antibacterial performance, paving a way for designing advanced clinical wound dressings.

Copper-based theranostic nanocatalysts for synergetic photothermal-chemodynamic therapy.

Chemodynamic therapy (CDT) has aroused extensive attention as a potent therapeutic modality. However, its practical application is severely restricted by the strong acidity requirement for Fenton reaction and upregulated antioxidant defense within metastatic breast cancer. Herein, a copper-based single-site nanocatalyst functionalized with carbonic anhydrase inhibitor (CAI) was constructed for magnetic resonance/photoacoustic imaging (MRI/PA)-guided synergetic photothermal therapy (PTT) and CDT. Once reaching tumor sites, the nanocatalyst can be recognized by tumor cell membranes-overexpressed carbonic anhydrase IX (CA IX). Subsequently, the single-site CuII can be reduced to CuI by the tumor-overexpressed glutathione (GSH), which simultaneously impaired the tumor antioxidant defense system and triggered CAI release for inducing intracellular H+ accumulation. Further, the decreased intracellular pH can accelerate the nanocatalyst biodegradation to release more CuII and CAI to participate in next-cycle GSH-depletion and cytoplasm acidification, respectively, thereby continuously supplying CuI and H+ for self-cyclically amplified CDT. Upon laser irradiation, the nanocatalyst can generate local heat, which not only permits PTT but also enhances the nanocatalyst-mediated CDT. Moreover, the suppression of CA IX can hinder the tumor extracellular matrix degradation to prevent tumor metastasis. Overall, this work highlighted the great application prospect in enhancing CDT via tumor acidic/redox microenvironment remodeling, and provides an insightful paradigm for inhibiting breast cancer metastasis. STATEMENT OF SIGNIFICANCE: The practical application of chemodynamic therapy (CDT) is severely restricted by the strong acidity requirement for Fenton reaction and upregulated antioxidant defense within cancer. Herein, we developed a carbonic anhydrase inhibitor (CAI)-functionalized Cu-based nanocatalyst. Once reaching tumor sites, the CuII can be reduced to CuI by the tumor-overexpressed glutathione (GSH), which simultaneously impaired the tumor antioxidant system and triggered CAI release for inducing intracellular H+ accumulation. Further, the decreased intracellular pH can accelerate the nanocatalyst biodegradation to release more CuII and CAI to participate in next-cycle GSH-depletion and cytoplasm acidification, respectively, thus continuously supplying CuI and H+ for self-cyclically amplified CDT. Upon laser irradiation, the nanocatalyst not only permits PTT but also enhances the CDT.

Single-Step Synthesis of Highly Tunable Multifunctional Nanoliposomes for Synergistic Cancer Therapy.

Cancer is still one of the major diseases that humans have not conquered yet. Nanotechnology has promoted the development of multifunctional nanoparticles, which integrate diagnostic and treatment abilities for tumor imaging and therapy. However, its preparation methods usually require complicated unit operations, which result in large batch-to-batch differences, poor reproducibility, high production costs, and difficulty in clinical transformation. Furthermore, precisely manufacturing nanoliposomes with different tunable features (e.g., size, surface charge, targeting ligands, and so forth) remains a challenge, limiting effective nanoliposome optimization for tumor therapy. Due to the accurate control of the synthesis process and continuous operation mode, microfluidic technology becomes an emerging approach for the manufacturing of nanoliposomes. However, there are few reports on the single-step preparation of complex nanoliposomes by precise tuning of the physical properties, while investigating the influence of anti-cancer efficiency. Herein, we have prepared multifunctional nanoliposomes with accurate tuning properties through a microfluidic device in a single step, with synergistic photodynamic and chemodynamic effects for targeted tumor therapy. The preparation method provides an effective way for the one-step preparation of multifunctional nanoparticles with controllable particle sizes and surface properties.

Design of light/ROS cascade-responsive tumor-recognizing nanotheranostics for spatiotemporally controlled drug release in locoregional photo-chemotherapy.

Carrier-free nanotheranostics with high drug loading and no carrier-related toxicity are highly promising cancer therapy agents. However, the limited tumor accumulation and poorly controlled drug release of these nanotheranostics continue to be major challenges that restrict clinical applications. In this study, we develop a tumor-recognizing carrier-free nanotheranostic with light/reactive oxygen species (ROS) cascade-responsiveness for spatiotemporally selective photo-chemotherapy. The nanotheranostic is constructed by co-assembly of the indocyanine green (ICG) photosensitizer and the mannose-thioketal-doxorubicin conjugate (MAN-TK-DOX) (abbreviated as IMTD), efficiently preventing premature DOX leakage during blood circulation while reducing nonspecific damage to normal tissues/cells. Once accumulated in tumor tissues, IMTD rapidly diffuses into cancer cells via lectin receptors-mediated endocytosis. Photoacoustic/fluorescence-imaging-guided laser irradiation induces local hyperthermia and ROS generation in tumor cells, thereby promoting apoptosis. Together, the ICG-generated ROS and the endogenous ROS in cancer cells synergistically enhance DOX release, resulting in more efficient chemotherapeutic effects. The in vitro and in vivo results consistently demonstrate that IMTD achieves superior tumor accumulation, highly controllable drug release, and synergetic photo-chemotherapy. Therefore, the co-assembly of an ROS-sensitive targeting ligand-chemodrug conjugate and a photosensitizer could be used to develop spatiotemporally light-activatable nanotheranostics for precision cancer therapy. STATEMENT OF SIGNIFICANCE: Synergistic phototherapy and chemotherapy have been considered as a promising cancer treatment modality to maximize the therapeutic efficacy. Unfortunately, most nanodrugs consisting of chemotherapeutic drug and photosensitizer suffer from suboptimal tumor accumulation and poorly controlled drug release, which results in reduced therapeutic outcome. In this study, Mannose (MAN) was conjugated to the anticancer drug doxorubicin (DOX) by a ROS-sensitive thioketal linker (TK), the obtained amphiphilic MAN-TK-DOX could serve as an ideal self-carrier material to deliver photosensitizer, thus to achieve high-efficient tumor-targeting, spatiotemporal controlled drug release, and superior antitumor effect. We believe that the ROS-sensitive amphiphilic targeting ligand-chemodrug conjugate could be developed as a universal approach for designing tumor-targeted nanodrugs with precisely controlled drug release.

Continuous synthesis of drug nanocrystals by solid hollow fiber cooling crystallization.

Size reduction of drug with poor water solubility to nanoscale is an effective way to help improve the efficacy of drug delivery to the human body. A solid hollow fiber cooling crystallization technique has been adopted to continuously produce griseofulvin drug nanoparticles under modest conditions with accurate controllability. In the solid hollow fiber cooling crystallization device, drug solution flowed through the bores of solid hollow fibers while the cooling liquid was circulated counter-currently in the shell side of the device to cool down the drug solution in the tube side. Due to intense heat exchange between the cooling liquid and the drug solution through the thin fiber walls, the temperature of drug solution decreased rapidly so that drug nanoparticles were precipitated out from the solution by sudden reduction of solubility. Through variation of the experimental conditions and parameters, the mean size of the produced nanoparticles was regulated and controlled. The nanoparticles were dispersed uniformly, the chemical structure and bonds of prepared nanoparticles was the same with as-received griseofulvin. Both raw material and NPs the polymorph(s) present form I, the melting point was 220 °C. Drug dissolution testing was also executed to verify that nanocrystals have a higher dissolution profile.

A pH-Sensitive Self-Assembled and Carrier-Free Nanoparticle Based on Charge Reversal for Enhanced Synergetic Chemo-Phototherapy.

To overcome biological barriers for nanoparticles (NPs) efficaciously accumulated at tumor sites, as well as enhancing the performance of drug delivery systems, a carrier-free nanoparticle based on charge reversal is designed for improved synergetic chemo-phototherapy for cancer treatment. In this system, doxorubicin (Dox) and zinc phthalocyanine (ZnPc) are self-assembled through noncovalent interactions (π-π stacking, hydrophobic forces) to avoid the possible toxicity of excipient, complex chemical conjugations and batch-to-batch variation. A trace amount of poly(2-(di-methylamino) ethylmethacrylate)- poly[(R)-3-hydroxybutyrate]- poly(2-(dimethylamino) ethylmethacrylate (PDMAEMA-PHB-PDMAEMA) is modified on the surface of Dox-ZnPc to construct the novel nanoparticles, namely DZP, with long-term stability, and with a dual-drug load content of up to ≈90％. The drug delivery system (DDS) can effectively decrease its toxicity among physical circulation and increase the accumulation at the tumor site. Moreover, the developed DZP nanoparticles show excellent photo-chemotherapy, photoacoustic (PA) and fluorescence (FL) imaging characteristics for multimodal imaging-guided synergetic therapy.

Small Molecular Theranostic Assemblies Functionalized by Doxorubicin-Hyaluronic Acid-Methotrexate Prodrug for Multiple Tumor Targeting and Imaging-Guided Combined Chemo-Photothermal Therapy.

Because of high drug payload and minimized burden of foreign materials in the course of metabolism and excretion, carrier-free nanomedicine based on self-assembly of small-molecule therapeutic agents has attracted considerable attention in cancer therapy. However, obstacles still remained, such as lack of targeting efficiency, poor physiological stability, and serious drug burst release. Herein, we developed a self-dual-targeting prodrug conjugate by coupling methotrexate (MTX) and doxorubicin (DOX) to a hyaluronic acid (HA) backbone which enveloped the small molecular drug coassemblies of DOX and indocyanine green for specific targeting and imaging-guided chemo-photothermal therapy (PTT). The constructed nanosystems exhibited a diameter of ∼200 nm, superior physiological stability, and improved photothermal effect. Taking advantage of functionality of MTX-HA-DOX conjugate, the nanosystems remarkably enhanced the accumulation in the tumor regions by enhanced penetration and retention effect and CD44/folate receptor-mediated endocytosis. Upon the stimuli of acid, the nanosystems showed the rapid disassembly followed by the accelerated drug release. Consequently, the nanosystems demonstrated highly efficient apoptosis in cancer cells and remarkable tumor ablation by synergy between chemotherapy and PTT upon the irradiation of near-infrared laser. The multifunctional nanosystems based on small molecular theranostic assemblies could provide a promising potential in developing dual-targeting drug delivery and imaging-guided combinational therapy.

Novel facile thermosensitive hydrogel as sustained and controllable gene release vehicle for breast cancer treatment.

The current research process in gene therapy for cancer treatment has brought much attention due to its great potential for both inherited and acquired diseases. Precise accumulation in target site and on-demand release of drug is critical factors for the efficient gene therapy. Since the delivery of suitable gene largely depends on the delivery carrier, the design of suitable gene delivery vehicle for the sustained gene release in target site are attracting increasingly interest among the researchers. In this report, an effective and relatively convenient gene delivery platform is developed by the electrostatic interaction between negative charged survivin antisense oligonucleotide (Sur-ASON) and positive charged PHB-b-PDMAEMA (PHB-P) co-polymer and then the induction of thermosensitive PF127 hydrogel. The prepared hydrogel could achieve a sustained gene release property in the tumor region after injection, thus to enhance the effect of Survivin antisense oligonucleotide and inhibit P-gp impaired drug uptake simultaneously. In vivo anti-tumor efficacy and H&E staining indicated that Sur-ASON/PHB-P/PF127 hydrogel was greatly effective in enhancing the treatment effects of Sur-ASON while reducing the degradation and the possible adverse side effects, and this novel hydrogel could achieve the controlled gene release up to maximum 16 days. The aforementioned properties indicated that the novel hydrogel could be applied as a promising and convenient anti-cancer agent for anticancer therapy with minimum injection frequency to possibly increase patient compliance.

Hyaluronic Acid-Methotrexate Conjugates Coated Magnetic Polydopamine Nanoparticles for Multimodal Imaging-Guided Multistage Targeted Chemo-Photothermal Therapy.

Combination cancer therapy with various kinds of therapeutic approaches could improve the effectiveness of treatment while reducing side effects. Herein, we elaborately developed a theranostics nanoplatform based on magnetic polydopamine (MPDA) coated with hyaluronic acid-methotrexate conjugates (MPDA@HA-MTX) for chemo-photothermal treatment (PTT). In this nanoplatform, Fe3O4 served as the core was applied as contrast agent for T2-weighted magnetic resonance imaging (MRI) and early phase magnet targeting. Meanwhile, PDA was used as a versatile shell for effective loading of chemotherapeutic doxorubicin (DOX) to achieve controlled release and PTT simultaneously. Moreover, HA-MTX conjugates could offer later-phase specific cellular dual-targeting ability during the therapy. Both in vitro and in vivo studies demonstrated that DOX-loaded MPDA@HA-MTX (MPDA/DOX@HA-MTX) exhibited the preferential tumor accumulation, enhanced specificity to target tumor cells, pH-/laser-responsive release, and high tumor cell-killing efficiency. By combined chemo-PTT under the guidance of fluorescence/MR imaging, the tumors in mice were completely eliminated after treatment, indicating that MPDA@HA-MTX nanoparticles have great potential as a novel drug-loading platform for imaging-guided multistage targeted chemo-photothermal combination therapy.

Zinc phthalocyanine-soybean phospholipid complex based drug carrier for switchable photoacoustic/fluorescence image, multiphase photothermal/photodynamic treatment and synergetic therapy.

For the purpose of precision theranostic of tumor, multifunctional drug delivery systems are always receiving great attentions. Here, we developed a zinc phthalocyanine-soybean phospholipid (ZnPc-SPC) complex based drug delivery system with doxorubicin (Dox) as loading cargo to achieve additional chemotherapy while the carrier itself could serve as multifunctional and switchable theranostic agent. In the early phase, the ZnPc-SPC complex assembled to nanostructure displaying photothermal therapy (PTT) and photoacoustic (PA) properties while in the late phase, the prepared NPs dis-assembled into ZnPc-SPC complex again performing photodynamic therapy (PDT) and low-background fluorescence (FL) image. With the decoration of folate receptors α (FRα) targeted MTX, Dox-loaded, MTX-decorated self-assembled ZnPc-SPC complex NPs (DZSM) was formed. In vitro and in vivo evaluations both indicated that DZSM presented high selectivity for FRα over-expressed tumor cells, excellent switchable PA/FL image, significant multiphase PTT/PDT effect, as well as great synergetic therapy potential, leading to notable inhibition of tumor growth.

Novel Core-Interlayer-Shell DOX/ZnPc Co-loaded MSNs@ pH-Sensitive CaP@PEGylated Liposome for Enhanced Synergetic Chemo-Photodynamic Therapy.

PURPOSE: This work was intended to develop novel doxorubicin (DOX)/zinc (II) phthalocyanine (ZnPc) co-loaded mesoporous silica (MSNs)@ calcium phosphate (CaP)@PEGylated liposome nanoparticles (NPs) that could efficiently achieve collaborative anticancer therapy by the combination of photodynamic therapy (PDT) and chemotherapy. The interlayer of CaP could be utilized to achieve pH-triggered controllable drug release, promote the cellular uptake, and induce cell apoptosis to further enhance the anticancer effects. METHODS: MSNs were first synthesized as core particles in which the pores were diffusion-filled with DOX, then the cores were coated by CaP followed by the liposome encapsulation with ZnPc to form the final DOX/ZnPc co-loaded MSNs@CaP@PEGylated liposome. RESULTS: A core-interlayer-shell MSNs@CaP@PEGylated liposomes was developed as a multifunctional theranostic nanoplatform. In vitro experiment indicated that CaP could not only achieve pH-triggered controllable drug release, promote the cellular uptake of the NPs, but also generate high osmotic pressure in the endo/lysosomes to induce cell apoptosis. Besides, the chemotherapy using DOX and PDT effect was achieved by the photosensitizer ZnPc. Furthermore, the MSNs@CaP@PEGylated liposomes showed outstanding tumor-targeting ability by enhanced permeability and retention (EPR) effect. CONCLUSIONS: The novel prepared MSNs@CaP@PEGylated liposomes could serve as a promising multifunctional theranostic nanoplatform in anticancer treatment by synergic chemo-PDT and superior tumor-targeting ability.

Novel theranostic zinc phthalocyanine-phospholipid complex self-assembled nanoparticles for imaging-guided targeted photodynamic treatment with controllable ROS production and shape-assisted enhanced cellular uptake.

The novel drug delivery system based on self-assembly of zinc phthalocyanine-soybean phosphatidylcholine (ZnPc-SPC) complex was developed by a co-solvent method followed by a nanoprecipitaion technique. DSPE-PEG-methotrexate (DSPE-PEG-MTX) was introduced on the surface of ZnPc-SPC self-assembled nanoparticles (ZS) to endow them with folate receptor-targeting property. NMR, XRD, FTIR, and UV-vis-NIR analysis demonstrated the weak molecular interaction between ZnPc and SPC. The ZS functionalized with DSPE-PEG-MTX (ZSPM) was successfully constructed with an average particle size of ∼170nm, a narrow size distribution, and could remain physiologically stable for at least 7days. In vitro cellular uptake and cytotoxicity studies demonstrated that ZSPM exhibited stronger cellular uptake efficacy and photodynamic cytotoxicity against HeLa and MCF-7 cells than ZS functionalized with DSPE-mPEG (ZSP) and free ZnPc. More importantly, ZSPM showed the enhanced accumulation effect at the tumor region compared with ZSP by the active-plus-passive targeting via enhanced permeability and retention (EPR) effect and folate receptor-mediated endocytosis. Furthermore, in vivo antitumor effect and histological analysis demonstrated the superior tumor growth inhibition effect of ZSPM. In addition, the needle-shape ZSP (ZSPN) exhibited better in vitro cellular uptake and in vivo tumor accumulation compared with ZSP due to the shape-assisted effect. Moreover, the interesting off-on switch effect of reactive oxygen species (ROS) production of ZnPc-SPC complex-based nanoparticles was discovered to achieve photodynamic treatment in a controllable way. These findings suggested that the ZnPc-SPC complex-based self-assembled nanoparticles could serve as a promising and effective formulation to achieve tumor-targeting fluorescence imaging and enhanced photodynamic treatment.

Methotrexate-Camptothecin Prodrug Nanoassemblies as a Versatile Nanoplatform for Biomodal Imaging-Guided Self-Active Targeted and Synergistic Chemotherapy.

"All-in-one" carrier-free-based nano-multi-drug self-delivery system could combine triple advantages of small molecules, nanoscale characteristics, and synergistic combination therapy together. Researches have showed that dual-acting small-molecular methotrexate (MTX) could target and kill the folate-receptor-overexpressing cancer cells. Inspired by this mechanism, a novel collaborative early-phase tumor-selective targeting and late-phase synergistic anticancer approach was developed for the self-assembly of chemotherapeutic drug-drug conjugate, which showed various advantages of more simplicity, efficiency, and flexibility over the conventional approach based only on single or combination cancer chemotherapy. MTX and 10-hydroxyl camptothecin (CPT) were chosen to conjugate through ester linkage. Because of the amphiphilicity and ionicity, MTX-CPT conjugates as molecular building blocks could self-assemble into MTX-CPT nanoparticles (MTX-CPT NPs) in aqueous solution, thus notably improving the aqueous solubility of CPT and the membrane permeability of MTX. The MTX-CPT NPs with a precise drug-to-drug ratio showed pH-/esterase-responsive drug release, sequential function "Targeting-Anticancer" switch, and real-time monitoring fluorescence "Off-On" switch. By doping with a lipophilic near-infrared (NIR) cyanine dye (e.g., 1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide, DiR), the prepared DiR-loaded MTX-CPT NPs acted as an effective probe for in vivo NIR fluorescence (NIRF) and photoacoustic (PA) dual-modal imaging. Both in vitro and in vivo studies demonstrated that MTX-CPT NPs could specifically codeliver multidrug to different sites of action with distinct anticancer mechanisms to kill folate-receptor-overexpressing tumor cells in a synergistic way. This novel, simple, and highly convergent self-targeting nanomulti-drug codelivery system exhibited great potential in cancer therapy.

Chemotherapeutic drug-photothermal agent co-self-assembling nanoparticles for near-infrared fluorescence and photoacoustic dual-modal imaging-guided chemo-photothermal synergistic therapy.

Multimodal imaging-guided synergistic combination therapy has shown great potential for cancer treatment. However, the nanocarrier-based theranostic systems suffer from batch-to-batch variation, complexity of multicomponent, poor drug loading, and carrier-related toxicity issues. To address these issues, herein we developed a novel carrier-free theranostic system with nanoscale characteristics for near-infrared fluorescence (NIRF) and photoacoustic (PA) dual-modal imaging-guided synergistic chemo-photothermal therapy (PTT). Indocyanine green (ICG) and epirubicin (EPI) could co-self-assemble into small molecular nanoparticles (NPs) in aqueous solution without any molecular precursor or excipient via collaborative interactions (electrostatic, π-π stacking, and hydrophobic interactions). The exceptionally high dual-drug loading (∼92wt%) ICG-EPI NPs showed good physiological stability, preferable photothermal response, excellent NIRF/PA imaging properties, pH-/photo-responsive drug release behavior, and promoted cellular endocytosis compared with free ICG or EPI. Importantly, the ICG-EPI NPs showed excellent tumor targeting ability with high spatial resolution and deep penetration via in vivo NIRF/PA dual-modal imaging. Moreover, in comparison with individual chemotherapy or PTT, the combinational chemo-PTT therapy of ICG-EPI NPs with NIR laser irradiation synergistically induced apoptosis and death of cancer cells in vitro, and showed synergistic chemo-PTT efficiency in vivo as evidenced by highly efficient tumor ablation. Furthermore, the ICG-EPI NPs exhibited inappreciable toxicity. This co-self-assembly of both FDA-approved agents provides a safe and "Molecular economical" strategy in the rational design of multifunctional nano-theranostic systems for real-time self-monitoring intracellular drug delivery and targeting multimodal imaging-guided synergistic combination therapy.

Core-interlayer-shell Fe3O4@mSiO2@lipid-PEG-methotrexate nanoparticle for multimodal imaging and multistage targeted chemo-photodynamic therapy.

Multimodal imaging-guided multistage targeted synergistic combination therapy possesses many advantages including increased tumoricidal effect, reduced toxicity, and retarded drug resistance. Herein, we have elaborately developed a core-interlayer-shell structure Fe3O4@mSiO2@lipid-PEG-methotrexatenanoparticle(FMLM), in which the Fe3O4 core could be used for magnet-stimulate-response drug release, magnetic resonance imaging, and early-phase magnet targeting ability; the mSiO2 layer could encapsulate anticancer drug doxorubicin (Dox) for chemotherapy; and the protective shell of lipid-PEG and lipid-PEG-methotrexate offered later-phase specific cellular targeting ability, good water dispersibility, and loading of photosensitizer zinc phthalocyanine (ZnPc) for simultaneous near-infrared fluorescence imaging and photodynamic therapy. Both in vitro and in vivo studies indicated that the both Dox and ZnPc-loaded FMLM (Dox/ZnPc-FMLM) exhibited the enhanced tumor accumulation, increased cellular uptake, improved anticancer activity, and weaked side effects compared with Dox/ZnPc-Fe3O4@mSiO2@lipid-PEG nanoparticle (Dox/ZnPc-FML) and free drug. For the first time, magnet targeting cooperative with methotrexate macromolecular prodrug targeting is successfully exploited to develop a promising versatile theranostic nanoplatform for dual-modal fluorescence and magnetic resonance imaging-guided combined chemo-photodynamic cancer therapy.

Membrane-Based Technologies in the Pharmaceutical Industry and Continuous Production of Polymer-Coated Crystals/Particles.

BACKGROUND: Membrane technologies are of increasing importance in a variety of separation and purification applications involving liquid phases and gaseous mixtures. Although the most widely used applications at this time are in water treatment including desalination, there are many applications in chemical, food, healthcare, paper and petrochemical industries. This brief review is concerned with existing and emerging applications of various membrane technologies in the pharmaceutical and biopharmaceutical industry. METHODS: The goal of this review article is to identify important membrane processes and techniques which are being used or proposed to be used in the pharmaceutical and biopharmaceutical operations. How novel membrane processes can be useful for delivery of crystalline/particulate drugs is also of interest. RESULTS: Membrane separation technologies are extensively used in downstream processes for bio-pharmaceutical separation and purification operations via microfiltration, ultrafiltration and diafiltration. Also the new technique of membrane chromatography allows efficient purification of monoclonal antibodies. Membrane filtration techniques of reverse osmosis and nanofiltration are being combined with bioreactors and advanced oxidation processes to treat wastewaters from pharmaceutical plants. Nanofiltration with organic solvent-stable membranes can implement solvent exchange and catalyst recovery during organic solvent-based drug synthesis of pharmaceutical compounds/intermediates. Membranes in the form of hollow fibers can be conveniently used to implement crystallization of pharmaceutical compounds. The novel crystallization methods of solid hollow fiber cooling crystallizer (SHFCC) and porous hollow fiber anti-solvent crystallization (PHFAC) are being developed to provide efficient methods for continuous production of polymer-coated drug crystals in the area of drug delivery. CONCLUSION: This brief review provides a general introduction to various applications of membrane technologies in the pharmaceutical/biopharmaceutical industry with special emphasis on novel membrane techniques for pharmaceutical applications. The method of coating a drug particle with a polymer using the SHFCC method is stable and ready for scale-up for operation over an extended period.