具有双重治疗机制的磁性纳米无定型氧化铁基药物递送系统（英文）

合成一种具有pH响应性的聚乙二醇(PEG)修饰无定形介孔氧化铁纳米粒子(AFe-PEG).这种纳米粒子可以高效负载药物分子如阿霉素(DOX),构成新型多功能AFe-PEG/DOX药物递送体系.DOX的负载率高达948 mg/g-纳米粒子.在酸性溶液中,AFePEG/DOX纳米粒子不仅可以有效释放DOX,同时可以释放Fe离子进行Fenton反应,将H_2 O_2转变成·OH自由基.体外实验结果表明,AFe-PEG/DOX纳米粒子对HeLa细胞同时具有化疗和化学动力学疗法的疗效.同时,由于AFe-PEG/DOX纳米粒子本身的磁性,使其在外部磁场中的细胞内化效率也得到了提高.     

引导磁场下磁性药物靶向治疗的理论分析

应用电磁场理论，对引导磁场下铁磁性“药物”颗粒在靶向治疗中的受力和运动轨迹进行了分析和研究.得到了磁场、血流和血管壁对铁磁性“药物”颗粒的作用及运动规律.给出了铁磁性“药物”在靶向治疗中可采用的一种新方法——利用体外磁激励装置产生的变化磁场来实现铁磁性“药物”靶向治疗，还给出了采用这种方法实现靶向治疗的条件. 关键词： 磁性药物 靶向治疗 血流动力学 引导磁场     

A Multifunctional Magnetic Composite Material as a Drug Delivery System and a Magnetic Resonance Contrast Agent

Magnetic iron oxide coated in hydrogenation silica (Fe₃O₄@HSiO₂) is constructed as both a tumor drug carrier and a magnetic resonance (MR) contrast agent. Colchicine (COLC) is loaded in Fe₃O₄@HSiO₂ with the highest amount of 28.3 wt% at pH 9. The release performance of COLC can be controlled by pH, as the porous HSiO₂ shell can partially shed at pH below 3.0 to facilitate the release of COLC. MR imaging (MRI) tests prove that Fe₃O₄@HSiO₂ at pH 3.0 (H⁺‐Fe₃O₄@HSiO₂) shows a stronger MR contrast enhancement than Fe₃O₄. Cytotoxicity experiment indicates that Fe₃O₄@HSiO₂ has excellent biocompatibility and magnetic targeting performance. Additionally, COLC‐loaded Fe₃O₄@HSiO₂ (Fe₃O₄@HSiO₂–COLC) displays a higher inhibition effect on tumor cells under a magnetic field than free COLC. The visibility upon MRI, high targeting, and pH‐controlled release characteristics of Fe₃O₄@HSiO₂–COLC are favorable to achieve the aim of reducing side effects to normal tissues, making Fe₃O₄@HSiO₂–COLC an attractive drug delivery system for nanomedicine.     

Magnetic Field‐Controlled Release of Paclitaxel Drug from Functionalized Magnetoelectric Nanoparticles

Using magnetoelectric nanoparticles (MENs) for targeted drug delivery and on‐demand, field‐controlled release can overcome the control challenges of the conventional delivery approaches. The magnetoelectric effect provides a new way to use an external magnetic field to remotely control the intrinsic electric fields that govern the binding forces between the functionalized surface of the MEN and the drug load. Here, a study is reported in which the composition of the intermediate functionalized layer is tailored to control not only the toxicity of the new nanoparticles but also the threshold magnetic field for the dissociation of the drug from 30‐nm CoFe₂O₄–BaTiO₃ core–shell MENs in a controllably wide field range, from below 10 to over 200 Oe, as required to facilitate superficial, intermediate, and deep‐tissue drug delivery. Paclitaxel is used as a test drug. Specific experiments are described to maintain low toxicity levels and to achieve controllable dissociation of the drug molecules from the MENs' surface at three different subranges—low (<10 Oe), moderate (100 Oe), and high (>200 Oe)—by selecting the following 2‐nm intermediate layers: i) glycerol monooleate (GMO), ii) Tween‐20, and iii) ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide (EDC). Field‐dependent FTIR, absorption spectra, atomic force microscopy, magnetometry analysis, zeta‐potential measurements, and blood circulation experiments are used to study the described functionalization effects.     

Construction of a Dual Drug Carrier on the Basis of Hollow Structured Upconversion Nanoparticles for pH‐Responsive Drug Delivery and UCL/MRI Dual Mode Imaging

A series of Gd³⁺ doping hollow upconversion nanoparticles NaYF₄:Yb,Gd,Tm (h‐UNCP) are prepared successfully. The hollow NaYF₄:Yb,Gd,Tm possess excellent upconversion luminescence (UCL) and large longitudinal relativity (r₁ = 128.3 mm ^?1 s^?1), which can be potentially used for UCL/magnetic resonance imaging (MRI) dual mode imaging. On the basis of the optimal h‐UCNP, doxorubicin hydrochloride (DOX) and methotrexate (MTX) are used as drug models to prepare a dual drug carrier. After the encapsulation of DOX on the h‐UCNP, chitosan (CS) is further wrapped and then used to load MTX to obtain a dual drug carrier h‐UCNPs/DOX/CS/MTX. The pH responsive release of DOX and MTX is discussed. The MTX release climbs from 33% to 100% by regulating the pH from 5.8 to 7.4. The DOX release is different at different pH conditions. The synergistic effect of DOX and MTX on the cancer cells is confirmed by cell viability. The h‐UCNPs/DOX/CS/MTX are tracked by cells UCL imaging and vivo MRI imaging. The excellent performance of UCL imaging and positive MRI images demonstrates that h‐UCNPs/DOX/CS/MTX can be used for UCL/MRI dual mode imaging. All the results show the potential application of h‐UCNPs/DOX/CS/MTX in pH responsive release and UCL/MRI dual imaging.     

Therapeutic Pretargeting with Gold Nanoparticles as Drug Candidates for Boron Neutron Capture Therapy

Boron neutron capture therapy (BNCT) is a binary approach for cancer treatment in which boron-10 atoms and thermal neutrons need to colocalize to become effective. Recent research in the development of BNCT drug candidates focuses increasingly on nanomaterials, with the advantages of high boron loadings and passive targeting due to the enhanced permeability and retention (EPR) effect. The use of small boron-rich gold nanoparticles (AuNPs) in combination with a pretargeting approach is proposed. Small sized polyethylene glycol–stabilized AuNPs (core size 4.1 ± 1.5 nm), are synthesized and functionalized with thiolated cobalt bis(dicarbollide) and tetrazine. To enable in vivo tracking of the AuNPs by positron emission tomography (PET), the core is doped with [⁶⁴Cu]CuCl₂. For the pretargeting approach, the monoclonal antibody Trastuzumab is functionalized with trans-cyclooctene-N-hydroxysuccinimide ester. After proving in vitro occurrence of the antibody conjugation onto the AuNPs by click reaction and the low toxicity of the AuNPs, the boron delivery system is evaluated in vivo using breast cancer xenograft bearing mice and PET imaging. Tumor uptake due to the EPR effect can be witnessed with ≈5% injected dose (ID) cm⁻³ at 24 h postinjection, but with slower clearance than expected. Therefore, no increased retention can be observed using the pretargeting strategy.     

A Functionalized Hollow Mesoporous Silica Nanoparticles‐Based Controlled Dual‐Drug Delivery System for Improved Tumor Cell Cytotoxicity

Multifunctional nanoparticles for selectively targeting tumor cells and effectively delivering multiple drugs are urgently needed in cancer therapy. Here, a dual‐drug delivery system is prepared, based on functionalized hollow mesoporous silica nanoparticles (HMSNs). Doxorubicin (DOX) hydrochloride is loaded into the hollow core, and dichloro(1,2‐diaminocyclohexane)platinum (II) (DACHPt) is stored in the pores of the shell by the coordination interaction with the carboxyl groups modified on the pore walls, which also serves as barriers to control the DOX release. Detailed studies in vitro indicate that the DACHPt release is triggered by Cl^? through the cleavage of the coordination interaction, and the DOX release depends on the release rate of DACHPt and the environmental pH value. The surface of the mechanized nanoparticles is also modified by transferrin (Tf) to achieve the tumor specificity. Compared with individual drug delivery systems, the dual‐drug delivery system shows synergistic efficacy on the cell cytotoxicity (combination index = 0.30), resulting in improved tumor cell killing. The present dual‐drug delivery system provides a promising strategy to develop controlled and targeted combination therapies for efficient cancer treatment.     

A Curcumin-Based MOF Embedded Ag NPs and Modified with Polydopamine for Dual-Drug Delivery and Dual Biological Window Responsive Synergetic Cancer Therapy

A dual-drug delivery, pH-responsive composite nanoplatform (MAPD NPs) that can respond to two biological windows is developed to improve the efficacy of synergetic chemotherapic/photothermal/chemodynamic therapy (CDT) against tumors. This nanoplatform is surface-modified polydopamine (PDA) with excellent biocompatibility as the shell and Ag NPs as the catalyst for CDT. The curcumin (Cur) acts as an organic ligand to be encapsulated in metal−biomolecule frameworks (Bio-MOFs) by self-assembly, and Bio-MOF acts as a delivery carrier to deliver of DOX•HCl and then releases the Cur when it degrades in vivo. Moreover, Bio-MOF can be taken up by cells faster and accelerate cell death compared to free Cur. PDA modification enables MAP (PDA@MOF-Ag) to have photothermal properties under 808 and 1064 nm light irradiation, which not only improves the biocompatibility of MAP but also makes it produce high heat and abundant ·OH. The photothermal performance of MAP is stable after irradiation at 808 or 1064 nm, and the photothermal conversion efficiency reaches 63.57% and 26.25%. The survival rate of HeLa cells co-incubation with MAPD NPs after irradiation at 808 and 1064 nm decreases to 19.52 ± 0.69% and 30.48 ± 0.49%, respectively, providing a feasible scheme for the realization of deep tumor killing.     

Self‐Assembly of Drug–Drug Conjugates as Drug Self‐Delivery System for Tumor‐Specific pH‐Triggered Release

An acid‐labile doxorubicin dimer (D‐DOX) is designed as drug–drug conjugate for tumor intracellular pH‐triggered release, by conjugating doxorubicin (DOX) with adipic acid dihydrazide (ADH). The dimer‐based surfactants modified with polyethylene glycol (PEG), DOX‐ADH‐DOX‐PEG or are synthesized by mono‐PEGylation and bi‐PEGylation, respectively. Then the prodrug nanoparticles are fabricated with different drug contents via dialyzing the mixture solution of D‐DOX and the PEGylated surfactants in dimethyl sulfoxide (DMSO) with different mass ratios against water. It is found that the smaller prodrug nanoparticles (142–163 nm) could be obtained with the mono‐PEGylated surfactant, than those of 157–225 nm with the bi‐PEGylated surfactant. Furthermore, the mono‐PEGylated surfactant results in a higher drug content of 51% due to their lower PEG contents. All prodrug nanoparticles could release DOX completely within 36 h at pH 5.0, with the premature drug leakage of less than 10% at pH 7.4. The 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assays demonstrate the proposed drug self‐delivery system possessed an enhanced anticancer efficacy against HepG2 cells than the free DOX.     

栅扫描重离子束治癌束流配送系统对运动靶区的适形放疗(Ⅱ)可行性实验

在栅扫描束流配送系统下, 进行了重离子束对运动靶体进行适形照射的可行性实验研究. 利用实时修正束流扫描参数的方法, 使得束流追踪靶体在横向上的运动; 在纵向上利用一个机械驱动的束流降能装置(称深度扫描器)迅速调节束流 能量, 使得重离子束高剂量的Bragg峰区落在运动靶体需治疗的断层之上. 实验结果表明: 栅扫描器主动补偿靶体横向运动及深度扫描器补偿靶体纵向运动是可行的.