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Synthesis and Characterization of Doxorubicin Loaded pH-Sensitive Magnetic Core–Shell Nanocomposites for Targeted Drug Delivery Applications

Wei Jiang,Juan Wu,Yewen Shen,Renbing Tian,Shuai Zhou,Wei Jiang

In order to improve the effects of medical therapy for cancer, we prepared magnetic nanocomposites (Fe 3 O 4 @SiO 2 –NH–NH 2 ) as doxorubicin (DOX) carriers via two different schemes. Scheme (I): the carriers were synthesized from magnetic silica nanoparticles (Fe 3 O 4 @SiO 2 ) via layer by layer modification, scheme (II): the carriers were obtained from amino-modified magnetic silica nanoparticles (Fe 3 O 4 @SiO 2 –NH 2 ) synthesized by one-step, and followed by surface modification. In order to load DOX effectively, the surface of the carriers were further modified to make the surface with a large number of hydrazine bonds which can form a pH-sensitive bond (hydrazone bond) with DOX. The two kinds of carriers both exhibited a size around 80 nm, high stability and superparamagnetic behavior. However, DOX-loaded carriers (Fe 3 O 4 @SiO 2 –DOX(2)) performed relatively poorer performance in terms of drug loading and releasing (the loading efficiency of DOX decreased from 67.33% to 42.15%, while the releasing efficiency of DOX decreased from 66.16% to 62.23% within 72 h at pH 4.0). Water-soluble tetrazolium salts (WST-1) assays in cancer cells (Hela) demonstrated that the Fe 3 O 4 @SiO 2 –DOX presented high anti-tumor activity, while the carriers were nearly nontoxic. Thus, the results suggested that the magnetic nanocomposites synthesized by the two different methods both can be employed to deliver DOX, while the carriers obtained via the first method may perform better and would be applied in the field of cancer therapy in the future.

pH-redox responsive polymer-doxorubicin prodrug micelles studied by molecular dynamics, dissipative particle dynamics simulations and experiments

Junxu Hao,Jinglei Wang,Hao Pan,Yuli Sang,Dazhuang Wang,Zeyu Wang,Jiao Ai,Bin Lin,Lijiang Chen

In this study, the ideal polymer materials were selected by molecular dynamics (MD) and dissipative particle dynamics (DPD) simulation methods, and pH and redox-sensitive micelles were prepared according to the simulation results. Through experiments, we successfully prepared hydrophilic block polyethylene glycol monomethyl ether (mPEG) connected hydrophobic block polylactic acid-glycolic acid (PLGA) amphiphilic polymer, and connected with redox fragment containing disulfide bond , and then connected with amide bond doxorubicin (DOX) to form mPEG-PLGA-SS-DOX prodrug , and further physical embedded free DOX. Finally, we obtained a particle size of 47.04 ± 0.103 nm, the potential of −23.8 ± 0.189 mV, Polymer dispersity index (PDI) of 0.231 ± 0.001, transmission electron microscopy (TEM) showed that it was spherical mPEG-PLGA-SS-DOX/DOX nanoparticles , its entrapment efficiency (EE) was 68.2%, loading content was 16.72%. The cumulative release of mPEG-PLGA-SS-DOX/DOX was 87.39% in a pH 5.0 and 10 mM Glutathione (GSH) tumor simulation environment. It was less toxic to normal cell HEK293 and more cytotoxic to HepG2 tumor cells. It showed that it was an excellent anti-tumor nano-drug. In addition, the application of computer simulation in the design of nanomedicine also provided a new research idea for the research of nanomedicine .

Ionic Microgel Loaded with Gold Nanoparticles for the Synergistic Dual-Drug Delivery of Doxorubicin and Diclofenac Sodium

Xianjing Zhou,Feng Chen,Haipeng Lu,Lingli Kong,Siyu Zhang,Wei Zhang,Jingjing Nie,Binyang Du,Xinping Wang

In this study, we designed and synthesized hybrid microgels with a positively charged cross-linking network and embedded gold nanoparticles. The hybrid microgels presented reversible thermosensitive behavior and the volume transition temperature of ∼37 °C, which was close to body temperature. These microgels were successfully applied as vectors to simultaneously deliver hydrophobic anticancer drug, doxorubicin, and anionic anti-inflammatory drug, diclofenac sodium. In the tumor microenvironment of low pH, high temperature, reduction condition, and the presence of ions, both drugs could controllably release from the microgels. Such microgels might be a promising platform for further development as an effective strategy for combination therapy.

Multistimuli Responsive Supramolecular Vesicles Based on the Recognition of p-Sulfonatocalixarene and its Controllable Release of Doxorubicin

Kui Wang,Dong-Sheng Guo,Xiang Wang,Yu Liu

We report the novel construction of nanosupramolecular binary vesicles based on host−guest complex formation between p-sulfonatocalix[4]arene and asymmetric viologen, which was identified by UV−vis and fluorescence spectroscopy, dynamic laser scattering, transmission electron microscopy, scanning electron microscopy, and surface tension experiments. The critical aggregation concentration of asymmetric viologen decreases pronouncedly by a factor of ca. 1000 owing to the complexation of p-sulfonatocalix[4]arene. Furthermore, we have demonstrated that the resulting vesicles can respond to multiple external stimuli, including temperature, host−guest inclusion, and redox. Methods of warming and inclusion of cyclodextrins were then employed to disrupt the vesicle architecture to release hydrophilic doxorubicin from the interior of the vesicle. Finally, cell experiments were performed to evaluate the cellular toxicity of the supramolecular binary vesicle and the anticancer efficiency of doxorubicin-loaded vesicle.

Poly(2-ethyl-2-oxazoline)–Doxorubicin Conjugate-Based Dual Endosomal pH-Sensitive Micelles with Enhanced Antitumor Efficacy

Jinwen Li,Yanxia Zhou,Chengwei Li,Dishi Wang,Yajie Gao,Chao Zhang,Lei Zhao,Yushu Li,Yan Liu,Xinru Li

Dual endosomal pH-sensitive micelles were designed and fabricated to deliver doxorubicin (DOX) for treating breast cancer based on a poly(2-ethyl-2-oxazoline) (PEOz)–DOX (PEOz–hyd–DOX) conjugate. PEOz–hyd–DOX was successfully synthesized by connecting DOX to PEOz via an acid cleavable hydrazone linker and self-assembled into nanosized micelles, which further physically encapsulated DOX. The conjugate and DOX-loaded conjugate micelles displayed faster release of DOX at pH 5.0 than at pH 7.4. This pH-dependent release behavior might assist the quick diffusion of DOX from acidic endosomes or lysosomes and the intracellular transfer into the nucleus after internalization, which was confirmed by confocal laser scanning microscopy images. As expected, PEOz–hyd–DOX conjugate and DOX-loaded conjugate micelles maintained cytotoxicity of DOX. In addition, the dual endosomal pH-sensitive micelles were found to substantially enhance antitumor efficacy and reduce side effects compared with free DOX. Therefore, PEOz–hyd–DOX conjugate-based micelles might be potential drug delivery vehicles of DOX for safe and effective breast cancer therapy.

Fabrication of doxorubicin-loaded ellipsoid micelle based on diblock copolymer with a linkage of enzyme-cleavable peptide

Haitao Huang,Jianqi Geng,Jafar Golzarian,Jin Huang,Jiahui Yu

In this study, a novel micellar drug carrier was fabricated from an amphiphilic diblock copolymer containing poly (ethylene glycol) monomethyl ether (mPEG) and stearic moiety (C 18 ) with a linkage of valine-citrulline (VC), which can be cleaved by cathepsin B (C B ) enriched in lysosome of tumor cell. Moreover, the self-assembled micelles were observed as ellipsoid shape with major and minor axis of ca. 169 and 103   nm, respectively. Such drug carrier was used to encapsulate anti-cancer drug doxorubicin (DOX), and hence showed a faster drug release behavior in a mimic lysosome condition containing cathepsin B. It was ascribed to the lysosome-sensitivity of the valine-citrulline linkage, which was verified by the size distribution curve shifted to greater size under the same mimic lysosome condition. Furthermore, in comparison with pristine doxorubicin, the encapsulation strategy of as-fabricated micellar carrier resulted in a predominant decrease of cytotoxicity. On the whole, a micellar drug carrier, which can be disassembled by cathepsin B, has been emerging as a potential of specific drug release in lysosome. Additionally, the controlled nanoscale together with elongated structure of such assembled ellipsoid micelles might contribute passive targeting function to tumor tissue and faster cellular uptake behavior (Zhou et al. [33] ).

Stimuli-responsive polymeric prodrug-based nanomedicine delivering nifuroxazide and doxorubicin against primary breast cancer and pulmonary metastasis

Lei Luo,Fanshu Xu,Huilan Peng,Yonghuang Luo,Xiaohe Tian,Giuseppe Battaglia,Hu Zhang,Qiyong Gong,Zhongwei Gu,Kui Luo

Functionalized drug delivery systems against malignant lung metastasis of breast cancer have been extensively studied, while metastasis remains a challenging issue. We propose a new strategy to achieve eradication of primary breast cancer cells and inhibition of pulmonary metastasis. A cathepsin B/pH dual-sensitive block copolymer with a molecular weight of 92 kDa was synthesized to conjugate with doxorubicin (DOX). The copolymer-DOX was further loaded with nifuroxazide (NFX) to self-assemble co-prodrug-loaded micelles (CLM). CLM displayed a drug release pattern in response to pH/enzyme dual stimuli and was enzymatically biodegradable. CLM was demonstrated to reduce viability and inhibit migration and invasion of 4T1 murine breast cancer cells in vitro. After i.v. injection of CLM, its nanoscale size and stimuli-responsiveness facilitated delivery of drugs to the tumor site in mice. Enhanced anti-tumor efficacy and great anti-metastatic effects were found in both orthotropic and lung metastasis 4T1 breast cancer mice models. Meanwhile, histological immunofluorescence and immunohistochemical analyses revealed a high level of apoptosis, suppressed expression of matrix metalloproteinases and reduction in MDSCs infiltration , and all these contributed to inhibit pulmonary metastasis. CLM may be explored as a potential nanomedicine against breast cancer metastasis.

Reversal of P-glycoprotein-mediated multidrug resistance by doxorubicin and quinine co-loaded liposomes in tumor cells

Qiying Shen,Liyan Qiu

Light-responsive α-TOS liposomal nanocarriers Co-delivering TiO2 and doxorubicin for the treatment of breast cancer

Kaixin Feng,Zhongkun Zhang,Jingjing Zhang,Xiaohan Xia,Siyu Yao,Yufei Wang,Min Wu

Doxorubicin (DOX) is limited by its clinical toxicity as a breast cancer therapy. Traditional liposomal formulations improve the tumor delivery of DOX but suffer from inadequate controlled release and low encapsulation efficiency of DOX. To address these, we developed a photo-responsive liposomal formulation DTTPL by co-encapsulating DOX and TiO 2 nanostructures (TiO 2 ) within D-α-tocopheryl succinate (α-TOS)-PEG liposomes. DTTPL successfully facilitated the release of DOX through the light-sensitive catalysis mechanism of TiO 2 , exhibiting 4.6 times greater cytotoxicity against MCF-7 cells compared to free DOX. Transcriptional analysis revealed synergistic DOX/DTTPL dysregulation of key genes (Brca1, Bcl-2, Bax, Caspase-3), aligning with cytotoxicity.   Eventually, light-triggered DOX/DTTPL formulation resulted in 70.09% of tumor growth inhibition (TGI) in mice with no significant organ toxicity. This photo-responsive nanoformulation enables efficient controlled release of DOX, offering an alternative strategy for small molecule delivery to treat triple negative breast cancer.

Star-shaped polymer of β‑cyclodextrin-g-vitamin E TPGS for doxorubicin delivery and multidrug resistance inhibition

Conglian Yang,Yuting Qin,Kun Tu,Chenfeng Xu,Zhen Li,Zhiping Zhang

Multidrug resistance (MDR) remains as an obstacle for effective cancer treatment. Herein, we developed a novel and efficient nanomedicine by virtue of the carrier characters and MDR inhibition effects of β-cyclodextrin (β-CD) and d-α-tocopheryl polyethylene glycol succinate (TPGS). A series of star-shaped polymers CD-g-TPGS with different TPGS substitution degree were synthesized for doxorubicin (DOX) delivery, where β-CD was identified as a core and TPGS as branches. These star polymers can self-assemble into nanoparticles with DOX . These nanoparticles showed no significant differences in size, zeta potential and morphology except for in vitro stability. They demonstrated good biocompatibility and enhanced cellular uptake in both drug sensitive and resistant cancer cells. Notably, the nanoparticles exhibited superiority of cytotoxicity in drug resistant cancer cells against free DOX . In vivo antitumor effect also demonstrated the improved cancer inhibition effect. This work suggests that star-shaped polymers CD-g-TPGS are promising drug carriers to overcome MDR in cancer treatment.

Polymer–Doxorubicin Prodrug with Biocompatibility, pH Response, and Main Chain Breakability Prepared by Catalyst-Free Click Reaction

Dian Li,Yue Song,Jinlin He,Mingzu Zhang,Peihong Ni

Click chemistry has increasing applications of the development of polymer materials and modification of drug carriers. The amino–yne click polymerization reacts quickly at room temperature without catalyst, and the enamine bond (-ena-) gained from the reaction is sensitive to acid and can be used to prepare stimulus-responsive polymeric prodrugs. Herein, we report an alkynyl-terminated polymer containing alternately distributed low molecular weight polyethylene glycol (PEG) and hexamethylenediamino (HMDA) linked by enamine bonds, abbreviated as A-P(PEG-alt-HMDA)-A, which was synthesized within 3 h at 35 °C without catalyst. The polymer was verified to have good water solubility, biocompatibility, and acid-sensitive fracturing. Then, a pH-responsive polymeric prodrug (DOX-ena-PPEG-ena-DOX) was further prepared through the amino–yne click reaction between the alkynyl groups of A-P(PEG-alt-HMDA)-A and the amino group of doxorubicin hydrochloride (DOX·HCl). The resulting prodrug can self-assemble into nanoparticles (NPs) in aqueous solution. The pH responsiveness of the prodrug NPs was demonstrated by a stability experiment of NPs and in vitro drug release behavior measurement. The accumulative release of doxorubicin (DOX) was tested with different pH media, which confirmed that the prodrug NPs could effectively dissociate and release drug under a weak acid microenvironment of lysosome/endosome. Subsequently, we investigated cell cytotoxicity and intracellular uptake of the prodrug. It turned out that the prodrug nanoparticles could be internalized into HeLa cells, release original DOX, and efficiently inhibit the proliferation of cancer cells. These results show that the pH-responsive DOX-ena-PPEG-ena-DOX has the potential for use in cancer therapy.

Erythrocyte-membrane camouflaged manganese dioxide-polydopamine nanocarriers for doxorubicin delivery and MRI-visualized chemo-photothermal cancer therapy

Xiaoming Wang,Zhiwei Duan,Xiaopo Wu,Yao Zhang,Longda Feng,Cui Wei,Shaofeng Chen,Qilei Chen,Xiaowen Zhou,Yi Zhou,Linghao Qin

Doxorubicin (DOX) chemotherapy is limited by systemic toxicity, poor tumor accumulation, and the acidic, hypoxic tumor microenvironment (TME). We developed MnO 2 -PDA-DOX@RBC/FA/PEG nanoparticles by coating manganese dioxide (MnO 2 ) cores with polydopamine (PDA) for DOX loading and cloaking the particles with folic acid (FA)- and polyethylene glycol (PEG)-modified erythrocyte membranes. The nanosystem combined colloidal stability, erythrocyte-membrane-associated long circulation, FA-mediated tumor targeting, near-infrared photothermal conversion, and TME-responsive drug release. MnO 2 catalyzed hydrogen peroxide decomposition to generate oxygen and consumed protons under acidic conditions, while acid-triggered MnO 2 degradation produced Mn 2 ⁺ for T 1 -weighted magnetic resonance imaging (MRI). In HepG2 cells, the nanoparticles enhanced DOX uptake, promoted lysosomal escape and mitochondrial accumulation, disrupted redox homeostasis, and strengthened apoptosis under 808 nm irradiation. In H22 tumor-bearing mice, MnO 2 -PDA-DOX@RBC/FA/PEG prolonged DOX circulation, reduced cardiac exposure, increased tumor accumulation, and achieved superior chemo-photothermal antitumor efficacy with reduced systemic inflammation. This biomimetic theranostic platform enables MRI- visualized, TME-responsive chemo-photothermal cancer therapy. Download: Download high-res image (195KB) Download: Download full-size image