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In the development of chemo-immunotherapy, many efforts have been focusing on designing suitable carriers to realize the co-delivery of chemotherapeutic and immunotherapeutic with different physicochemical properties and mechanisms of action. Besides, rapid drug release at the tumor site with minimal drug degradation is also essential to facilitate the antitumor effect in a short time. Here, we reported a cancer cell membrane-coated pH-responsive nanogel (NG@M) to co-deliver chemotherapeutic paclitaxel (PTX) and immunotherapeutic agent interleukin-2 (IL-2) under mild conditions for combinational treatment of triple-negative breast cancer. In the designed nanogels, the synthetic copolymer PDEA-co-HP-β-cyclodextrin-co-Pluronic F127 and charge reversible polymer dimethylmaleic anhydride-modified polyethyleneimine endowed nanogels with excellent drug-loading capacity and rapid responsive drug-releasing behavior under acidic tumor microenvironment. Benefited from tumor homologous targeting capacity, NG@M exhibited 4.59-fold higher accumulation at the homologous tumor site than heterologous cancer cell membrane-coated NG. Rapidly released PTX and IL-2 enhanced the maturation of dendritic cells and quickly activated the antitumor immune response in situ, followed by prompted infiltration of immune effector cells. By the combined chemo-immunotherapy, enhanced antitumor effect and efficient pulmonary metastasis inhibition were achieved with a prolonged median survival rate (39 days).
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@#To construct PTEN/PLGA-(HE)10-MAP nanoparticles, which encapsulated PTEN plasmid DNA and combined with the pH-responsive cell-penetrating peptides (CPPs), and to investigate their effects of gene delivery and anti-tumor targets in vitro. Poly (lactic-co-glycolic acid) (PLGA) nanoparticles loaded with PTEN plasmid DNA were prepared by double emulsification-solvent evaporation method. PTEN/PLGA-(HE)10-MAP nanoparticles were prepared by coupling the histidine-glutamic acid-model amphipathic peptide nanocomplex [(HE)10-MAP] to the surface through amide condensation reaction. Particle size, Zeta potential, encapsulation rate and drug loading were tested to characterize the nanoparticles. By analyzing the cytotoxicity, cellular uptake, targeted transfection of eukaryotic expression plasmids and anti-tumor cell proliferation, the feasibility as a targeted gene delivery system were evaluated. The particle size of PTEN/PLGA-(HE)10-MAP nanoparticles was (266.5 ± 2.86) nm, with the encapsulation efficiency (80.6 ± 6.11)%. Zeta potentials were -(6.7 ± 0.26) mV, +(0.7 ± 0.22) mV and +(37.5 ± 0.85) mV at pH 7.4, 7.0 and 6.5, respectively. In the cytotoxicity test, the cell survival rates of tumor and normal cells were above 80%.Non-loading PLGA-(HE)10-MAP nanoparticles showed no obvious cytotoxicity. The results of cellular uptake experiments showed that PTEN/PLGA-(HE)10-MAP nanoparticles were more readily taken up by cells.The results of CCK-8 showed that the nanoparticles could pH-specifically inhibit proliferation of tumor cell in vitro.And PTEN/PLGA-(HE)10-MAP nanoparticles may be applied in tumor gene therapy.
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Hyaluronic acid (HA) is a natural ligand of tumor-targeted drug delivery systems (DDS) due to the relevant CD44 receptor overexpressed on tumor cell membranes. However, other HA receptors (HARE and LYVE-1) are also overexpressing in the reticuloendothelial system (RES). Therefore, polyethylene glycol (PEG) modification of HA-based DDS is necessary to reduce RES capture. Unfortunately, pegylation remarkably inhibits tumor cellular uptake and endosomal escapement, significantly compromising the antitumor efficacy. Herein, we developed a Dox-loaded HA-based transformable supramolecular nanoplatform (Dox/HCVBP) to overcome this dilemma. Dox/HCVBP contains a tumor extracellular acidity-sensitive detachable PEG shell achieved by a benzoic imine linkage. The and investigations further demonstrated that Dox/HCVBP could be in a "stealth" state at blood stream for a long circulation time due to the buried HA ligands and the minimized nonspecific interaction by PEG shell. However, it could transform into a "recognition" state under the tumor acidic microenvironment for efficient tumor cellular uptake due to the direct exposure of active targeting ligand HA following PEG shell detachment. Such a transformative concept provides a promising strategy to resolve the dilemma of natural ligand-based DDS with conflicting two processes of tumor cellular uptake and nonspecific biodistribution.
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Objective To establish a simple and gentle antigen loading method to prepare pH-responsive and biodegradable microcapsules for efficient antigen delivery.Methods Co-precipitation method was used to embed chicken egg albumin (OVA) in CaCO3 particles.Then,TA and Al (Ⅲ) were coated on the surface of CaCO3 particles template by metal-organic coordination bonds.The CaCO3 template was removed from disodium edetate to obtain TA-Al(Ⅲ) microcapsules carrying OVA,i.e.the OVA@TA-Al(Ⅲ) microcapsules.The microcapsules were characterized by field emission scanning electron microscopy,transmission electron microscopy,X-ray energy spectrometry and atomic force microscopy.The distribution of OVA in the microcapsules was observed by laser scanning confocal microscopy.The cumulative release rate of OVA in the microcapsules at different pH phosphate buffers was also investigated.The cytotoxicity of the microcapsules on immortalized mouse dendritic cells DC2.4 was observed by thiazolyl blue assay.The phagocytosis of the microcapsules by DC2.4 cells was observed by laser scanning confocal microscopy.Results The results of field emission scanning electron microscope and transmission electron microscopy showed that the OVA@TA-Al(Ⅲ) microcapsules have a intact structure and a hollow and collapsed appearance with a diameter of about 4 μm.X-ray energy spectrum showed that there are five kinds of elements,i.e.C,O,Al,Si and Na,in the microcapsules,among which C,Al and some O elements belong to the composition of the microcapsules.Atomic force microscopy showed that the microcapsules have an ultra-thin wall,and the walls of the microcapsules are uniform in thickness (about 16 nm).Laser scanning confocal microscopy showed that OVAs were evenly distributed in the CaCO3 particles.Moreover,the pH sensitivity of the coordination bond makes the OVA@TA-Al(Ⅲ) microcapsules have pH responsiveness.In addition,the microcapsules also have good biocompatibility,and the DC2.4 cells also have good phagocytic ability to the microcapsules.Conclusion A simple and gentle antigen-encapsuling method was developed to achieve effective antigen payload and pH responsive delivery.The prepared microcapsules are expected to be used as a novel antigen delivery vector for clinical research.
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Objective To prepare pH-responsive osmotic nanocarriers (pMPPs),observe their distribution in the genital tract mucosa in mice,and evaluate their radiosensitizing effects in tumor cells.Methods Amphiphilic polymers containing pH-sensitive hydrazone bonds were synthesized and pMPPs were prepared by ultrasonic emulsification.At the same time,the hydrophobic polymer polylactic acid-glycolic acid copolymer (PLGA) and the amphiphilic polymer PLGA-polyethylene glycol without hydrazine bond were selected,and the mucoadhesive nanoparticles(MPs) and mucus-penetrating particles (MPPs) were prepared in the same way.Fluorescence microscopy was used to observe the distribution of three kinds of nanocarriers labeled with fluorescent dye Cy5.5 in the genital tract mucosa.The toxicity of nanocarriers to human cervical cancer cell line HeLa was tested by thiazolyl blue assay.The amphiphilic polymer containing pH-sensitive hydrazone bond was combined with oil-soluble gold nanoparticles to form a multi-encapsulated nanocarrier,and its radiotherapy sensitization effect in HeLa cells was evaluated by thiazole blue assay.Results The pMPPs were successfully prepared with relatively uniform particle size and good dispersion.Fluorescence microscopy showed that pMPPs not only had good mucus permeability,but also could improve the endocytosis efficiency of the nanocarriers in reproductive tract mucosa.The results of thiazolyl blue test showed that when the concentration of the carrier reached to 0.80 mg/ml,the survival rate of HeLa cells in the pMPPs group was higher than 90％ which was higher than that in the MPs and the MPPs groups,indicating that pMPPs had good biosafety.The HeLa cell survival rate of the CMNa group (0.80 mg/ml) was higher than that of the multi-package nanocarrier group under different doses of X-ray irradiation (4 Gy:82.90％ vs.61.79％;8 Gy:64.75 ％ vs.42.36％).This result indicated that compared with the CMNa,a commonly used clinical radiotherapy sensitizer,the multi-encapsulated nanocarriers can more effectively enhance the sensitivity of tumor cells to radiation therapy,thereby improving the lethality of radiation therapy on tumor cells.Conclusion This study solved the conflict between mucus permeation and endocytosis design of nanocarriers in mucosal tissue application,and provided new insight for the treatment of mucosal tissue diseases.
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Objective To prepare and evaluate As2O3 loaded polyethylene glycol-polycaprolactone-polyethyleneimine (PEG-PCL- PEI, PPP) nanoparticles (As2O3-PPP-NPs) in vitro. Methods As2O3-PPP-NPs was prepared by one-step electrostatic loading method using PPP triblock polymer as carrier. The drug loading and entrapment efficiency of the nano-drug were determined by ICP-OES. In vitro drug release property was studied by the dialysis bag method. Hemolytic toxicity of As2O3-PPP-NPs was investigated by UV spectrophotometry. Cytotoxicity of As2O3-PPP-NPs on human cervical cancer (HeLa) and human hepatocellular carcinoma cells (HepG2) was evaluated by MTT assay. Finally, ICP-OES and confocal microscopy was used to investigate the uptake efficiency and uptake mechanism of As2O3-PPP-NPs by HepG2 cells. Results The prepared nano-formulations were spherical and well-dispersed with particle size of 88.7 nm. The encapsulation efficiency and the drug loading rate were (92.75 ± 3.83)% and (4.39 ± 0.26) %, respectively. In vitro release studies showed that As2O3-PPP-NPs had the characteristics of sustained release and low pH responsive drug release, which could achieve specific drug release in the tumor environment. The loading of As2O3 neutralized the positive charge of PPP, and the hemolytic toxicity of the material was reduced. MTT assay showed that the median lethal concentrations (IC50 values) of As2O3-PPP- NPs to HeLa and HepG2 cells were 6.24 μmol/L and 5.85 μmol/L, respectively, which showed strong inhibiting effect on tumor cells. Cellular uptake studies showed that As2O3-PPP-NPs was rapidly taken up by cells due to positively charged surface and featured the lysosomal escaping ability, so the drug could be released in the cytoplasm and exert its anti-tumor effect. Conclusion As2O3-PPP-NPs exhibits significantly sustained and low pH responsive release characteristics, and has the ability to escape from lysosomes. As2O3-PPP-NPs is a potential drug delivery system against solid tumor.
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Objective To design and synthesize a novel type of combined anti-tumor drug-doxorubicin modified silver nanoparticles(DOX-Ag NPs)with pH response,characterize its physical and chemical properties,and investigate its drug responsive release and anti-tumor activity in vitro.Methods DOX-Ag NPs were prepared by coupling silver nanoparticles (Ag NPs) with doxorubicin (DOX) via a LA-NHNH2linker. The structure of LA-NHN=DOX was confirmed by nuclear magnetic resonance(1H NMR)and high resolution mass spectrometry(HRMS).The particle size and micromorphology of the nanoparticles were detected by dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. The optical properties of the nanoparticles were characterized by UV-vis absorption spectroscopy and fluorescence spectroscopy.The DOX release kinetics of DOX-Ag NPs under different pH conditions were examined by dialysis method combined with fluorescence spectroscopy. The in vitro anti-tumor effects of DOX-Ag NPs were evaluated by MTT assay. Results DOX-Ag NPs were spherical nanoparticles with a particle size of (40.4 ± 3.8) nm. DOX-Ag NPs could rapidly release DOX under weak acid condition.DOX-Ag NPs significantly inhibited the proliferation and cell viability of HepG2 cells in concentration dependent manner.When DOX concentration was 0.5-20 mg/L(Ag concentration was 0.45-18 mg/L), the cell survival rate was significantly lower in DOX-Ag NPs group than that of DOX group and Ag NPs group(P<0.05). Conclusion DOX-Ag NPs are a combined anti-tumor nano-drug with pH-responsive ability, which can release DOX rapidly in tumor tissues and play an anti-tumor effect through synergistic treatment with Ag NPs in vitro.
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Objective To prepare doxorubicin-loaded pH/magnetic dual responsive nanocomplex denoted as Fe3O4@SiO2 @PEG-6-PAsp@DOX and to determine its chemo-physical properties, pH/magnetic dual responsive release, and cytotoxicity against human lung cancer A549 cells. Methods The nanocomplex was synthesized through a sequential process involving hydrothermal treatment, Stober method, sol-gel technique, and cross-linking. The morphology, diameter, zeta potential and magnetic properties of the nanocomplex were characterized by transmission electron microscopy, zeta potential measurement analyzer, and hysteresis loop tester, respectively. Drug loading efficiency and encapsulation efficiency were examined by ultraviolet visible absorption spectroscopy; pH-stimulated drug release was investigated by dialysis in vitro; and the antiproliferative activity apoptosis-induction effect of the complex nanoparticles were investigated by CCK-8 method and flow cytometer, respectively. Results The average particle size of drug-loaded system Fe3O4 @ SiO2 @ PEG-b-PAsp @ DOX was (197. 7±1. 5) nm and the zeta potential was (— 35. 9 ± 0. 6) mV. Drug loading efficiency and encapsulation efficiency were20. 36 ± 0. 67) % and (83. 71 ± 0. 53) %, respectively. Cumulative release rate was significantly increased in mild acid condition (pH = 5. 5) (P<0. 05). The nanocomplex also demonstrated a good magnetic response and targeting ability under outside magnetic field. Moreover, the drug-loaded nanoparticle showed a significant cytotoxicity effect against human lung A549 cells in vitro. Conclusion Fe3O4 @ SiO2 @ PEG-b-PAsp @ DOX possesses a good pH/magnetic dual responsive release characteristics and exhibits efficient antitumor activity in vitro against lung cancer A549 cells.
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Objective: To prepare polyacrylic acid grafted arsenic trioxide-loaded pH-responsive mesoporous silica nanoparticles (PAA-ATO-MSNs) and to investigate their physicochemical properties, in vitro release behavior, and pharmacokinetics in rats. Methods: PAA was covalently attached to the exterior surface of amino group functionalized MSNs prepared by co-condensation method and ATO was loaded into them by electrostatic adsorption. Transmission electron microscope (TEM), small angle X-ray diffraction (SAXRD), nitrogen adsorption, thermogravimetric analysis (TGA), fourier transform infrared (FT-IR) spectra, and laser particle size analyzer were used to determine the physicochemical properties. The entrapment efficiency (EE) and drug loading (DL) of PAA-ATO-MSNs were investigated with the method of high speed centrifugation combined with inductively coupled plasma emission spectrum (ICP). The drug release behavior of PAA-ATO-MSNs was studied using dynamic dialysis method, PBS (pH 5.0, 6.0, and 7.4) chosen as release media. Pharmacokinetic behavior of PAA-ATO-MSNs after iv injection in rats was studied. Results: Morphology of PAA-ATO-MSNs was spherical and the mean particle size, Zeta potential, EE, and DL of PAA-ATO-MSNs were (158.60 ± 1.32) nm, (-28.40 ± 0.34) mV, (40.95 ± 3.21)%, and (11.42 ± 1.75)%, respectively. In vitro release behavior of PAA-ATO-MSNs showed pH-responsive characteristic and the cumulative release amount was increased with the decrease of pH value. Compared with ATO-Sol and ATO-MSNs group, t1/2β was significantly prolonged and AUC was significantly increased (P < 0.01). Conclusion: Release of ATO from PAA-ATO-MSNs showed the obvious pH-responsive characteristic and sustained-release in vitro and PAA-ATO-MSNs could improve the pharmacokinetic behavior in rats. PAA-MSNs might be promising carrier to load ATO for cancer therapy.
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Smart polymers have enormous potential in various applications. In particular, smart polymeric drug delivery systems have been explored as "intelligent" delivery systems able to release, at the appropriate time and site of action, entrapped drugs in response to specific physiological triggers. These polymers exhibit a non-linear response to a small stimulus leading to a macroscopic alteration in their structure/properties. The responses vary widely from swelling/contraction to disintegration. Synthesis of new polymers and crosslinkers with greater biocompatibility and better biodegradability would increase and enhance current applications. The most fascinating features of the smart polymers arise from their versatility and tunable sensitivity. The most significant weakness of all these external stimuli-sensitive polymers is slow response time. The versatility of polymer sources and their combinatorial synthesis make it possible to tune polymer sensitivity to a given stimulus within a narrow range. Development of smart polymer systems may lead to more accurate and programmable drug delivery. In this review, we discuss various mechanisms by which polymer systems are assembled in situ to form implanted devices for sustained release of therapeutic macromolecules, and we highlight various applications in the field of advanced drug delivery.