3D-printed engineered bacteria-laden gelatin/sodium alginate composite hydrogels for biological detection of ionizing radiation

Nuclear safety is a global growing concern,where ionizing radiation(IR)is a major injury factor resulting in serious damage to organisms.The detection of IR is usually conducted with physical dosimeters;however,biological IR detection methods are deficient.Here,a living composite hydrogel consisting of engineered bacteria and gelatin/sodium alginate was 3D-printed for the biological detection of IR.Three strains of PrecA::egfp gene circuit-containing engineered Escherichia coli were constructed with IR-dependent fluorescence,and the DH5αstrain was finally selected due to its highest radiation response and fluorescence.Engineered bacteria were loaded in a series of gelatin/sodium alginate matrix hydrogels with different rheology,3D printability and bacterial applicability.A high-gelatin-content hydrogel containing 10%gelatin/1.25%sodium alginatewas optimal.The optimal living composite hydrogelwas 3D-printedwith the special bioink,which reported significant green fluorescence underγ-ray radiation.The living composite hydrogel provides a biological strategy for the detection of environmental ionizing radiation.

3D printing-based drug-loaded implanted prosthesis to prevent breast cancer recurrence post-conserving surgery

Systemic chemotherapy of breast cancer is commonly delivered as a large dose and has toxic side effects.Local chemotherapy would overcome the shortcomings of systemic reconstruction and could play an important role in breast cancer surgery according to personalized demand.The application of three-dimensional(3D)printing technology makes personalized customization possible.We designed and prepared a prosthesis containing paclitaxel(PTX)and doxorubicin(DOX)microspheres(PPDM)based on 3D printing to prevent tumor recurrence and metastasis after breast conserving surgery.Polydimethysiloxane has good biocompatibility and was used as a drug carrier in this study.The average particle size of the PTX and DOX microspheres were approximately 3.1μm and 2.2μm,respectively.The drug loading of PTX and DOX microspheres was 4.2% and 2.1%,respectively.In vitro drug release studies demonstrated that the 3D-printed prosthesis loaded with PTX and DOXmicrospheres could release the drugs continuously for more than 3 weeks and thereby suppress cancer recurrence with reduced side effects.The PTX and DOX microspheres not only exerted a synergistic effect,but also achieved a good sustained release effect.In vivo evaluation showed that the PPDM could effectively inhibit breast cancer recurrence andmetastasis inmice with breast cancer.PPDM are expected to achieve postoperative chemotherapy for breast cancer and be highly efficient to prevent local breast cancer recurrence and metastasis.

Cancer cell membrane-coated bacterial ghosts for highly efficient paclitaxel delivery against metastatic lung cancer

Chemotherapy is one of the major approaches for the treatment of metastatic lung cancer,although it is limited by the low tumor delivery efficacy of anticancer drugs.Bacterial therapy is emerging for cancer treatment due to its high immune stimulation effect;however,excessively generated immunogenicity will cause serious inflammatory response syndrome.Here,we prepared cancer cell membrane-coated liposomal paclitaxel-loaded bacterial ghosts(LP@BG@CCM)by layer-by-layer encapsulation for the treatment of metastatic lung cancer.The preparation processes were simple,only involving film formation,electroporation,and pore extrusion.LP@BG@CCM owned much higher 4T1 cancer cell toxicity than LP@BG due to its faster fusion with cancer cells.In the 4T1 breast cancer metastatic lung cancer mouse models,the remarkably higher lung targeting of intravenously injected LP@BG@CCM was observed with the almost normalized lung appearance,the reduced lung weight,the clear lung tissue structure,and the enhanced cancer cell apoptosis compared to its precursors.Moreover,several major immune factors were improved after administration of LP@BG@CCM,including the CD4^(+)/CD8a^(+)T cells in the spleen and the TNF-α,IFN-γ,and IL-4 in the lung.LP@BG@CCM exhibits the optimal synergistic chemo-immunotherapy,which is a promising medication for the treatment of metastatic lung cancer.

Predatory bacterial hydrogels for topical treatment of infected wounds

Wound infection is becoming a considerable healthcare crisis due to the abuse of antibiotics and the substantial production of multidrug-resistant bacteria.Seawater immersion wounds usually become a mortal trouble because of the infection of Vibrio vulnificus.Bdellovibrio bacteriovorus,one kind of natural predatory bacteria,is recognized as a promising biological therapy against intractable bacteria.Here,we prepared a B.bacteriovorus-loaded polyvinyl alcohol/alginate hydrogel for the topical treatment of the seawater immersion wounds infected by V.vulnificus.The B.bacteriovorus-loaded hydrogel(BG)owned highly microporous structures with the mean pore size of 90μm,improving the rapid release of B.bacteriovorus from BG when contacting the aqueous surroundings.BG showed high biosafety with no L929 cell toxicity or hemolysis.More importantly,BG exhibited excellent in vitro anti-V.vulnificus effect.The highly effective infected wound treatment effect of BG was evaluated on mouse models,revealing significant reduction of local V.vulnificus,accelerated wound contraction,and alleviated inflammation.Besides the high bacterial inhibition of BG,BG remarkably reduced inflammatory response,promoted collagen deposition,neovascularization and re-epithelization,contributing to wound healing.BG is a promising topical biological formulation against infected wounds.

Recent progress in drug delivery

Drug delivery systems(DDS)are defined as methods by which drugs are delivered to desired tissues,organs,cells and subcellular organs for drug release and absorption through a variety of drug carriers.Its usual purpose to improve the pharmacological activities of therapeutic drugs and to overcome problems such as limited solubility,drug aggregation,low bioavailability,poor biodistribution,lack of selectivity,or to reduce the side effects of therapeutic drugs.During 2015-2018,significant progress in the research on drug delivery systems has been achieved along with advances in related fields,such as pharmaceutical sciences,material sciences and biomedical sciences.This review provides a conciseoverview of current progress in this research area through its focus on the delivery strategies,construction techniques and specific examples.It is a valuable reference for pharmaceutical scientists who want to learn more about the design of drug delivery systems.

Inhalation treatment of primary lung cancer using liposomal curcumin dry powder inhalers

Lung cancer is the leading cause of cancer-related deaths. Traditional chemotherapy causes serious toxicity due to the wide bodily distribution of these drugs. Curcumin is a potential anticancer agent but its low water solubility, poor bioavailability and rapid metabolism significantly limits clinical applications. Here we developed a liposomal curcumin dry powder inhaler(LCD) for inhalation treatment of primary lung cancer. LCDs were obtained from curcumin liposomes after freeze-drying. The LCDs had a mass mean aerodynamic diameter of 5.81 μm and a fine particle fraction of 46.71%, suitable for pulmonary delivery. The uptake of curcumin liposomes by human lung cancer A549 cells was markedly greater and faster than that of free curcumin. The high cytotoxicity on A549 cells and the low cytotoxicity of curcumin liposomes on normal human bronchial BEAS-2B epithelial cells yielded a high selection index partly due to increased cell apoptosis. Curcumin powders, LCDs and gemcitabine were directly sprayed into the lungs of rats with lung cancer through the trachea. LCDs showed higher anticancer effects than the other two medications with regard to pathology and the expression of many cancer-related markers including VEGF, malondialdehyde, TNF-α, caspase-3 and BCL-2. LCDs are a promising medication for inhalation treatment of lung cancer with high therapeutic efficiency.

Inhalable oridonin-loaded poly(lactic-co-glycolic)acid large porous microparticles for in situ treatment of primary non-small cell lung cancer

Non-small cell lung cancer(NSCLC) accounts for about 85% of all lung cancers. Traditional chemotherapy for this disease leads to serious side effects. Here we prepared an inhalable oridonin-loaded poly(lactic-co-glycolic)acid(PLGA) large porous microparticle(LPMP) for in situ treatment of NSCLC with the emulsion/solvent evaporation/freeze-drying method. The LPMPs were smooth spheres with many internal pores. Despite a geometric diameter of 10 mm, the aerodynamic diameter of the spheres was only 2.72 mm, leading to highly efficient lung deposition. In vitro studies showed that most of oridonin was released after 1 h, whereas the alveolar macrophage uptake of LPMPs occurred after 8 h, so that most of oridonin would enter the surroundings without undergoing phagocytosis. Rat primary NSCLC models were built and administered with saline, oridonin powder, gemcitabine, and oridonin-loaded LPMPs via airway, respectively. The LPMPs showed strong anticancer effects. Oridonin showed strong angiogenesis inhibition and apoptosis. Relevant mechanisms are thought to include oridonin-induced mitochondrial dysfunction accompanied by low mitochondrial membrane potentials, downregulation of BCL-2 expressions, upregulation of expressions of BAX, caspase-3 and caspase-9. The oridonin-loaded PLGALPMPs showed high anti-NSCLC effects after pulmonary delivery. In conclusion, LPMPs are promising dry powder inhalations for in situ treatment of lung cancer.

Intranasal temperature-sensitive hydrogels of cannabidiol inclusion complex for the treatment of post-traumatic stress disorder

Post-traumatic stress disorder(PTSD)is a psychiatric disease that seriously affects brain function.Currently,selective serotonin reuptake inhibitors(SSRIs)are used to treat PTSD clinically but have decreased efficiency and increased side effects.In this study,nasal cannabidiol inclusion complex temperature-sensitive hydrogels(CBD TSGs)were prepared and evaluated to treat PTSD.Mice model of PTSD was established with conditional fear box.CBD TSGs could significantly improve the spontaneous behavior,exploratory spirit and alleviate tension in open field box,relieve anxiety and tension in elevated plus maze,and reduce the freezing time.Hematoxylin and eosin and c-FOS immunohistochemistry slides showed that the main injured brain areas in PTSD were the prefrontal cortex,amygdala,and hippocampus CA1.CBD TSGs could reduce the level of tumor necrosis factor-a caused by PTSD.Western blot analysis showed that CBD TSGs increased the expression of the 5-HT1 A receptor.Intranasal administration of CBD TSGs was more efficient and had more obvious brain targeting effects than oral administration,as evidenced by the pharmacokinetics and brain tissue distribution of CBD TSGs.Overall,nasal CBD TSGs are safe and effective and have controlled release.There are a novel promising option for the clinical treatment of PTSD.

Interfacial properties and micellization of triblock poly(ethylene glycol)-poly(ε-caprolactone)-polyethyleneimine copolymers

This study aimed to explore the link between block copolymers’interfacial properties and nanoscale carrier formation and found out the influence of length ratio on these characters to optimize drug delivery system.A library of diblock copolymers of PEG-PCL and triblock copolymers with additional PEI(PEG-PCL-PEI)were synthesized.Subsequently,a systematic isothermal investigation was performed to explore molecular arrangements of copolymers at air/water interface.Then,structural properties and drug encapsulation in self-assembly were investigated with DLS,SLS and TEM.We found the additional hydrogen bond in the PEG-PCL-PEI contributes to film stability upon the hydrophobic interaction compared with PEG-PCL.PEG-PCL-PEI assemble into smaller micelle-like(such as PEGPCL4006-PEI)or particle-like structure(such as PEG-PCL8636-PEI)determined by their hydrophilic and hydrophobic block ratio.The distinct structural architectures of copolymer are consistent between interface and self-assembly.Despite the disparity of constituent ratio,we discovered the arrangement of both chains guarantees balanced hydrophilic-hydrophobic ratio in self-assembly to form stable construction.Meanwhile,the structural differences were found to have significant influence on model drugs incorporation including docetaxel and siRNA.Taken together,these findings indicate the correlation between molecular arrangement and self-assembly and inspire us to tune block compositions to achieve desired nanostructure and drug loading.

Inhaled curcumin mesoporous polydopamine nanoparticles against radiation pneumonitis

Radiation therapy is an effective method to kill cancer cells and shrink tumors using highenergy X-ray or γ-ray. Radiation pneumonitis(RP) is one of the most serious complications of radiation therapy for thoracic cancers, commonly leading to serious respiratory distress and poor prognosis. Here,we prepared curcumin-loaded mesoporous polydopamine nanoparticles(CMPN) for prevention and treatment of RP by pulmonary delivery. Mesoporous polydopamine nanoparticles(MPDA) were successfully synthesized with an emulsion-induced interface polymerization method and curcumin was loaded in MPDA via π-π stacking and hydrogen bonding interaction. MPDA owned the uniform spherical morphology with numerous mesopores that disappeared after loading curcumin. More than 80% curcumin released from CMPN in 6 h and mesopores recovered. CMPN remarkably protected BEAS-2 B cells from γ-ray radiation injury by inhibiting apoptosis. RP rat models were established after a single dose of15 Gy^(60)Co γ-ray radiation was performed on the chest area. Effective therapy of RP was achieved by intratracheal administration of CMPN due to free radical scavenging and anti-oxidation ability, and reduced proinflammatory cytokines, high superoxide dismutase, decreased malondialdehyde, and alleviated lung tissue damages were observed. Inhaled CMPN paves a new avenue for the treatment of RP.

Chemo-photothermal immunotherapy for eradication of orthotopic tumors and inhibition of metastasis by intratumoral injection of polydopamine versatile hydrogels

Cancer remains one of the leading causes of death globally and metastasis always leads to treatment failure.Here,we develop a versatile hydrogel loading photothermal agents,chemotherapeutics,and immune-adjuvants to eradicate orthotopic tumors and inhibit metastasis by combinational therapy.Hydrogel networks were synthesized via the thiol-Michael addition of polydopamine(PDA)with thiolated hyaluronic acid.PDA acted as a cross-linking agent and endowed the hydrogel with excellent photothermal property.Meanwhile,a chemotherapeutic agent,doxorubicin(DOX),was loaded in the hydrogel viaπ-πstacking with PDA and an immune-adjuvant,CpG-ODN,was loaded via electrostatic interaction.The release of DOX from the hydrogel was initially slow but accelerated due to near infrared light irradiation.The hydrogels showed remarkably synergistic effect against 4T1 cancer cells and stimulated plenty of cytokines secreting from RAW264.7 cells.Moreover,the hydrogels eradicated orthotopic murine breast cancer xenografts and strongly inhibited metastasis after intratumoral injection and light irradiation.The high anticancer efficiency of this chemo-photothermal immunotherapy resulted from the strong synergistic effect of the versatile hydrogels,including the evoked host immune response.The combinational strategy of chemo-photothermal immunotherapy is promising for highly effective treatment of breast cancer.

Inhaled amifostine for the prevention of radiation-induced lung injury

Objective:To alleviate radiation-induced lung injury and prevent the related pneumonitis and pulmonary fibrosis by inhaled amifostine(AMI).Methods:15 Gy 60Coγ-ray irradiation was performed on the thoracic area of rats once to establish the radiation injury model.AMI was intraperitoneally(i.p.)injected or intratracheally(i.t.)administered to the rats 30 min preirradiation.The protective effects of the two AMI administration manners were compared in the aspects of hematopoietic system,lung edema,and histopathological examination,and the mechanisms were explored.Results:Compared to i.p.AMI,i.t.AMI remarkably alleviated radiation-induced lung injury and prevented consequent pneumonitis or pulmonary fibrosis.Specifically,i.t.AMI notably protected white blood cells and platelets,reduced the lung wet/dry weight ratio,and decreased collagen volume fractions compared to the model group(P<0.05),while i.p.AMI showed no significant difference with the model group(P>0.05).The high therapeutic efficiency of i.t.AMI was related to its high antioxidation and anti-inflammation effects with downregulation of pro-inflammatory cytokines,the enhanced superoxide dismutase activity,the low levels of malondialdehyde and total proteins.Conclusion:Inhaled AMI is a promising medicine for preventing radiation-induced lung injury,including pneumonitis and pulmonary fibrosis.