ABSTRACT
BACKGROUND: Antibacterial multidrug resistance has emerged as one of the foremost global problems affecting human health. The emergence of resistant infections with the increasing number of multidrug-resistant pathogens has posed a serious problem, which required innovative collaborations across multiple disciplines to address this issue. METHODS: In this review, we will explain the mechanisms of bacterial multidrug resistance and discuss different strategies for combating it, including combination therapy, the use of novel natural antibiotics, and the use of nanotechnology in the development of efflux pump inhibitors. RESULTS: While combination therapy will remain the mainstay of bacterial multi-drug resistance treatment, nanotechnology will play critical roles in the development of novel treatments in the coming years. CONCLUSION: Nanotechnology provides an encouraging platform for the development of clinically relevant and practical strategies to overcome drug resistance in the future.
Subject(s)
Anti-Bacterial Agents/pharmacology , Bacterial Infections , Drug Resistance, Multiple, Bacterial , Bacterial Proteins/antagonists & inhibitors , Humans , Membrane Transport Proteins , NanotechnologyABSTRACT
Sustained release of thermal-instable and water-soluble drugs with low molecule weight is a challenge. In this study, sodium bicarbonate was encapsulated in ethyl cellulose microspheres by a novel solid-in-oil-in-oil (S/O/O) emulsification method using acetonitrile/soybean oil as new solvent pairs. Properties of the microspheres such as size, recovery rate, morphology, drug content, and drug release behavior were evaluated to investigate the suitable preparation techniques. In the case of that the ratio of the internal and external oil phase was 1: 9, Tween 80 as a stabilizer resulted in the highest drug content (2.68%) and a good spherical shape of microspheres. After the ratio increased to 1: 4, the microspheres using Tween 80 as the stabilizer also had high drug content (1.96%) and exhibited a sustained release behavior, with 70% of drug released within 12 h and a sustained release of more than 40 h. Otherwise, different emulsification temperatures at which acetonitrile was evaporated could influence the drug release behaviour of microspheres obtained. This novel method is a potential and effective method to achieve the encapsulation and the sustained release of thermal-instable and water-soluble drugs with low molecule weight.
ABSTRACT
Spinal cord injury (SCI) leads to immediate disruption of neuronal membranes and loss of neurons, followed by extensive secondary injury process. Treatment of SCI still remains a tremendous challenge clinically. Minocycline could target comprehensive secondary injury via anti-inflammatory, anti-oxidant and anti-apoptotic mechanisms. Polyethylene glycol (PEG), a known sealing agent, is able to seal the damaged cell membranes and reduce calcium influx, thereby exerting neuroprotective capacity. Here, an E-selectin-targeting sialic acid - polyethylene glycol - poly (lactic-co-glycolic acid) (SAPP) copolymer was designed for delivering hydrophobic minocycline to achieve combinational therapy of SCI. The obtained SAPP copolymer could self-assemble into micelles with critical micelle concentration being of 13.40⯵g/mL, and effectively encapsulate hydrophobic minocycline. The prepared drug-loaded micelles (SAPPM) displayed sustained drug release over 72â¯h, which could stop microglia activation and exhibited excellent neuroprotective capacity in vitro. The SAPP micelles were efficiently accumulated in the lesion site of SCI rats via the specific binding between sialic acid and E-selectin. Due to the targeting distribution and combinational effect between PEG and minocycline, SAPPM could obviously reduce the area of lesion cavity, and realize more survival of axons and myelin sheaths from the injury, thus distinctly improving hindlimb functional recovery of SCI rats and conferring superior therapeutic effect in coparison with other groups. Our work presented an effective and safe strategy for SCI targeting therapy. Besides, neuroprotective capacity of PEG deserves further investigation on other central nervous system diseases.
Subject(s)
Micelles , N-Acetylneuraminic Acid/chemistry , Polyethylene Glycols/chemistry , Spinal Cord Injuries/therapy , Animals , Combined Modality Therapy , Female , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Mice , Microglia/drug effects , Microglia/pathology , Minocycline/pharmacology , Minocycline/therapeutic use , Myelin Sheath/drug effects , Myelin Sheath/metabolism , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , Rats, Sprague-Dawley , Spinal Cord/pathology , Spinal Cord/ultrastructure , Spinal Cord Injuries/drug therapyABSTRACT
The prevalence of antibiotic resistance and lack of alternative drugs have posed an increasing threat to public health. Here, we prepared ß-Ga2O3:Cr3+ nanoparticles modified with ICAM1-antibody-conjugated TPGS (I-TPGS/Ga2O3) as a novel antibiotic carrier for the treatment of drug-resistant infections. Methods: I-TPGS/Ga2O3 were firstly characterized by measuring particle size, morphology, crystal structure, drug loading capacity, and in vitro drug release behaviors. The in vitro antibacterial activities of I-TPGS/Ga2O3/TIG were evaluated using standard and drug-resistant bacteria. The internalization of I-TPGS/Ga2O3 was observed by fluorescence confocal imaging, and the expression levels of the efflux pump genes of TRKP were analyzed by real-time RT-PCR. In vitro cellular uptake and in vivo biodistribution study were performed to investigate the targeting specificity of I-TPGS/Ga2O3 using HUEVC and acute pneumonia mice, respectively. The in vivo anti-infective efficacy and biosafety of I-TPGS/Ga2O3/TIG were finally evaluated using acute pneumonia mice. Results: It was found that TPGS could down-regulate the over-expression of the efflux pump genes, thus decreasing the efflux pump activity of bacteria. I-TPGS/Ga2O3 with small particle size and uniform distribution facilitated their internalization in bacteria, and the TPGS modification resulted in a significant reduction in the efflux of loaded antibiotics. These properties rendered the encapsulated tigecycline to exert a stronger antibacterial activity both in vitro and in vivo. Additionally, targeted delivery of I-TPGS/Ga2O3 mediated by ICAM1 antibodies contributed to a safe and effective therapy. Conclusion: It is of great value to apply I-TPGS/Ga2O3 as a novel and effective antibiotic delivery system for the treatment of drug-resistant infections.
Subject(s)
Anti-Bacterial Agents/administration & dosage , Drug Carriers/administration & dosage , Klebsiella Infections/drug therapy , Molecular Targeted Therapy/methods , Nanocomposites/administration & dosage , Tigecycline/administration & dosage , Animals , Disease Models, Animal , Drug Carriers/chemical synthesis , Drug Resistance, Bacterial , Intercellular Adhesion Molecule-1/administration & dosage , Klebsiella Infections/microbiology , Klebsiella pneumoniae/drug effects , Mice , Treatment Outcome , Vitamin E/administration & dosageABSTRACT
Multiple drug resistance and the increase in the appearance of superbugs together with the exceedingly scant development of new potent antibiotic drugs pose an urgent global medical threat and imminent public security crisis. In the present study, we fabricated well-dispersed tocopherol polyethylene glycol succinate (TPGS)-capped silver nanoparticles (AgNPs) of about 10 nm in size. The hollow structure of the TPGS-capped AgNPs (TPGS/AgNPs) was confirmed and applied to load antibiotics. The TPGS/AgNPs proved to be able to cross the bacterial cell wall and penetrate into bacteria, thereby delivering more of the antibiotic to the interior of bacteria and thus enhancing the in vitro antibacterial effect of the antibiotic, even overcoming the drug-resistance in drug-resistant E. coli and Acinetobacter baumannii. It was found that the TPGS modification in the TPGS/AgNPs could decrease the activity of the efflux pumps AdeABC and AdeIJK in drug-resistant Acinetobacter baumannii via inhibiting the efflux pump genes adeB and adeJ, thus increasing the accumulation of the delivered antibiotic and overcoming the drug-resistance. Tigecycline delivered by TPGS/AgNPs could effectively antagonize drug-resistance in an acute peritonitis model mice, thereby increasing the survival rate and alleviating the inflammatory response. TPGS/AgNPs were developed as a novel and effective antibiotic delivery system and TPGS was demonstrated to have great potential as a pharmaceutical excipient for use in drug-resistant infection therapy.
Subject(s)
Drug Carriers/chemistry , Drug Resistance, Bacterial/drug effects , Metal Nanoparticles/chemistry , Silver/chemistry , Vitamin E/chemistry , Animals , Biological Transport , Cell Line , Drug Carriers/metabolism , Humans , Mice , Particle Size , Tigecycline/chemistry , Tigecycline/pharmacology , Vitamin E/metabolismABSTRACT
An ointment containing retinoic acid deformable liposomes (TRA DLs) and epidermal growth factor cationic deformable liposomes (EGF CDLs) was prepared for the treatment of deep partial-thickness burns. The characterization tests confirmed both liposomes featured small particle sizes, high drug entrapment efficiencies and sustained drug release behavior. Compared with the free drug, TRA DLs and EGF CDLs exhibited superior skin permeation and remarkably increased drug deposition by 2.9 and 18.8 folds, respectively. Results on HaCaT cells indicated the combined application of two liposomes exerted a synergistic effect and prominently promoted cell proliferation and migration. Application of the dual liposomal ointment on a deep partial-thickness burn model stimulated wound closure (p < 0.001), promoted skin appendage formation and increased collagen production, thus improving healing quality. Finally, it was demonstrated that TRA significantly up-regulated the expression of EGFR and HB-EGF to enhance the therapeutic effect of EGF. Therefore, the dual liposomal ointment is a promising topical therapeutic for burn treatment.
Subject(s)
Burns/physiopathology , Epidermal Growth Factor/administration & dosage , Epidermal Growth Factor/pharmacology , Mechanical Phenomena , Tretinoin/administration & dosage , Tretinoin/pharmacology , Wound Healing/drug effects , Animals , Cell Line , Cell Movement/drug effects , Cell Proliferation/drug effects , Epidermal Growth Factor/metabolism , Epidermal Growth Factor/toxicity , Humans , Liposomes , Permeability , Rats , Skin/drug effects , Skin/metabolism , Tretinoin/metabolism , Tretinoin/toxicityABSTRACT
Spinal cord injury (SCI) routinely causes the immediate loss and disruption of neurons followed by complicated secondary injuries, including inflammation, oxidative stress, and dense glial scar formation. Inhibitory factors in the lesion scar and poor intrinsic neural regeneration capacity restrict functional recovery after injury. Minocycline, which has neuroprotective activity, can alleviate secondary injury, but the long-term administration of this drug may cause toxicity. Polysialic acid (PSA) is a large cell-surface carbohydrate that is critical for central nervous system development and is capable of promoting precursor cell migration, axon path finding, and synaptic remodeling; thus, PSA plays a vital role in tissue repair and regeneration. Here, we developed a PSA-based minocycline-loaded nanodrug delivery system (PSM) for the synergistic therapy of spinal cord injury. The prepared PSM exerted marked anti-inflammatory and neuroprotective activities both in vitro and in vivo. The administration of PSM could significantly protect neurons and myelin sheaths from damage, reduce the formation of glial scar, recruit endogenous neural stem cells to the lesion site, and promote the regeneration of neurons and the extension of long axons throughout the glial scar, thereby largely improving the locomotor function of SCI rats and exerting a superior therapeutic effect. The findings might provide a novel strategy for SCI synergistic therapy and the utilization of PSA in other central nervous system diseases.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Drug Carriers/therapeutic use , Minocycline/therapeutic use , Nerve Regeneration/drug effects , Neuroprotective Agents/therapeutic use , Sialic Acids/therapeutic use , Spinal Cord Injuries/drug therapy , Animals , Anti-Inflammatory Agents/therapeutic use , Micelles , Neurons/cytology , Neurons/drug effects , Neurons/pathology , Rats , Spinal Cord Injuries/pathology , Spinal Cord Injuries/physiopathologyABSTRACT
Both targeted and stimuli-sensitive drug-delivery systems (DDSs) have been developed to augment antitumor effects. However, lack of knowledge regarding tumor tissue targeting and different effects of the stimuli-sensitive DDSs in orthotropic and ectopic tumors have impeded further advances in their clinical applications. Herein, we first reported a pH-triggered micelle with sialic acid (SA)-driven targeting ability (SA-poly(ethylene glycol)-hydrazone linker-doxorubicin (DOX), SPD). The SPD micelles encapsulated with DOX (SPDD) showed sustained drug release over 48 h in response to the pH gradient in vivo, slow under physical conditions and accelerated in the acid tumor microenvironment. In addition, the SPD micelles showed 2.3-fold higher accumulation in tumors after 48 h compared to the micelles lacking the SA moiety. The overexpression of E-selectin on the inflammatory vascular endothelial cells surrounding the tumors increased the accumulation of SPD micelles in tumor tissues, whereas that on the tumor cells increased the internalization of micelles. Consequently, SPDD micelles exerted remarkable antitumor effects in both orthotopic and ectopic models. Application of SPDD micelles in the in situ model reduced the tumor volume (77.57 mm3 vs 62.13 mm3) and metastasis after treatment for 25 days. These results suggest that SA-driven targeted DDS with a pH-responsive switch has the potential to treat hepatocarcinoma effectively both ectopically and orthotopically.
Subject(s)
Antineoplastic Agents/administration & dosage , Carcinoma, Hepatocellular/drug therapy , Drug Delivery Systems/methods , Liver Neoplasms/drug therapy , Micelles , N-Acetylneuraminic Acid/chemistry , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Survival/drug effects , Doxorubicin/administration & dosage , Doxorubicin/chemistry , Doxorubicin/toxicity , Drug Carriers/chemistry , Female , Humans , Hydrogen-Ion Concentration , Liver Neoplasms/pathology , Mice , Mice, Inbred BALB CABSTRACT
Scaffold-based tissue engineering is widely used for spinal cord injury (SCI) treatment by creating supporting and guiding neuronal tissue regeneration. However, how to enhance the axonal regeneration capacity following SCI still remains a challenge. Polysialic acid (PSA), a natural, biodegradable polysaccharide, has been increasingly explored for controlling central nervous system (CNS) development by regulating cell adhesive properties and promoting axonal growth. Here, a polycaprolactone (PCL)/PSA hybrid nanofiber scaffold encapsulating glucocorticoid methylprednisolone (MP) is developed for SCI treatment. Rat models with spinal cord transection is established and the PCL/PSA/MP scaffold is transplanted into lesion area. PCL/PSA/MP scaffold decreases tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) release by inhibiting ionized calcium-binding adapter molecule 1 (Iba1) positive microglia/macrophage activation and reduces apoptosis-associated Caspase-3 protein expression. In addition, the PCL/PSA/MP scaffold inhibits axonal demyelination and glial fibrillary acidic protein (GFAP) expression, increases neurofilament 200 (NF-200) expression and improves functional outcome by Basso, Beattie and Bresnahan (BBB) test. These results demonstrate the therapeutic potential of PSA hybrid nanofiber scaffold in promoting axonal growth and enhancing the functional recovery following SCI. STATEMENT OF SIGNIFICANCE: Scaffold-based tissue engineering is widely used for spinal cord injury (SCI) treatment by creating supporting and guiding neuronal tissue regeneration. And how to enhance the axonal regeneration capacity following SCI still remains a challenge. Polysialic acid (PSA), a natural, biodegradable polysaccharide, has been increasingly explored for controlling central nervous system (CNS) development by regulating cell adhesive properties and promoting axonal growth. However, in vivo therapeutic effect of PSA scaffolds towards SCI is still lack of evidence and needs to be further explored. In this study, a novel electrospun polycaprolactone/PSA scaffold loaded with methylprednisolone (MP) was developed to achieve efficient therapeutic effects towards SCI. And we believe that it broadens the application of PSA for SCI treatment.
Subject(s)
Nanofibers/chemistry , Nerve Regeneration/drug effects , Polyesters/chemistry , Sialic Acids/chemistry , Spinal Cord Injuries/therapy , Animals , Animals, Newborn , Apoptosis , Astrocytes/metabolism , Axons/physiology , Caspase 3/metabolism , Cell Adhesion , Cell Line, Tumor , Cell Proliferation , Cell Survival , Glucocorticoids/administration & dosage , Humans , Interleukin-6/metabolism , Methylprednisolone/administration & dosage , Rats , Rats, Sprague-Dawley , Spinal Cord/pathology , Tissue Engineering , Tissue Scaffolds/chemistry , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Based on the abnormally increased expression of CD44 receptors on renal tubule epithelial cells during ischemia/reperfusion-induced acute kidney injury (AKI), we developed a hyaluronic acid-curcumin (HA-CUR) polymeric prodrug targeting to epithelial cells and then relieving oxidative stress damages. The water solubility of HA-CUR was significantly enhanced and approximately 27-fold higher than that of CUR. Cellular uptake test showed HA-CUR was preferably internalized by H2O2-pretreated tubular epithelial (HK-2) cells compared with free CUR benefiting from the specific binding between HA and CD44 receptors. Biodistribution results further demonstrated the increased accumulation of HA-CUR in kidneys with 13.9-fold higher than that of free CUR. Pharmacodynamic studies indicated HA-CUR effectively ameliorated AKI, and the exact mechanism was that HA-CUR protected renal tubule epithelial cells from oxidative stress damage via inhibiting PtdIns3K-AKT-mTOR signaling pathway. Taken together, this study provides a new therapeutic strategy for the treatment of AKI based on the pathogenesis of the disease.
Subject(s)
Curcumin/pharmacology , Epithelial Cells/drug effects , Hyaluronan Receptors/antagonists & inhibitors , Hyaluronic Acid/pharmacology , Kidney Tubules/drug effects , Oxidative Stress/drug effects , Prodrugs/pharmacology , Cell Survival/drug effects , Cells, Cultured , Curcumin/chemistry , Epithelial Cells/metabolism , Epithelial Cells/pathology , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/metabolism , Human Umbilical Vein Endothelial Cells/pathology , Humans , Hyaluronan Receptors/metabolism , Hyaluronic Acid/chemistry , Hydrogen Peroxide/pharmacology , Kidney Tubules/metabolism , Kidney Tubules/pathology , Molecular Structure , Myocardial Reperfusion Injury/drug therapy , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/pathology , Prodrugs/chemical synthesis , Prodrugs/chemistry , SolubilityABSTRACT
Rheumatoid arthritis (RA) patients have suffered from the current drug therapeutic regimen because of its high toxicity and the absence of bone regeneration for existing erosion, seriously affecting the quality of life. Herein, a sialic acid-dextran-octadecanoic acid (SA-Dex-OA) conjugate was synthesized to form micelles with a 55.06 µg mL-1 critical micelle concentration. The obtained micelles can encapsulate a disease-modifying anti-rheumatic drug, methotrexate (MTX), with 4.28% (w/w) drug content, featuring sustained drug release behavior over 48 h. In vitro and in vivo studies showed that SA-Dex-OA micelles significantly improved accumulation and transportation through a combination of SA and E-selectin receptors in inflamed cells and arthritic paws highly expressing E-selectin. MTX-loaded SA-Dex-OA micelles not only significantly inhibited the inflammatory response, but also diminished the adverse effects of MTX, as reflected by the reduced alanine aminotransferase, aspartate aminotransferase, creatinine, and urea nitrogen levels. Most importantly, the bone mineral density in rats treated with MTX-loaded SA-Dex-OA micelles was significantly higher as compared to in those treated with free MTX and Dex-OA/MTX micelles (increasing from 391.4 to 417.4 to 492.7 mg cc-1), benefiting from the effects of endogenous sialic acid in promoting MC3T3-E1 cell differentiation and mineralization. It is anticipated that SA-based micelles with bone repair activities have great potential for RA treatment and other metabolic bone diseases with serious bone erosion.
Subject(s)
Arthritis, Rheumatoid/drug therapy , Bone Density , Drug Carriers/chemistry , Methotrexate/administration & dosage , Micelles , N-Acetylneuraminic Acid/chemistry , 3T3 Cells , Animals , Dextrans/chemistry , Human Umbilical Vein Endothelial Cells , Humans , Mice , Quality of Life , Rats , Rats, Wistar , Stearic Acids/chemistry , Tissue DistributionABSTRACT
In an attempt to improve therapeutic efficacy of dexamethasone (DXM)-loaded solid lipid nanoparticles (NPs) for renal ischemia-reperfusion injury (IRI)-induced acute renal injury (AKI), sialic acid (SA) is used as a ligand to target the inflamed vascular endothelium. DXM-loaded SA-conjugated polyethylene glycol (PEG)ylated NPs (SA-NPs) are prepared via solvent diffusion method and show the good colloidal stability. SA-NPs reduce apoptotic human umbilical vein endothelial cells (HUVECs) via downregulating oxidative stress-induced Bax, upregulating Bcl-xL, and inhibiting Caspase-3 and Caspase-9 activation. Cellular uptake results suggest SA-NPs can be specifically internalized by the inflamed vascular endothelial cells (H2O2-pretreated HUVECs), and the mechanism is associated with the specific binding between SA and E-selectin receptor expressed on the inflamed vascular endothelial cells. Bio-distribution results further demonstrated the enhanced renal accumulation of DXM is achieved in AKI mice treated with SA-NPs, and its content is 2.70- and 5.88-fold higher than those treated with DXM and NPs at 6 h after intravenous administration, respectively. Pharmacodynamic studies demonstrate SA-NPs effectively ameliorate renal functions in AKI mice, as reflected by improved blood biochemical indexes, histopathological changes, oxidative stress levels and pro-inflammatory cytokines. Moreover, SA-NPs cause little negative effects on lymphocyte count and bone mineral density while DXM leads to severe osteoporosis. It is concluded that SA-NPs provide an efficient and targeted delivery of DXM for ischemia-reperfusion-induced injury-induced AKI, with improved therapeutic outcomes and reduced adverse effects.
Subject(s)
Acute Kidney Injury/drug therapy , Drug Carriers/chemistry , Endothelium, Vascular/drug effects , Lipids/chemistry , N-Acetylneuraminic Acid/chemistry , Nanoparticles/chemistry , Reperfusion Injury/drug therapy , Acute Kidney Injury/metabolism , Animals , Caspase 3/metabolism , Cell Line , Dexamethasone/pharmacology , E-Selectin/metabolism , Endothelium, Vascular/metabolism , Human Umbilical Vein Endothelial Cells , Humans , Kidney/drug effects , Kidney/metabolism , Male , Mice , Mice, Inbred ICR , Nanoparticles/administration & dosage , Oxidative Stress/drug effects , Polyethylene Glycols/chemistry , Reperfusion Injury/metabolism , bcl-2-Associated X Protein/metabolism , bcl-X Protein/metabolismABSTRACT
The effective treatment for acute kidney injury (AKI) is currently limited, and care is primarily supportive. Sialic acid (SA) is main component of Sialyl Lewisx antigen on the mammalian cell surface, which participates in E-selectin binding. Therefore, dexamethasone(DXM)-loaded E-selectin-targeting sialic acid-polyethylene glycol-dexamethasone (SA-PEG-DXM/DXM) conjugate micelles are designed for ameliorating AKI. The conjugates are synthesized via the esterification reaction between PEG and SA or DXM, and can spontaneously form micelles in an aqueous solution with a 65.6 µg/mL critical micelle concentration. Free DXM is incorporated into the micelles with 6.28 ± 0.21% drug loading content. In vitro DXM release from SA-PEG-DXM/DXM micelles can be prolonged to 48h. Much more SA-PEG-DXM micelles can be internalized by lipopolysaccharide (LPS)-activated human umbilical vein endothelial cells (HUVECs) in comparison to PEG-DXM micelles due to specific interaction between SA and E-selectin expressed on HUVECs, and consequently more SA-PEG-DXM micelles are accumulated in the kidney of AKI murine model. Furthermore, SA in SA-PEG-DXM conjugates can significantly ameliorate LPS-induced production of pro-inflammatory cytokines via suppressing LPS-activated Beclin-1/Atg5-Atg12-mediated autophagy to attenuate toxicity. Compared with free DXM and PEG-DXM/DXM micelles, SA-PEG-DXM/DXM micelles show better therapeutical effects, as reflected by the improved renal function, histopathological changes, pro-inflammatory cytokines, oxidative stress and expression of apoptotic related proteins.
Subject(s)
Acute Kidney Injury/drug therapy , Anti-Inflammatory Agents/metabolism , Dexamethasone/metabolism , E-Selectin/metabolism , Molecular Targeted Therapy/methods , N-Acetylneuraminic Acid/metabolism , Polyethylene Glycols/metabolism , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/adverse effects , Dexamethasone/administration & dosage , Dexamethasone/adverse effects , Disease Models, Animal , Endocytosis , Histocytochemistry , Human Umbilical Vein Endothelial Cells , Humans , Kidney/pathology , Kidney Function Tests , Mice , Micelles , N-Acetylneuraminic Acid/administration & dosage , Polyethylene Glycols/administration & dosage , Treatment OutcomeABSTRACT
The development of combinational anti-tumor therapy is of great value. Here, the thermal-sensitive and hepatic tumor cell targeting peptide-A54 modified polymer, A54-poly(ethylene glycol)-g-poly(acrylamide-co-acrylonitrile) (A54-PEG-g-p(AAm-co-AN)) can self-assemble into an 80 nm-sized micelle, which shows a thermal-sensitive behavior with an upper critical solution temperature (UCST) of 43 °C. This self-assembled and targeted A54-PEG-g-p(AAm-co-AN) micelle can co-encapsulate anti-tumor drug doxorubicin (DOX) and magnetic nanoparticles (MNPs) taking advantage of the hydrophobic core of the core-shell micellar structure, when the temperature is lower than 43 °C. A much higher accumulation of the MNPs@A54-PEG-g-p(AAm-co-AN) to the tumor navigated by the A54 targeting peptide is achieved. Due to the thermal-agent effect of the accumulated MNPs in tumor, the mild microwave (8 W) applied afterwards specifically elevates the local tumor temperature by 13 °C, compared to 6 °C without MNPs accumulation in 30 min. The greater temperature rise resulted from the thermal-agent effect of MNPs doesn't only activate the drug release inside tumor cells, but also achieve an augmented hyperthermia. A mild microwave activated, chemo-thermal combinational tumor therapy is thus developed.
Subject(s)
Antibiotics, Antineoplastic/therapeutic use , Delayed-Action Preparations/chemistry , Doxorubicin/therapeutic use , Liver Neoplasms/therapy , Magnetite Nanoparticles/therapeutic use , Micelles , Acrylic Resins/chemistry , Animals , Antibiotics, Antineoplastic/administration & dosage , Cell Line, Tumor , Combined Modality Therapy , Doxorubicin/administration & dosage , Female , Humans , Hyperthermia, Induced , Liver/drug effects , Liver/pathology , Liver Neoplasms/pathology , Magnetite Nanoparticles/administration & dosage , Magnetite Nanoparticles/ultrastructure , Mice, Inbred BALB C , Mice, Nude , Microwaves , Peptides/chemistry , Polyethylene Glycols/chemistryABSTRACT
Acute lung injury (ALI) is a critical illness without effective therapeutic modalities currently. Recent studies indicated potential efficacy of statins for ALI, while high-dose statins was suggested to be significant for attenuating inflammation in vivo. Therefore, a lung-targeted drug delivery system (DDS) delivering simvastatin (SV) for ALI therapy was developed, attempting to improve the disease with a decreased dose and minimize potential adverse effects. SV-loaded nanostructured lipid carriers (SV/NLCs) with different size were prepared primarily. With particle size increasing from 143.7 nm to 337.8 nm, SV/NLCs showed increasing drug-encapsulated efficiency from 66.70% to 91.04%. Although larger SV/NLCs exhibited slower in vitro cellular uptake by human vascular endothelial cell line EAhy926 at initial stage, while in vivo distribution demonstrated higher pulmonary accumulation of the larger ones. Thus, the largest size SV/NLCs (337.8 nm) were conjugated with intercellular adhesion molecule 1 (ICAM-1) antibody (anti-ICAM/SV/NLCs) for lung-targeted study. The anti-ICAM/SV/NLCs exhibited ideal lung-targeted characteristic in lipopolysaccharide-induced ALI mice. In vivo i.v. administration of anti-ICAM/SV/NLCs attenuated TNF-α, IL-6 and inflammatory cells infiltration more effectively than free SV or non-targeted SV/NLCs after 48-h administration. Significant histological improvements by anti-ICAM/SV/NLCs were further revealed by H&E stain. Therefore, ICAM-1 antibody-conjugated NLCs may represent a potential lung-targeted DDS contributing to ALI therapy by statins.
Subject(s)
Acute Lung Injury/drug therapy , Drug Carriers/administration & dosage , Drug Delivery Systems/methods , Intercellular Adhesion Molecule-1/administration & dosage , Nanostructures/administration & dosage , Simvastatin/administration & dosage , A549 Cells , Acute Lung Injury/metabolism , Animals , Antibodies/administration & dosage , Antibodies/chemistry , Antibodies/metabolism , Dose-Response Relationship, Drug , Drug Carriers/chemistry , Humans , Intercellular Adhesion Molecule-1/chemistry , Intercellular Adhesion Molecule-1/metabolism , Male , Mice , Mice, Inbred BALB C , Nanostructures/chemistry , Particle Size , Random Allocation , Simvastatin/chemistry , Simvastatin/metabolismABSTRACT
Specific delivery of chemotherapy drugs and magnetic resonance imaging (MRI) contrast agent into tumor cells is one of the issues to highly efficient tumor targeting therapy and magnetic resonance imaging. Here, A54 peptide-functionalized poly(lactic-co-glycolic acid)-grafted dextran (A54-Dex-PLGA) was synthesized. The synthesized A54-Dex-PLGA could self-assemble to form micelles with a low critical micelle concentration of 22.51 µg. mL-1 and diameter of about 50 nm. The synthetic A54-Dex-PLGA micelles can encapsulate doxorubicin (DOX) as a model anti-tumor drug and superparamagnetic iron oxide (SPIO) as a contrast agent for MRI. The drug-encapsulation efficiency was about 80% and the in vitro DOX release was prolonged to 72 hours. The DOX/SPIO-loaded micelles could specifically target BEL-7402 cell line. In vitro MRI results also proved the specific binding ability of A54-Dex-PLGA/DOX/SPIO micelles to hepatoma cell BEL-7402. The in vivo MR imaging experiments using a BEL-7402 orthotopic implantation model further validated the targeting effect of DOX/SPIO-loaded micelles. In vitro and in vivo anti-tumor activities results showed that A54-Dex-PLGA/DOX/SPIO micelles revealed better therapeutic effects compared with Dex-PLGA/DOX/SPIO micelles and reduced toxicity compared with commercial adriamycin injection.