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Hydrogel containing nanoparticle-stabilized liposomes for topical antimicrobial delivery.

ABSTRACT: Adsorbing small charged nanoparticles onto the outer surfaces of liposomes has become an effective strategy to stabilize liposomes against fusion prior to "seeing" target bacteria, yet allow them to fuse with the bacteria upon arrival at the infection sites. As a result, nanoparticle-stabilized liposomes have become an emerging drug delivery platform for treatment of various bacterial infections. To facilitate the translation of this platform for clinical tests and uses, herein we integrate nanoparticle-stabilized liposomes with hydrogel technology for more effective and sustained topical drug delivery. The hydrogel formulation not only preserves the structural integrity of the nanoparticle-stabilized liposomes, but also allows for controllable viscoeleasticity and tunable liposome release rate. Using Staphylococcus aureus bacteria as a model pathogen, we demonstrate that the hydrogel formulation can effectively release nanoparticle-stabilized liposomes to the bacterial culture, which subsequently fuse with bacterial membrane in a pH-dependent manner. When topically applied onto mouse skin, the hydrogel formulation does not generate any observable skin toxicity within a 7-day treatment. Collectively, the hydrogel containing nanoparticle-stabilized liposomes hold great promise for topical applications against various microbial infections.

SUBMITTER: Gao W

PROVIDER: S-EPMC4004330 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Hydrogel containing nanoparticle-stabilized liposomes for topical antimicrobial delivery.

Gao Weiwei W Vecchio Drew D Li Jieming J Zhu Jingying J Zhang Qiangzhe Q Fu Victoria V Li Jiayang J Thamphiwatana Soracha S Lu Diannan D Zhang Liangfang L

ACS nano 20140205 3

Adsorbing small charged nanoparticles onto the outer surfaces of liposomes has become an effective strategy to stabilize liposomes against fusion prior to "seeing" target bacteria, yet allow them to fuse with the bacteria upon arrival at the infection sites. As a result, nanoparticle-stabilized liposomes have become an emerging drug delivery platform for treatment of various bacterial infections. To facilitate the translation of this platform for clinical tests and uses, herein we integrate nano ...[more]

PMID: 24483239

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Project description:Topical ophthalmic antibiotics show low efficacy due to the well-known physiological defense mechanisms of the eye, which prevents the penetration of exogenous substances. Here, we aimed to incorporate besifloxacin into liposomes containing amines as positively charged additives and to evaluate the influence of this charge on drug delivery in two situations: (i) iontophoretic and (ii) passive treatments. Hypothesis are (i) charge might enhance the electromigration component upon current application improving penetration efficiency for a burst drug delivery, and (ii) positive charge might prolong formulation residence time, hence drug penetration. Liposomes elaborated with phosphatidylcholine (LP PC) or phosphatidylcholine and spermine (LP PC: SPM) were stable under storage at 6 ºC for 30 days, showed mucoadhesive characteristics, and were non-irritant, according to HET-CAM tests. Electron paramagnetic resonance spectroscopy measurements showed that neither the drug nor spermine incorporations produced evident alterations in the fluidity of the liposome's membranes, which retained their structural stability even under iontophoretic conditions. Mean diameter and zeta potential were 177.2 ± 2.7 nm and - 5.7 ± 0.3 mV, respectively, for LP PC; and 175.4 ± 1.9 nm and + 19.5 ± 1.0 mV, respectively, for LP PC:SPM. The minimal inhibitory concentration (MIC) and the minimal bactericide concentration (MBC) of the liposomes for P. aeruginosa showed values lower than the commercial formulation (Besivance). Nevertheless, both formulations presented a similar increase in permeability upon the electric current application. Hence, liposome charge incorporation did not prove to be additionally advantageous for iontophoretic therapy. Passive drug penetration was evaluated through a novel in vitro ocular model that simulates the lacrimal flow and challenges the formulation resistance in the passive delivery situation. As expected, LP PC: SPM showed higher permeation than the control (Besivance). In conclusion, besifloxacin incorporation into positively charged liposomes improved passive topical delivery and can be a good strategy to improve topical ophthalmic treatments.

Project description:The targeted local delivery of anticancer therapeutics offers an alternative to systemic chemotherapy for oral cancers not amenable to surgical excision. However, epithelial barrier function can pose a challenge to their passive topical delivery. The charged, deformable liposomes-"iontosomes"-described here are able to overcome the buccal mucosal barrier via a combination of the electrical potential gradient imposed by iontophoresis and their shape-deforming characteristics. Two chemotherapeutic agents with very different physicochemical properties, cisplatin (CDDP) and docetaxel (DTX), were co-encapsulated in cationic iontosomes comprising 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and Lipoid-S75. The entrapment of CDDP was improved by formulating it in anionic reverse micelles of dipalmitoyl-sn-glycero-3-phospho-rac-glycerol sodium (DPPG) prior to loading in the iontosomes. Cryo-TEM imaging clearly demonstrated the iontosomes' electroresponsive shape-deformable properties. The in vitro transport study using porcine mucosa indicated that iontosomes did not enter the mucosa without an external driving force. However, anodal iontophoresis resulted in significant amounts of co-encapsulated CDDP and DTX being deposited in the buccal mucosa; e.g., after current application for 10 min, the deposition of CDDP and DTX was 13.54 ± 1.78 and 10.75 ± 1.75 μg/cm2 cf. 0.20 ± 0.07 and 0.19 ± 0.09 μg/cm2 for the passive controls-i.e., 67.7- and 56.6-fold increases-without any noticeable increase in their transmucosal permeation. Confocal microscopy confirmed that the iontosomes penetrated the mucosa through the intercellular spaces and that the penetration depth could be controlled by varying the duration of current application. Overall, the results suggest that the combination of topical iontophoresis with a suitable nanocarrier system can be used to deliver multiple "physicochemically incompatible" chemotherapeutics selectively to oral cancers while decreasing the extent of systemic absorption and the associated risk of side effects.

Project description:BackgroundFumaria species (Fumariacea) has traditionally been used in wound healing in Iranian folk medicine. However, with the discovery of newer agents, its use has faded off into total obscurity. This study explored the wound healing potential of a gel containing 10% Fumaria vaillantii Loisel through topical application of total extract in a model of excisional as well as incisional wound healing in albino Wistar rats.MethodsRats were anesthetized, and excisional skin wound was established using a sterilized surgical scissors. The animals were then treated with 10% F.vaillantii topical gel formulation along with the gel base. The treatments were administered once a day after the injury for 21 days. For topical treatment, the hydrogel was formulated and evaluated for chemical and physical characteristics. Histopathological analysis with hematoxylin and eosin (H&E) was used for microscopic examination of the skin tissues on 21-day-old sections of excision wound. To verify collagen formation, hydroxyproline determination was performed 21 days post wound healing. Breaking strength was determined in a 10-day-old incision wound by the uniaxial tensile test.ResultsTopical administration of F.vaillantii gel formulation significantly enhanced skin wound closure on the 6th post-wounding day compared to both gel base and the negative control, indicating an accelerated wound healing process, while a significant difference was observed on 10th and 14th post -wound days in F.vaillantii treatment compared to the negative control groups. Gel formulation prepared with a 10% F. vaillantii extract exhibited a response in terms of wound epithelialization, angiogenesis and number of hair follicles at wound area better than the gel base on the 21st post-wound day. Application of gel base produced further advantages by increasing hydroxyproline content and collagen fiber thickness. Our results on incision wound model were supported by histopathological data indicating the role of gel base in the enhancement of breaking strength.ConclusionTraditional use of Fumaria species in the skin diseases was justified in this study by revealing the increase in wound healing activity after hydrogel containing F. vaillantii total extract administration.

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Hydrogel containing nanoparticle-stabilized liposomes for topical antimicrobial delivery.

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Hydrogel containing nanoparticle-stabilized liposomes for topical antimicrobial delivery.

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