Is the use of Pentoxifylline and Tocopherol effective in the treatment of Osteoradionecrosis of the jaws or for the treatment of medicationosteonecrosis of the jaw? An overview.

PURPOSE: The aim of the present study was to determine the methodological quality of systematic reviews that evaluated the effectiveness of pentoxifylline and tocopherol (PENTO) in the treatment of osteoradionecrosis of the jaw (ORNJ) and medication-related osteonecrosis of the jaw (MRONJ). METHODS: Searches were performed in Databases including PubMed, Scopus, LILACS, DARE, Cochrane Library, and SIGLE through OpenGrey until March 2024, were evaluated by two independent reviewers to answer the following question: Is the use of PENTO protocol effective in the treatment of ORNJ or for the treatment of MRONJ? RESULTS: A total of 256 articles were initially identified; however, following the use of appropriate inclusion and exclusion criteria, five systematic reviews were identified for detailed analysis. The final study sample comprised 588 patients: 397 patients with ORN and 197 patients with MRONJ who were treated with PENTO. The total recovery of individuals who used the PENTO protocol was 62,2 % for ORN and 100 % for MRONJ, with a follow-up period of 1 month to 10 years. The methodological quality of the studies was assessed using the AMSTAR 2 tool, in which four were of low quality and 1 moderate quality. CONCLUSION: The treatment of ORN and MRONJ with pentoxifylline and tocopherol has shown good results in the studies presented, with a partial or total reduction in bone exposure. However, the low quality of the relevant reports highlights the need for primary and secondary studies with better methodological rigor to reduce bias and provide reassurance for this treatment option.

Incorporation of tocopherol acetate-containing particles in acrylic bone cement.

Acrylic bone cement (BC) is used in orthopaedic surgery to anchor cemented prostheses to bone. Association of antioxidant molecules to BC may suppress reactive species injury which contributes to implant failure. Tocopherol acetate (ATA)-loaded polymethylmethacrylate (PMMA) particles (ATA(PMMA)) were prepared by single emulsion solvent evaporation technique and were incorporated into BC. An encapsulation efficiency of 84% (w/w) was obtained and drug release studies showed distinct ATA release profiles and mechanisms before and after particle incorporation into BC. Experimental data, analysed using first-order, Higuchi and Korsmeyer-Peppas models revealed that ATA was released from particles by a Fickian diffusion mechanism while a non-Fickian transport was observed upon particle incorporation in BC. There were no changes in the mechanical properties of BC specimens containing ATA(PMMA) particles, in contrast to what was observed when ATA was loaded directly into BC. Overall, ATA(PMMA) particles are potential carriers for the incorporation of an antioxidant drug into BC.

Hyaluronic-acid-based ß-cyclodextrin grafted copolymers as biocompatible supramolecular hosts to enhance the water solubility of tocopherol.

Hyaluronic acid (HA), a common biopolymer found in the extracellular fluid, was grafted with ß-cyclodextrin (ß-CD) to form a composite polymer that could form inclusion complexes with tocopherol (VE), enhancing its water-solubility and serving as a model drug delivery system. Herein, different copolymers were prepared with varying HA:ß-CD ratios and characterized. VE loading capacity was directly correlated with increased ß-CD composition in the polymers and morphological changes were observed upon VE binding. The host materials and their VE inclusion complexes are not cytotoxic, and are thus useful for VE and drug delivery.

Structure-activity relationship of serotonin derived tocopherol lipids.

Tocopherol-based lipids are widely used for nucleic acid delivery. Using tocopherol molecules, we designed and synthesized 5-HT functionalized lipids by tethering 5-hydroxytryptamine (5-HT), a small molecule ligand as the head group to a natural amphiphilic molecule namely α-tocopherol (Vitamin E). This is with the aim of delivering nucleic acids specifically into cells expressing the serotonin receptors (5-hydroxytryptamine[5-HT]) which are abundant in the central nervous system. In order to achieve target recognition, we adopted an approach wherein two structurally different lipid molecules having serotonin as the head group was conjugated to tocopherol via different linkers thus generating lipids with either free -NH2 or -OH moiety. The corresponding lipids designated as Lipid A (Tocopheryl carbonate serotonin-NH2) and Lipid B (Tocopheryl 2-hydroxy propyl ammonium serotonin-OH), were formulated with co-lipids 1,2-dioleoyl-sn-glycero-3-phosphatidyl-ethanolamine (DOPE) and 1,2-dioleoyl-sn-glycero-sn-3-phosphatidylcholine (DOPC) and evaluated for their ability to deliver plasmid DNA through reporter gene expression assays in vitro. Furthermore, the physicochemical characteristics and cellular interactions of the formulations were examined using serotonin-receptor enriched cells in order to distinguish the structural and functional attributes of both lipids. Cell-based gene expression studies reveal that in comparison to Lipid A, a formulation of Lipid B prepared with DOPE as the co-lipid, contributes to efficient uptake leading to significant enhancement in transfection. Specific interactions explored by molecular docking studies suggests the role of the hydroxyl moiety and the enantiospecific significance of serotonin- conjugated tocopherol lipids in recognizing these receptors thus signifying a promising lipid-based approach to target the serotonin receptors in the central nervous system.

Ability of antioxidant liposomes to prevent acute and progressive pulmonary injury.

We recently showed that acute oxidant-related lung injury (ALI) in rats after application of 2-chloroethyl ethyl sulfide (CEES) is attenuated by the airway instillation of antioxidants. We investigated whether intratracheal administration of antioxidant-containing liposomes immediately after instillation of CEES would attenuate short-term as well as long-term (fibrotic) effects of CEES-induced lung injury. In the acute injury model (4 h after injury), N-acetylcysteine (NAC)-containing liposomes were protective and reduced to baseline levels both the lung permeability index and the appearance of proinflammatory mediators in bronchoalveolar lavage fluids from CEES-exposed lungs. Similar results were obtained when rat alveolar macrophages were incubated in vitro with either CEES or lipopolysaccharide in the presence of NAC-liposomes. When lung fibrosis 3 weeks after CEES was quantitated by using hydroxyproline content, liposomes containing NAC or NAC + glutathione had no effects, but liposomes containing alpha/gamma-tocopherol alone or with NAC significantly suppressed the increase in lung hydroxyproline. The data demonstrate that delivery of antioxidants via liposomes to CEES-injured lungs is, depending on liposomal content, protective against ALI, prevents the appearance of proinflammatory mediators in bronchoalveolar fluids, and suppresses progressive fibrosis. Accordingly, the liposomal strategy may be therapeutically useful in CEES-induced lung injury in humans.

Tocopherol-loaded transfersomes: In vitro antioxidant activity and efficacy in skin regeneration.

Transfersomes were prepared by using different polysorbates (i.e., Tween 20, 40, 60 and 80) and loaded with tocopherol acetate, a naturally-occurring phenolic compound with antioxidant activity. The vesicles showed unilamellar morphology, small size (∼85 nm), low polydispersity index (≤0.27), and high entrapment efficiency, which increased as a function of the length of the Tween fatty acid chain (from 72% to 90%). The long-term stability of the formulations was evaluated by means of the Turbiscan™ technology, which indicated their good stability, irrespective of the Tween used. The vesicles efficiently delivered tocopherol to the skin, and showed biocompatibility in vitro in keratinocytes and fibroblasts. Regardless of the Tween used, the transfersomes were able to protect skin cells from the oxidative damage induced by hydrogen peroxide. Additionally, transfersomes promoted cell proliferation and migration, which resulted in an acceleration of skin wound closure. These results demonstrated that tocopherol-loaded transfersomes bear potential as topical delivery system with antioxidant activity and wound healing properties.

Isolated lichen planus of the lip.

Oral lichen planus (OLP) is a relatively common disorder whose cause is still unknown. It occurs mostly on the buccal mucosa, but the gingivae, tongue, floor of the mouth and retromalar pads may also be affected. It rarely occurs on the lips and usually in association with oral lesions. We report a case series of ten patients with a history of isolated swelling of the lower and/or upper lip, erosions and crusting. General medical history, examination of the oral cavity and recording of signs and symptoms were carried out for each patient. Among the six different clinical variants of OLP described by Andreasen, the atrophic-erosive form was the most common in the course of isolated LP of the lip in our series. Five cases presented HCV hepatitis. A complete remission of lesions was observed in eight patients after topical treatment with clobetasol propionate 0.05 percent and tocopherol oil, while partial improvement was noted in those remaining. Isolated LP of the lip is unusual and presents a diagnostic challenge; however an appropriate differential diagnosis is fundamental. Lesions of the lips might represent a more or less precocious phase of oral involvement. Moreover the reasons for the unique localization on the lips need to be explored. Several variables, including age, duration of lesions, concomitance of other diseases, and genetic predisposition may be involved. Isolated LP of the lip is a well-known condition which responds well to topical treatment with corticosteroids. A thorough medical management and active early treatment are necessary to improve symptoms and might also be a relevant prevention strategy from squamous cell carcinoma risk, although data to fully support this statement still need investigation.

Liposomal or nanoparticle alpha-TEA reduced 66cl-4 murine mammary cancer burden and metastasis.

Efficacy of alpha-TEA formulated in liposome or biodegradable poly(D, L-lactide-co-glycolide) (PLGA) nanoparticle was evaluated in a BALB/c clone 66cl-4 mammary cancer mouse model using oral delivery. alpha-TEA-loaded liposome or nanoparticle at 5 mg, but not 2.5 mg/day, significantly reduced tumor burden (p < 0.001). Both formulations at 5 mg significantly reduced visible lung metastases and lymph node and lung micrometastatic tumor foci. Surprisingly, nanoparticle control mice exhibited significantly reduced tumor burden, lymph node, and lung micrometastatic tumor foci. Both formulations at 5 mg significantly enhanced tumor apoptosis. In summary, liposomes and nanoparticles are effective means for administering the lipophilic anticancer drug alpha-TEA.

Development and evaluation of injectable nanosized drug delivery systems for apigenin.

The purpose of this study was to develop different injectable nanosized drug delivery systems (NDDSs) i.e. liposome, lipid nanocapsule (LNC) and polymeric nanocapsule (PNC) encapsulating apigenin (AG) and compare their characteristics to identify the nanovector(s) that can deliver the largest quantity of AG while being biocompatible. Two liposomes with different surface characteristics (cationic and anionic), a LNC and a PNC were prepared. A novel tocopherol modified poly(ethylene glycol)-b-polyphosphate block-copolymer was used for the first time for the PNC preparation. The NDDSs were compared by their physicochemical characteristics, AG release, storage stability, stability in serum, complement consumption and toxicity against a human macrovascular endothelial cell line (EAhy926). The diameter and surface charge of the NDDSs were comparable with previously reported injectable nanocarriers. The NDDSs showed good encapsulation efficiency and drug loading. Moreover, the NDDSs were stable during storage and in fetal bovine serum for extended periods, showed low complement consumption and were non-toxic to EAhy926 cells up to high concentrations. Therefore, they can be considered as potential injectable nanocarriers of AG. Due to less pronounced burst effect and extended release characteristics, the nanocapsules could be favorable approaches for achieving prolonged pharmacological activity of AG using injectable NDDS.

Stability studies on colloidal suspensions of polyurethane nanocapsules.

Generally nanocapsules suspensions are a colloidal system in a metastable state, there is aggregation due to attraction and repulsion forces between particles. The objective of this work was to bring the role of the polymeric membrane in the protection of the active drug against damaging caused by external agents and to select the monomer which leads to obtain stable formulation with the highest possible payload of the active drug. The stability testing involving visual aspect, particle size measurement, transmission electron microscopy (TEM) examination, and drug loss was conduced after 6 months of storage at different temperatures (4, 25, and 45 degrees C). The colloidal suspensions of nanocapsules were obtained using the combined interfacial polycondensation and spontaneous emulsification, the technique was used to encapsulate alpha-tocopherol using polyurethanes polymers. It is a one step procedure: An organic phase composed of a water miscible solvent (acetone), lipophilic monomer (Isophorone diisocyanate IPDI), oil, and a lipophilic surfactant, is injected in an aqueous phase containing hydrophilic monomer (diol with various molecular weight: 1,2-ethanediol (ED), 1,4-butanediol (BD), and 1,6-hexanediol (HD)) and hydrophilic emulsifying agent. The water miscible solvent diffuses to the aqueous phase, the oil precipitates as nano-droplets, and the two monomers react at the interface, forming a membrane around the nanoemulsion leading to nanocapsules. A good physical stability of suspensions corresponds to absence of symptoms such as sedimentation or agglomeration, significant size change and alpha-tocopherol degradation due to external agents such as oxygen, temperature, and ultraviolet (UV) irradiation. The size of nanocapsules before storage was about 232 +/- 3, 258 +/- 29, and 312 +/- 4 nm for ED, BD, and HD, respectively. After 6 months of storage, polyurethanes nanocapsules possess good stability against aggregation at 4 and 25 degrees C. Comparing results obtained using different monomers, it reveals that the polyurethane based on HD offers good protection of alpha-tocopherol against damaging caused by the temperature and UV irradiation.

Effect of oxygen plasma treatment on the release behaviors of poly(epsilon-caprolactone) microcapsules containing tocopherol.

The biodegradable poly(epsilon-caprolactone) microcapsules (PCL) containing tocopherol (TC) were prepared by emulsion solvent evaporation method, and microcapsules were treated by oxygen plasma to enhance the hydrophilic microcapsules. The morphologies and thermal properties of the microcapsules were determined by SEM and DSC measurements. The microcapsules studied were characterized by surface free energy or work of adhesion through contact angle measurement. As a result, the features of the microcapsules could be adjusted by manufacturing condition, such as surfactant and core ratio. The surface free energy or work of adhesion of the microcapsules was increased with increasing the time of plasma treatment, which could be attributed to the increased hydrophilic groups during oxygen plasma treatment. The release profile of the microcapsules was determined by UV-vis spectroscopy and the microcapsules containing tocopherol showed the rapid release rate, as compared with untreated ones.

Targeting delivery of tocopherol and doxorubicin grafted-chitosan polymeric micelles for cancer therapy: In vitro and in vivo evaluation.

In this study, we report the development of a novel, redox-sensitive chitosan-based targeted drug delivery system, containing two drugs. We determined whether the synthesized polymeric micelles (HPTOC-DOX) were suitable as a drug carrier. The formation of HPTOC-DOX micelles was confirmed by (1)H NMR. HPTOC-DOX formed micelles of approximately 151.9-311.2nm in size in aqueous solution. Analysis of the drug release profile of HPTOC-DOX in different pH conditions (pH 5.2, 6.2, and 7.4) indicated that DOX was released from HPTOC-DOX micelles at acidic pH (5.2 or 6.2), while almost no DOX was released at pH 7.4. In vitro cell cytotoxicity and hemolysis assays indicated that HPTOC-DOX micelles safely deliver anti-cancer drugs and decrease the cytotoxicity of DOX. In vitro anti-cancer activity assays, confocal laser scanning microscopy analysis of SK-BR-3 cells, and in vivo anti-tumor activity in SK-BR-3-derived tumor-bearing mice were used to evaluate synergistic drug effects and the effect of the targeting peptide (anti-human epidermal growth factor receptor 2 [HER2] target peptide, epitope form; LTVSPWY) on receptor-mediated endocytosis.

Shrapnel nanoparticles loading docetaxel inhibit metastasis and growth of breast cancer.

Metastasis is one of the major obstacles for the successful therapy of breast cancer. To inhibit the metastasis and growth of breast cancer simultaneously, a new docetaxel (DTX) loaded shrapnel nano delivery system with the reduction- and enzyme-sensitive properties was designed and developed. Firstly, methoxy polyethylene glycol-peptide-vitamin E succinate (PPV), a matrix metalloproteinases (MMPs)-sensitive copolymer, was synthesized by conjugating mPEG and vitamin E succinate (VES) using an enzyme-sensitive peptide. Then, DTX loaded methoxy polyethylene glycol-s-s-vitamin E succinate (PSV) micelles (DPM) @ PPV-based liposomes (DPM@PL) were prepared by the incorporation of DPM into the PPV-based liposomes. DPM@PL showed a shrapnel structure with average particle size 113.3 ± 2.7 nm. The drug loading and encapsulation efficiency of DPM@PL were 1.93% and 99.02%, respectively. An obvious burst release (>90%) of drug was observed in the simulated tumor microenvironment with MMPs and reductive glutathione. The cellular uptake and cytotoxicity of DPM@PL in 4T1 cells were significantly enhanced after the pre-treatment of activated MMP-9. Compared with Taxotere(®), DPM@PL remarkably increased the distribution of DTX in lung and tumor of 4T1 tumor-bearing mice, and inhibited the in situ tumor growth and pulmonary metastasis formation effectively through the enhanced DTX-induced apoptosis and the reduced metastasis-promoting proteins expression. Compared with saline group, the inhibitory rates of DPM@PL against tumor volume and lung metastasis were about 81% and 92%, respectively, and it didn't produce the significant systemic toxicity. As a result, DPM@PL could be a promising nano delivery system for the successful therapy of breast cancer.

Pentoxifylline and tocopherol in the management of patients with osteoradionecrosis, the Portsmouth experience.

Osteoradionecrosis of the jaw remains the most problematic consequence of radiotherapy for the management of head and neck cancer. Treatment is often complex and multimodal. New theories on its pathophysiology have allowed the development of potential treatment modalities, including the use of pentoxifylline and tocopherol. In this retrospective case series we examined the outcomes of patients with ORN prescribed pentoxifylline and tocopherol.

Randomized, multicenter trial of a single dose of AS03-adjuvanted or unadjuvanted H1N1 2009 pandemic influenza vaccine in children 6 months to <9 years of age: safety and immunogenicity.

BACKGROUND: During the 2009-2010 influenza pandemic, we evaluated the immunogenicity and safety of different H1N1 2009 pandemic influenza vaccines delivering various viral hemagglutinin (HA) doses with or without AS03 (a tocopherol oil-in-water emulsion-based adjuvant system) in children (NCT00976820). METHODS: Three hundred twenty-two healthy children 6 months to <9 years of age were randomized to receive 2 doses of nonadjuvanted (15 µg or 7.5 µg HA) or adjuvanted vaccine (3.75 µg HA/AS03A or 1.9 µg HA/AS03B), 21 days apart. Blood samples before and after each dose were tested for immune responses using hemagglutination inhibition and microneutralization assays. Safety assessments were done up to day 385. RESULTS: The first dose of both AS03-adjuvanted vaccines elicited strong immune responses (seroprotection rates: 98.3%/99.0%; seroconversion rates: 94.9%/97.0%; geometric mean fold rises: 36.2/33.6), which were higher post-dose 2 (seroprotection rate: 100.0%/100%; seroconversion rate: 100.0%/98.8%; geometric mean fold rise: 157.1/151.6), meeting European regulatory criteria on days 21 and 42. The nonadjuvanted 15 µg HA vaccine also met the regulatory criteria after each dose; the 7.5 µg HA vaccine met them only post-dose 2. Six months post-dose 1, all vaccines except the nonadjuvanted 7.5 µg HA vaccine met European regulatory criteria. Neutralizing antibody response paralleled the hemagglutination inhibition immune response after each dose. Pain at the injection site, lasting 2-3 days, was more common following adjuvanted than nonadjuvanted vaccination. CONCLUSIONS: AS03-adjuvanted H1N1 2009 pandemic influenza vaccine (3.75 µg or 1.9 µg HA), administered as 2 doses, was highly immunogenic, induced long-term immune response to 6 months, with a clinically acceptable safety profile in children aged 6 months to <9 years of age.

Adjuvant System AS03 containing α-tocopherol modulates innate immune response and leads to improved adaptive immunity.

AS03 is an Adjuvant System (AS) containing α-tocopherol and squalene in an oil-in-water (o/w) emulsion. AS03 has been considered for the development of pandemic and seasonal influenza vaccines. Key features of AS03's mode of action were investigated in vivo in mice and ex vivo in human cells. AS03's adjuvant activity was superior to that of aluminium hydroxide and required the spatio-temporal co-localisation of AS03 with the antigen. This requirement coincided with AS03 triggering a transient production of cytokines at the injection site and in the draining lymph nodes (dLNs). The nature of the cytokines produced was consistent with the enhanced recruitment of granulocytes and of antigen-loaded monocytes in the dLNs. The presence of α-tocopherol in AS03 was required for AS03 to achieve the highest antibody response. The presence of α-tocopherol also modulated the expression of some cytokines, including CCL2, CCL3, IL-6, CSF3 and CXCL1; increased the antigen loading in monocytes; and increased the recruitment of granulocytes in the dLNs. Hence, AS03's promotion of monocytes as the principal antigen-presenting cells, and its effects on granulocytes and cytokines, may all contribute to enhancing the antigen-specific adaptive immune response.

Role of MAPK/AP-1 signaling pathway in the protection of CEES-induced lung injury by antioxidant liposome.

We have recently reported that antioxidant liposomes can be used as antidotes for mustard gas induced lung injury in guinea pigs. The maximum protection was achieved with a liposome composed of tocopherols (alpha, gamma, delta) and N-acetylcysteine (NAC) when administered after 5 min of exposure of 2-chloroethyl ethyl sulfide (CEES), a half sulfur mustard gas. We also reported an association of mustard gas-induced lung injury with an activation of MAPK/AP-1 signaling pathway and cell proliferation. The objective of the present study was to investigate whether CEES-induced MAPKs/AP-1 signaling pathway is influenced by antioxidant liposome therapy. A single dose (200 microl) of the antioxidant liposome was administered intratracheally after 5 min of exposure of CEES (0.5 mg/kg). The animals were sacrificed after 1h and 30 days of CEES exposure. Although the liposome treatment did not have any significant effect on the activation of the MAPKs family (ERK1/2, p38 and JNK1/2), it significantly counteracted the CEES-induced activation of AP-1 transcription factors and corresponding increase in the protein levels of Fos, ATF and Jun family members. The liposome treatment significantly blocked the CEES-induced increase in the protein levels of cyclin D1, a cell cycle protein and PCNA, a cell differentiation marker. Furthermore, it protected lung against CEES-induced inflammation and infiltration of neutrophils, eosinophils and erythrocytes in the alveolar space. This suggests that the protective effect of antioxidant liposome against CEES-induced lung damage is mediated via control of AP-1 signaling.

Vitamin E analog, alpha-tocopherol ether-linked acetic acid analog, alone and in combination with celecoxib, reduces multiplicity of ultraviolet-induced skin cancers in mice.

The goals of this study were to determine whether alpha-tocopherol ether-linked acetic acid analog (alpha-TEA), a novel vitamin E analog, and celecoxib, alone or in combination, when administered as a late intervention can reduce the ultraviolet-induced nonmelanoma skin-tumor burden of established tumors, prevent additional tumors from developing, and prevent tumor recurrence once treatments are stopped. Hairless SKH-1 female mice were ultraviolet-irradiated for 24 weeks, divided into treatment groups so that each group had approximately 5.8 tumors/mouse, and then treated with 72 mug of liposome-formulated alpha-TEA by aerosol inhalation, 500 p.p.m. celecoxib in AIN-76 A diet, or a combination of alpha-TEA and celecoxib for 4 weeks. At the end of 4 weeks of treatment, each treatment group was subdivided, with one subgroup continuing to receive treatment and with treatment being stopped in the other. Skin-tumor development was monitored visually throughout the study and by histologic evaluation at the end. After 4 weeks of treatment, all treatments showed statistically significant reductions in tumor number when compared with controls. After termination of treatment, only alpha-TEA prevented a significant increase in tumor recurrence; however, continuous combination treatment resulted in the lowest total number of tumors. In conclusion alpha-TEA is an effective late-stage chemopreventive agent for nonmelanoma skin cancer that exhibits lasting benefits.

Major healing of refractory mandible osteoradionecrosis after treatment combining pentoxifylline and tocopherol: a phase II trial.

BACKGROUND: Osteoradionecrosis (ORN) is a nonhealing wound of the bone that is difficult to manage. Is a treatment combining pentoxifylline (PTX) and tocopherol (vitamin E) boosted by clodronate effective in reversing this fibronecrotic process? METHODS: Eighteen consecutive patients previously irradiated for head and neck cancer had exteriorized mandible ORN. Length of exposed bone (L) was 13.4 +/- 8 mm, and the mean subjective objective medical management and analytic evaluation of injury (SOMA) score was 12.6 +/- 4.9. Between June 1995 and January 2002, all 18 were given a daily oral combination of 800 mg of PTX and 1000 IU of vitamin E for 6 to 24 months. In addition, the last eight patients who were the worst cases were given 1600 mg/day clodronate 5 days a week. RESULTS: The treatment was well tolerated. All patients improved at 6 months, with 84% mean L and 67% mean SOMA score reductions. Sixteen (89%) of 18 patients achieved complete recovery, 14 in 5 +/- 2.6 months. The remaining two patients exhibited a 75% response at 6 months. CONCLUSION: PTX-vitamin E boosted by clodronate is an effective treatment of mandibular ORN that induces mucosal and bone healing in a median period of 6 months.

Use of Tween 40 and Tween 80 to deliver a mixture of phytochemicals to human colonic adenocarcinoma cell (CaCo-2) monolayers.

Epidemiological evidence suggests that dietary intake of carotenoids and tocopherols may influence the risk of certain chronic diseases, such as cancer and CVD. In vitro studies investigating the synergistic effects of mixtures of carotenoids and tocopherols have been hindered due to the difficulty of solubilising these lipophilic compounds. The objective of the present study was to develop a system for delivering tocopherols and carotenoids simultaneously to cells in culture. Differentiated human colonic adenocarcinoma cells (CaCo-2) were incubated with a mixture of these phytochemicals for 24 h. The phytochemical mixture included carotenoids (astaxanthin, canthaxanthin, lutein, lycopene, alpha-carotene, beta-carotene) and tocopherols (alpha-tocopherol and gamma-tocopherol). The emulsifiers polyoxyethylene sorbitan monopalmitate (Tween 40) and polyoxyethylene sorbitan monooleate (Tween 80) were employed as the delivery vehicles, and were compared with tetrahydrofuran (THF). Each vehicle was added at a maximum concentration of 1 ml/l. No toxic effects to the CaCo-2 cells were noted when Tween 40 or Tween 80 were used. Both Tween 40 and Tween 80 resulted in greater solubility of the mixture and delivered substantially more carotenoids and tocopherols to the cells than THF. In particular, lycopene was detected within the cells when Tween 40 and Tween 80 were employed, whereas it was below the limits of detection by HPLC when THF was used as the delivery vehicle. The phytochemicals were retained within the cells for 24 h after supplementation. Tween 40 and Tween 80 have potential as simple, rapid and non-toxic methods for delivering mixtures of carotenoids and tocopherols to cells in culture.