NANO-SBT-PEDF delivery system: A promising approach against ovarian cancer?

Pigment epithelium-derived factor (PEDF) is a secreted glycoprotein involved in various biological processes. Its expression declines during ovarian carcinogenesis where it could decrease macrophages polarization, inhibit angiogenesis and induce apoptosis. Altogether, PEDF represents an ideal anti-cancer agent against ovarian cancer. We previously proposed the non-viral Sleeping Beauty transposon (SBT) system to stably integrate the PEDF transgene into ovarian cancer cells. Here, we report the development of liposomes and lipid nanoparticles for SBT-PEDF gene therapy. We determined that the SBT-PEDF nanolipid delivery system was the best system to increase the expression of PEDF in ovarian cancer spheroids. We also developed an ex vivo model of ovarian tumors which allowed us to show that nanolipoplexe in combination to paclitaxel exhibits synergistic and effective anti-tumor efficacy on ovarian tumors. These findings demonstrate that lipid nanoparticle for SBT-PEDF gene therapy may be a promising therapeutic approach for ovarian cancer.

Antibiofilm Activity and Synergistic Effects of Thymol-Loaded Poly (Lactic-Co-Glycolic Acid) Nanoparticles with Amikacin against Four Salmonella enterica Serovars.

Background: Salmonella species are frequently linked to biofilm-associated infections. Biofilm formation intensively reduces the efficacy of antibiotics and the host immune system. Therefore, new therapeutic strategies are needed. Thymol, the main monoterpene phenol found in Thymus vulgaris, has been shown to possess potent antibiofilm activity. Our previous findings showed that thymol enhanced the antibiofilm activity of aminoglycosides against Salmonella enterica serovars. However, the clinical potential of thymol has not yet been realized due to its low aqueous solubility and high volatility. Nano-based drug delivery systems have emerged as a novel strategy to resolve these problems. This study aimed to investigate the antibiofilm activity of thymol-loaded poly (lactic-co-glycolic acid) nanoparticles (TH-NPs) and their synergism when used in combination with amikacin antibiotics. Methods: The antibacterial activity of TH-NPs was evaluated using the broth microdilution method. Biofilm formation and antibiofilm assays were performed by the miniaturized microtiter plate method. Interaction studies between TH-NPs and amikacin against biofilm were determined using the checkerboard method. Results: TH-NPs exhibited antibacterial activity against planktonic cells of S. enterica serovars that were more efficient (8 to 32 times) than free thymol alone. S. Typhimurium and S. Choleraesuis isolates were considered strong biofilm producers. The combination of TH-NPs with amikacin showed synergistic activity in the inhibition and eradication of S. enterica serovar biofilm. The minimum biofilm inhibitory concentration (MBIC) and minimum biofilm eradication concentration (MBEC) of amikacin were reduced by 32 to 128-fold when used in combination with TH-NPs. Time-kill kinetic studies showed that the combination of TH-NPs with amikacin possesses bactericidal action. Conclusion: This study suggests that the combination of TH-NPs with amikacin can be an alternative to overcome biofilm-associatedSalmonella diseases and therefore should be further explored as a model to search for new antibiofilm drugs.

Bioadhesive Perivascular Microparticle-Gel Drug Delivery System for Intimal Hyperplasia Prevention: In Vitro Evaluation and Preliminary Biocompatibility Assessment.

Intimal hyperplasia (IH) is an undesirable pathology occurring after peripheral or coronary bypass surgery. It involves the proliferation and migration of vascular smooth muscle cells, leading to a reduction in the diameter of the vascular lumen, which can lead to stenosis and graft failure. Topically applied atorvastatin (ATV) has been shown to slow down this process. To be effective, the drug delivery system should remain at the perivascular site for 5-8 weeks, corresponding to the progression of IH, and be capable of releasing an initial dose of the drug followed by a sustained release. Ideally, bioadhesion would anchor the gel to the application site. To meet these needs, we encapsulated ATV in a 2-component system: a hyaluronic acid-dopamine bioadhesive gel for rapid release and biodegradable microparticles for sustained release. The system was characterized by scanning electron microscopy, rheology, bioadhesion on porcine arteries, and a release profile. The rheological properties were adequate for perivascular application, and we demonstrated superior bioadhesion and cohesion compared to the control HA formulations. The release profile showed a burst, generated by free ATV, followed by sustained release over 8 weeks. A preliminary evaluation of subcutaneous biocompatibility in rats showed good tolerance of the gel. These results offer new perspectives on the perivascular application towards an effective solution for the prevention of IH.

Antibiofilm Synergistic Activity of Streptomycin in Combination with Thymol-Loaded Poly (Lactic-co-glycolic Acid) Nanoparticles against Klebsiella pneumoniae Isolates.

Background: Thymol is an important component of essential oils found in the oil of thyme, is extracted mainly from Thymus vulgaris, and was shown to act synergistically with streptomycin against Klebsiella pneumoniae biofilms. Additionally, thymol could be encapsulated into poly (lactic-co-glycolic acid) (PLGA) nanoparticles to overcome issues related to its low water solubility and high volatility. The present study aimed to investigate the antibiofilm activity of thymol-loaded PLGA nanoparticles (Thy-NPs) alone and in combination with streptomycin against biofilms of K. pneumoniae isolates. Methods: The broth microdilution method was used to determine the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). The antibiofilm activities were determined by the safranin dye assay. The synergistic effect of Thy-NPs with streptomycin was assessed by the checkerboard method. The kinetic study of the biofilm biomass and time-kill assay were further performed. Results: Thy-NPs exhibited the highest antibacterial activity against K. pneumoniae isolates, with MIC values ranging from 1 to 8 µg/mL. Additionally, Thy-NPs showed the highest antibiofilm activity against K. pneumoniae isolates with minimal biofilm inhibitory concentration (MBIC) and minimal biofilm eradication concentration (MBEC) values ranging from 16 to 64 µg/mL and from 32 to 128 µg/Ml, respectively. The combination treatment combining Thy-NPs with streptomycin showed a synergistic effect against the inhibition of biofilm formation and eradication of biofilms of K. pneumoniae isolates with fractional inhibitory concentration index values ranging from 0.13 to 0.28. In addition, the MBIC and MBEC values of streptomycin against K. pneumoniae isolates were dramatically reduced (up to 128-fold) in combination with Thy-NPs, suggesting that Thy-NPs would enhance the antibiofilm activity of streptomycin. The biomass and time-kill kinetics analysis confirmed the observed synergistic interactions and showed the bactericidal activity of streptomycin in combination with Thy-NPs. Conclusions: Our results indicate that the synergistic bactericidal effect between streptomycin and Thy-NPs could be a promising approach in the control of biofilm-associated infections caused by K. pneumoniae.

Antimicrobial and Cytotoxic Activities of Constituents from the Fruit of Albizia lebbeck L. Benth (Fabaceae).

Twenty-two compounds were isolated from the fruit of Albizia lebbeck including one unprecedented, rare amino acid-derived zwitterionic and one new flavone derivative. The isolation was performed on repeated column chromatography over silica gel and their structures were determined by 1D-, 2D-NMR and HR-ESI-MS spectra together with reported data in the literature. The chemophenetic significance is also discussed. Some isolated compounds were reported for the first time to be found in the species. Additionally, compound 2 showed antibacterial activity and compounds 1 and 2 revealed moderate cytotoxic activity against the Raw 264.7 cancer cell line with IC50 values of 37.19 µM and 29.36 µM, respectively. Furthermore, a proposed biosynthetic pathway of compound 1 is described.

Bioadhesive Hyaluronic Acid/Dopamine Hydrogels for Vascular Applications Prepared by Initiator-Free Crosslinking.

Intimal hyperplasia, a vascular pathology characterized by vessel wall thickening, is implicated in vein graft failures. For efficient prevention, a biodegradable drug delivery system should be applied externally to the graft for an extended time. Finding a gel suitable for such a system is challenging. We have synthesized HA-Dopamine conjugates (HA-Dop) with several degrees of substitution (DS) and used two crosslinking methods: initiator-free crosslinking by basic pH shift or commonly used crosslinking by a strong oxidizer, sodium periodate. The rheological properties, bioadhesion to vascular tissue, cytocompatibility with fibroblasts have been compared for both methods. Our results suggest that initiator-free crosslinking provides HA-Dop gels with more adequate properties with regards to vascular application than crosslinking by strong oxidizer. We have also established the cytocompatibility of the initiator-free crosslinked HA-Dop gels and the cytotoxicity of dopamine-sodium periodate combinations. Furthermore, we have incorporated a drug with anti-restenotic effect in perivascular application, atorvastatin, into the gel, which showed adequate release profile for intimal hyperplasia prevention. The oxidizer-free formulation with improved bioadhesion holds promise as an efficient and safe drug delivery system for vascular applications.

Pharmacological prevention of intimal hyperplasia: A state-of-the-art review.

Intimal hyperplasia (IH) occurs in a considerable number of cases of blood vessel reconstruction by stenting or balloon angioplasty, venous bypass grafting, and arteriovenous dialysis accesses. It is triggered by endothelial injury during the vascular intervention and leads to vessel restenosis with life-threatening consequences for patients. To date, the drugs used for IH prevention in clinics-paclitaxel and rapalog drugs-have been focusing primarily on the vascular smooth muscle cell (VSMC) proliferation pathway of IH development. Limitations, such as endothelial toxicity and inappropriate drug administration timing, have spurred the search for new and efficient pharmacological approaches to control IH. In this state-of-the-art review, we present the pathways of IH development, focusing on the key events and actors involved in IH. Subsequently, we discuss different drugs and drug combinations interfering with these pathways based on their effect on peripheral circulation IH models in animal studies, or on clinical reports. The reports were obtained through an extensive search of peer-reviewed publications in Pubmed, Embase, and Google Scholar, with search equations composed based on five concepts around IH and their various combinations. To improve vascular intervention outcomes, rethinking of conventional therapeutic approaches to IH prevention is needed. Exploring local application of drugs and drug combinations acting on different pathophysiological pathways of IH development has the potential to provide effective and safe restenosis prevention.

New cytotoxic obacunone-type limonoid and others constituents from the stem bark of Carapa procera DC (Meliaceae).

The phytochemical study of the CH2Cl2- MeOH (1:1, v/v) extract of the stem bark of Carapa procera DC (Meliaceae) led to the isolation and characterisation of a new natural limonoid 7ß-obacunol (6), along with seven known compounds. Their structures were elucidated by spectroscopic means, including 1 D and 2 D NMR, HRESI-MS and by comparison with published data. The cytotoxicity of compounds 1-6 was assessed in vitro by the WST-1 assay on human lung adenocarcinoma A549 and Raw 264.7 mouse macrophage cell lines. Results suggested that obacunone (3) exhibited the most potent cytotoxic effect against A549 and Raw 264.7 cells with respective IC50 values of 25.24 µM and 29.14 µM, while the new natural limonoid 7ß-obacunol (6) exhibited 32.75 µM and 39.19 µM, respectively on both cell lines. Therefore, limonoid derivatives might be promising sources of natural bioactive metabolites against cancer.

Antitumor Effect of 5-Fluorouracil-Loaded Liposomes Containing n-3 Polyunsaturated Fatty Acids in Two Different Colorectal Cancer Cell Lines.

It has been shown that long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) could act synergistically with 5-fluorouracil (5-FU) to kill cancer cells. To facilitate their simultaneous transport in the bloodstream, we synthesized, for the first time, liposomes (LIPUFU) containing 5-FU in the aqueous core and docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA) at a ratio of 1:2 in the lipid bilayer. LIPUFU werestable with uniform size of 154 ± 4 nm, PDI of 0.19 ± 0.03 and zeta potential of -41 ± 2 mV. They contained 557 ± 210 µmol/l DHA, 1467 ± 362 µmol/l EPA, and 9.8 ± 1.1 µmol/l 5-FU. Control liposomes without (LIP) or with only 5-FU (LIFU) or n-3 PUFAs (LIPU) were produced in a similar way. The effects of these different liposomal formulations on the cell cycle, growth, and apoptosis were evaluated in two human colorectal cancer (CRC) cell lines differing in sensitivity to 5-FU, using fluorescence-activated cell sorting analyses. LIPUFU were more cytotoxic than LIP, LIFU, and LIPU in both LS174T (p53+/+, bax-/-) and HT-29 (p53-/0, bax+/+) cell lines. Similar to LIFU, LIPUFU increased the percentage of cells in S phase, apoptosis, and/or necrosis. The cytotoxic potential of LIPUFU was confirmed in vivo by tumor growth inhibition in the chicken chorioallantoic membrane model. These results suggest that LIPUFU could be considered to facilitate the simultaneous transport of 5-FU and n-3 PUFAs to the tumor site, in particular in case of CRC liver metastases.

Cytotoxicity of a new tirucallane derivative isolated from Stereospermum acuminatissimum K. Schum stem bark.

One new tirucallan derivative, leutcharic acid (1) was isolated from Stereospermum acuminatissimum stem bark together with the known compounds 3-oxo-22-hydroxyhopane (2), 3,4-secotirucalla-4(28),7,24-trien-3,21-dioic acid (3), 3-oxotirucalla-7,24-dien-21-oic acid (7), lupeol (4), ß-sitosterol (5) and stigmasterol (6). The structures of the isolated compounds were elucidated using 1 D and 2 D NMR spectroscopy in combination with literature data. To the best of our knowledge, this is the first report on the cytotoxic properties' constituents of S. acuminatissimum. Cytotoxicity of compounds 1 and 2 was assessed in vitro with the WST-1 assay on human lung adenocarcinoma A549 and THP-1 human monocytic leukaemia cell lines. Both compounds showed antiproliferative activity on the cancer cells. Compound 2 was more active against THP-1 with an IC50 value of 26.83 µM. The sensitivity of THP-1 cells to compounds 1 and 2 indicated that these compounds might be potential leads for anticancer agent development against leukaemia.

Antiproliferative activity of a new xanthone derivative from leaves of Garcinia nobilis Engl.

A new xanthone, mboudiexanthone (1), together with five known compounds, euxanthone (2), isogarcinol (3), garcinol (4), betulinic acid (5) and zeorin (6) were isolated from the leaves of Garcinia nobilis Engl. The structures were determined by 1D and 2D NMR techniques and X-ray diffraction for 6. The in vitro antiproliferative properties of isolated compounds were evaluated against the human breast cancer cell line MCF-7. All compounds showed an antiproliferative activity with an IC50 value down to ∼11 µM for isogarcinol.

Bioguided identification of pentacyclic triterpenoids as anti-inflammatory bioactive constituents of Ocimum gratissimum extract.

ETHNOPHARMACOLOGICAL RELEVANCE: Ocimum gratissimum is a plant spice widely used in African traditional medicine to treat pain-related conditions. However, the anti-inflammatory mechanisms underlying this activity and the main active ingredients in O. gratissimum have not yet been fully characterized. AIM OF THE STUDY: To isolate and identify the main anti-inflammatory active constituents of Ocimum gratissimum extract and their underlying mechanisms in murine macrophages. MATERIAL AND METHODS: Chromatographic techniques and spectroscopic data were used for compounds isolation and identification. Inflammatory conditions were produced in cultured RAW 264.7 macrophage cells by the application of lipopolysaccharide (LPS). The WST-1 assay was used to evaluate the cell viability, and the nitric oxide production was quantified by the Griess reagent method. The fluorometric cyclooxygenase (COX) activity assay kit was used to assess the activity of COX-1 and COX-2 enzymes. The levels of IFN-γ, TNF-α, IL-2, IL-4, IL-6, and IL-10 cytokines and the apoptosis-inducing effect were measured by flow cytometer using the cytometric Bead Array (CBA) Human Th1/Th2 Cytokine Kit II and FITC Annexin V Apoptosis Detection kit, respectively. RESULTS: The results showed that the extract and fractions of Ocimum gratissimum inhibit nitric oxide production and the proliferation of Raw 264.7 macrophage cells. The bioguided fractionation led to the identification of pentacyclic triterpenes as anti-inflammatory bioactive compounds. Pomolic and tormentic acids being the most active, inhibiting the secretion of IFN-γ cytokine, COX enzyme, and inducing apoptosis in activated Raw 264.7 macrophage cells. CONCLUSIONS: This study revealed that pomolic and tormentic acids are the main active principles responsible at least in part for the anti-inflammatory effect of the extract of Ocimum gratissimum. Besides of providing more evidence for the traditional use of Ocimum gratissimum against inflammatory disorders, this study reveals the multitarget potential of pomolic and tormentic acids as promising future drugs against inflammatory diseases.

PLGA Nanoparticles for the Intraperitoneal Administration of CBD in the Treatment of Ovarian Cancer: In Vitro and In Ovo Assessment.

The intraperitoneal administration of chemotherapeutics has emerged as a potential route in ovarian cancer treatment. Nanoparticles as carriers for these agents could be interesting by increasing the retention of chemotherapeutics within the peritoneal cavity. Moreover, nanoparticles could be internalised by cancer cells and let the drug release near the biological target, which could increase the anticancer efficacy. Cannabidiol (CBD), the main nonpsychotropic cannabinoid, appears as a potential anticancer drug. The aim of this work was to develop polymer nanoparticles as CBD carriers capable of being internalised by ovarian cancer cells. The drug-loaded nanoparticles (CBD-NPs) exhibited a spherical shape, a particle size around 240 nm and a negative zeta potential (-16.6 ± 1.2 mV). The encapsulation efficiency was high, with values above 95%. A controlled CBD release for 96 h was achieved. Nanoparticle internalisation in SKOV-3 epithelial ovarian cancer cells mainly occurred between 2 and 4 h of incubation. CBD antiproliferative activity in ovarian cancer cells was preserved after encapsulation. In fact, CBD-NPs showed a lower IC50 values than CBD in solution. Both CBD in solution and CBD-NPs induced the expression of PARP, indicating the onset of apoptosis. In SKOV-3-derived tumours formed in the chick embryo model, a slightly higher-although not statistically significant-tumour growth inhibition was observed with CBD-NPs compared to CBD in solution. To sum up, poly-lactic-co-glycolic acid (PLGA) nanoparticles could be a good strategy to deliver CBD intraperitoneally for ovarian cancer treatment.

Malignant ascites: a source of therapeutic protein against ovarian cancer?

Ovarian cancer is the fifth leading cause of cancer-related death in the world. Some ovarian cancer patients present large amount of ascites at the time of diagnosis which may play an active role in tumor development. In earlier studies, we demonstrated that the acellular fraction of ascites can induce apoptosis of ovarian cancer cells. The current study identifies pigment epithelium derived factor (PEDF) as the molecule responsible for the apoptotic effect of ascites and evaluates the Sleeping Beauty transposon (SBT) system as a new tool for PEDF gene therapy against ovarian cancer. We utilize gel filtration, mass spectrometry, affinity column, cell viability assay, tumor development on chick chorioallantoic membrane and molecular biology techniques for these purposes. PEDF was thus identified as the agent responsible for the effects of ascites on ovarian cancer cell viability and tumor growth. Interestingly, the PEDF expression is decreased in ovarian cancer cells compared to healthy ovarian cells. However, the level of PEDF is higher in ascites than in serum of ovarian cancer patients suggesting that cells present in the tumor environment are able to secrete PEDF. We then used the SBT system to stably induce PEDF expression in ovarian cancer cells. The overexpression of PEDF significantly reduced the tumor growth derived from these cells. In conclusion, the results presented here establish that PEDF is a therapeutic target and that PEDF from ascites or SBT could be utilized as a therapeutic strategy for the treatment of ovarian cancer.

Development of resiquimod-loaded modified PLA-based nanoparticles for cancer immunotherapy: A kinetic study.

Resiquimod (R848), a member of the imidazoquinoline family, is a Toll-like receptor 7/8 agonist with high potency for cancer immunotherapy. However, tolerance induction and adverse effects limit its development as a drug. Encapsulation in a polymer matrix can circumvent these limitations, as shown in our formerly published approach where R848 was loaded into polylactic acid (PLA)-based nanoparticles (NP). Although the results were encouraging, low rates of encapsulation and rapid release of the drug were observed. In this study, we present a new strategy using mixed NP from modified linear PLA in order to improve the encapsulation and modulate the release profile of R848. Modified PLA polymers were designed and synthesized by microwave-assisted ring opening polymerization of d,l-lactide, using polyethylene glycol as initiator to increase the hydrophilic properties of the polymer or linear saturated aliphatic chains (C8 or C20) to increase the affinity with hydrophobic R848. NP were prepared by solvent evaporation method, leading to particles of 205-288 nm loaded with either R848 or DiO as a tracking agent. The release profile showed longer retention of R848 at both neutral and acidic pH for NP from grafted polymers. Upon exposure to phagocytic immune cells, NP were actively taken up by the cells and no impact on cell viability was observed, independently of the constitutive polymer. All R848-loaded NP activated macrophages to secrete interleukin-6, demonstrating that the drug cargo was immunologically active. Importantly, macrophage activation by NP-delivered R848 was slower than with free R848, in accordance with the in vitro release profiles. Thus, NP prepared from modified PLA polymers showed no signs of toxicity to immune cells and efficiently delivered their immunoactive cargo in a delayed manner. This delivery strategy may enhance the efficacy and safety of small-molecule immunostimulants.

Imaging the porous structure in the core of degrading PLGA microparticles: The effect of molecular weight.

The aim of this study was to understand the pore formation mechanisms of degrading poly(d,l-lactic-co-glycolic acid) (PLGA) microparticulate systems. This was investigated through an original microparticles cross-section imaging method. Atorvastatin (ATV)-loaded 16- to 18-µm spherical microparticles with polymers of varying molecular weights (8 to 45 kDa) were prepared. The evolution of the particles during in vitro drug release experiments was monitored in terms of molecular weight, pore formation and glass transition temperature. During the 2nd phase of release, two types of pores were observed: small pores near the particle's periphery and larger pores in the core. The pattern of pore formation was shown to be related to the shape of the drug release curve. At the onset of the 3rd phase, the polymer transitions to a less glassy state, allowing for the swelling of the microparticles. Overall, we present evidence that pore formation is not uniformly distributed throughout PLGA microparticles, and that it could determine the drug release kinetics.

Evaluating intimal hyperplasia under clinical conditions.

OBJECTIVES: Open arterial revascularization using venous segments is frequently associated with the development of intimal hyperplasia (IH), leading to severe restenosis and graft failure. The lack of treatment to prevent this pathology is a major problem. Therefore, we generated a new porcine model, which closely mimics the clinical development of human IH, to test the therapeutic potential of candidate drugs. METHODS: A patch of jugular vein was sutured to the right common carotid artery of pigs, to expose the vein to haemodynamic conditions of the arterial bed. Four weeks after surgery, the operated vessels which received no further treatment (the control group) were compared with (i) contralateral, non-operated vessels (the healthy group); (ii) vessels of pigs that received a perivascular application of a drug-free microparticle gel (the placebo group) and (iii) vessels of pigs that perioperatively received the same gel loaded with 10-mg atorvastatin (the atorvastatin group). RESULTS: When compared with non-operated vessels, all operated segments displayed a sizable IH which was thicker in the venous patch than in the host artery. These alterations were associated with a thickening of the intima layer of both vessels in the absence of inflammation. The intima/media ratio has been significantly increased by 2000-fold in the vein patches. Perivascular application of atorvastatin did not prevent IH formation. However, the drug increased the adventitial neovascularization in the operated vessels. CONCLUSIONS: The novel porcine model allows for monitoring IH formation under haemodynamic conditions which mimic clinical situations. It should facilitate the screening of innovative treatments to prevent restenosis.

Design and characterization of a perivascular PLGA coated PET mesh sustaining the release of atorvastatin for the prevention of intimal hyperplasia.

Following vascular bypass interventions, autologous saphenous vein grafts are prone to fail due to intimal hyperplasia development. An atorvastatin (ATV)-eluting tubular mesh coated with poly(d,l-lactide-co-glycolisde) acid (PLGA) was designed for perivascular application, in order to prevent the development of this pathology. Formulation parameters such as PLGA molecular weight, concentration of ATV and PLGA in the coating solution and number of coatings were investigated to optimise the mesh in terms of drug loading efficacy, drug release kinetics and mechanical properties. Using the dip-coating technique, 1.6 mg of ATV was loaded on a tubular 5 cm long mesh. The most important parameter influencing ATV loading was the concentration of the drug in the coating solution. In vitro an ATV release profile combining an initial fast release over 3 days and a sustained release over 40 days was obtained; consistent with the timeframe of hyperplasia development. The amount of PLGA polymer coating as well as the molecular weight of the polymer were optimized to achieve these kinetics. A poly(d,l-lactide-co-caprolactone) (PLCL) layer was sprayed on the external side of the PLGA coated tubular mesh to restrict the ATV release to the vascular tissue. Scanning electron microscopy observation showed that the macroporosity of the mesh was preserved after coating, while texture analysis demonstrated that its elasticity decreased slightly.

Functionalized PLA polymers to control loading and/or release properties of drug-loaded nanoparticles.

Advantages associated with the use of polylactic acid (PLA) nano- or microparticles as drug delivery systems have been widely proven in the field of pharmaceutical sciences. These biodegradable and biocompatible carriers have demonstrated different loading and release properties depending on interactions with the cargo, preparation methods, particles size or molecular weight of PLA. In this study, we sought to show the possibility of influencing these properties by modifying the structure of the constituting polymer. Seven non-functionalized or functionalized PLA polymers were specifically designed and synthesized by microwave-assisted ring-opening polymerization of d,l-lactide. They presented short hydrophobic and/or hydrophilic groups thanks to the use of C20 aliphatic chain, mPEG1000, sorbitan esters (Spans®) or polysorbates (Tweens®), their PEGylated analogues, as initiators. Then, seven types of drug-loaded nanoparticles (NP) were prepared from these polymers and compared in terms of physico-chemical characteristics, drug loading and release profiles. Although the loading properties were not improved with any of the functionalized PLA NP, different release profiles were observed in an aqueous medium at 37 °C and over a period of five days. The presence of PEG moieties in the core of PLA-polysorbates NP induced a faster release while the addition of a single aliphatic chain induced a slower release due to better interactions with the active molecule.