Synthesis of Block Copolymer Brush by RAFT and Click Chemistry and Its Self-Assembly as a Thin Film.

A well-defined block copolymer brush poly(glycidyl methacrylate)-graft-(poly(methyl methacrylate)-block- poly(oligo(ethylene glycol) methyl ether methacrylate)) (PGMA-g-(PMMA-b-POEGMA)) is synthesized via grafting from an approach based on a combination of click chemistry and reversible addition-fragmentation chain transfer (RAFT) polymerization. The resulting block copolymer brushes were characterized by 1H-NMR and size exclusion chromatography (SEC). The self-assembly of the block copolymer brush was then investigated under selective solvent conditions in three systems: THF/water, THF/CH3OH, and DMSO/CHCl3. PGMA-g-(PMMA-b-POEGMA) was found to self-assemble into spherical micelle structures as analyzed by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The average size of the particles was much smaller in THF/CH3OH and DMSO/CHCl3 as compared with the THF/water system. Thin film of block copolymer brushes with tunable surface properties was then prepared by the spin-coating technique. The thickness of the thin film was confirmed by scanning electron microscopy (SEM). Atom force microscopy (AFM) analysis revealed a spherical morphology when the block copolymer brush was treated with poor solvents for the backbone and hydrophobic side chains. The contact angle measurements were used to confirm the surface rearrangements of the block copolymer brushes.

Design and Development of Immunomodulatory Antigen Delivery Systems Based on Peptide/PEG-PLA Conjugate for Tuning Immunity.

Cancer vaccines are considered to be a promising tool for cancer immunotherapy. However, a well-designed cancer vaccine should combine a tumor-associated antigen (TAA) with the most effective immunomodulatory agents and/or delivery system to provoke intense immune responses against the TAA. In the present study, we introduced a new approach by conjugating the immunomodulatory molecule LD-indolicidin to the hydrophilic chain end of the polymeric emulsifier poly(ethylene glycol)-polylactide (PEG-PLA), allowing the molecule to be located close to the surface of the resulting emulsion. A peptide/polymer conjugate, named LD-indolicidin-PEG-PLA, was synthesized by conjugation of the amine end-group of LD-indolicidin to the N-hydroxysuccinimide-activated carboxyl end-group of PEG. As an adjuvant for cancer immunotherapeutic use, TAA vaccine candidate formulated with the LD-indolicidin-PEG-PLA-stabilized squalene-in-water emulsion could effectively help to elicit a T helper (Th)1-dominant antigen-specific immune response as well as antitumor ability, using ovalbumin (OVA) protein/EG7 cells as a TAA/tumor cell model. Taken together, these results open up a new approach to the development of immunomodulatory antigen delivery systems for vaccine adjuvants and cancer immunotherapy technologies.

In vivo degradation of copolymers prepared from L-lactide, 1,3-trimethylene carbonate and glycolide as coronary stent materials.

A series of high molecular weight polymers were prepared by ring opening polymerization of L-lactide (L-LA), 1,3-trimethylene carbonate (TMC) and glycolide using stannous octoate as catalyst. The resulting polymers were characterized by gel permeation chromatography, (1)H nuclear magnetic resonance, differential scanning calorimeter and tensile tests. All the polymers present high molecular weights. Compared with PLLA and PTLA copolymers, the terpolymers exhibit interesting properties such as improved toughness and lowered crystallinity with only slightly reduced mechanical strength. In vivo degradation was performed by subcutaneous implantation in rats to evaluate the potential of the copolymers as bioresorbable coronary stent material. The results show that all the polymers conserved to a large extent their mechanical properties during the first 90 days, except the strain at break which exhibited a strong decrease. Meanwhile, significant molecular weight decrease and weight loss are detected in the case of terpolymers. Therefore, the PTLGA terpolymers present a good potential for the development of totally bioresorbable coronary stents.

Chitosan-based GOx@Co-MOF composite hydrogel: A promising strategy for enhanced antibacterial and wound healing effects.

A novel composite hydrogel was synthesized via Schiff base reaction between chitosan and di-functional poly(ethylene glycol) (DF-PEG), incorporating glucose oxidase (GOx) and cobalt metal-organic frameworks (Co-MOF). The resulting CS/PEG/GOx@Co-MOF composite hydrogel was characterized using Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), thermogravimetric analysis (TGA), and energy-dispersive X-ray spectroscopy (EDS). The results confirmed successful integration and uniform distribution of Co-MOF within the hydrogel matrix. Functionally, the hydrogel exploits the catalytic decomposition of glucose by GOx to generate gluconic acid and hydrogen peroxide (H2O2), while Co-MOF gradually releases metal ions and protects GOx. This synergy enhanced the antibacterial activity of the composite hydrogel against both Gram-positive (S. aureus) and Gram-negative bacteria (E. coli), outperforming conventional chitosan-based hydrogels. The potential of the composite hydrogel in treating wound infections was evaluated through antibacterial and wound healing experiments. Overall, CS/PEG/GOx@Co-MOF hydrogel holds great promise for the treatment of wound infections, paving the way for further research and potential clinical applications.

In situ Hydrogels Prepared by Photo-initiated Crosslinking of Acrylated Polymers for Local Delivery of Antitumor Drugs.

A triblock copolymer was synthesized by ring opening polymerization of ε-caprolactone in the presence of poly(ethylene glycol) (PEG). The resulted PCL-PEG-PCL triblock copolymer, PEG and monomethoxy (MPEG) were functionalized by end group acrylation. NMR and FT-IR analyses evidenced the successful synthesis and functionalization of polymers. A series of photo-crosslinked hydrogels composed of acrylated PEG-PCL-Acr and MPEG-Acr or PEG-Acr were prepared by exposure to visible light using lithium phenyl-2,4,6-trimethylbenzoylphosphinate as initiator. The hydrogels present a porous and interconnected structure as shown by SEM. The swelling performance of hydrogels is closely related to the crosslinking density and hydrophilic content. Addition of MPEG or PEG results in increase in water absorption capacity of hydrogels. In vitro degradation of hydrogels was realized in the presence of a lipase from porcine pancreas. Various degradation rates were obtained which mainly depend on the hydrogel composition. MTT assay confirmed the good biocompatibility of hydrogels. Importantly, in situ gelation was achieved by irradiation of a precursor solution injected in the abdomen of mice. Doxorubicin (DOX) was selected as a model antitumor drug to evaluate the potential of hydrogels in cancer therapy. Drug-loaded hydrogels were prepared by in situ encapsulation. In vitro drug release studies showed a sustained release during 28 days with small burst release. DOX-loaded hydrogels exhibit antitumor activity against A529 lung cancer cells comparable to free drug, suggesting that injectable in situ hydrogel with tunable properties could be most promising for local drug delivery in cancer therapy.

Correlations between rheological and mechanical properties of fructo-polysaccharides extracted from Ornithogalum billardieri as biobased adhesive for biomedical applications.

Polysaccharides are extracted from Ornithogalum by maceration using different ultrasound (US) treatment times (0%US, 50%US, 100%US), and under optimized extraction conditions (OP%US). The total carbohydrates content (TCC) and proteins content of the extracts were determined. Data show that the extraction parameters significantly influence the extracts composition. Rheological measurements allowed determining the liquid, intermediate and gel states of the extract's solutions. The adhesion strength of the solutions was evaluated on paper and polylactide (PLA) substrates to evaluate their potential as environmentally friendly adhesive. OP%US presents the highest adhesion strength (1418.3 kPa) on paper, and is further tested on pork skin substrates. The adhesion strength is higher on skin/paper (870 kPa) than on skin/skin (411 kPa) substrate due to the capillary force of paper which allows penetration of adhesive into the micropores of paper. The correlation between rheological properties and adhesion strength indicates that the adhesion strength strongly depends on the state of adhesives and the substrate type. SEM analyses show that higher adhesion strength (intermediate and gel states) involves both cohesive and adhesive failure, whereas only adhesive failure is observed in liquid state on PLA substrates. Therefore, these polysaccharides extracts could be very promising as tissue adhesive in medical applications.

Anisotropic self-assembling micelles prepared by the direct dissolution of PLA/PEG block copolymers with a high PEG fraction.

A series of polylactide-poly(ethylene glycol) (PLA-PEG) block copolymers with a high PEG fraction were synthesized by the ring-opening polymerization of L- or D-lactide in the presence of mono- or dihydroxyl PEG using nontoxic zinc lactate as a catalyst. Micelles were then prepared by direct dissolution of the obtained water-soluble copolymers in an aqueous medium without heating or using any organic solvents. Large anisotropic micelles instead of conventional spherical ones were observed from a transmission electron microscopy examination. Various parameters influencing the structure of the novel micelles were considered, such as the copolymer chain structure, molar mass, PEG fraction, copolymer concentration, and stereocomplexation between L- and D-PLA blocks. Anisotropic micelles were obtained for both diblock and triblock copolymers but vanished with increasing molar mass of the copolymers. The morphology of micelles strongly depends on the PEG fraction. Anisotropic micelles were found only in an intermediate EO/LA ratio range in which a higher PEG fraction leads to a higher length/width ratio of micelles. Stereocomplexation between L- and D-PLA or a lower concentration disfavors the formation of anisotropic micelles. Under appropriate concentrations, spherical and anisotropic micelles coexist in the same micellar solution. Moreover, it was found that anisotropic micelles are susceptible to further self-assemble into more organized complex aggregates. Similar results were obtained from light scattering and aqueous gel permeation chromatography measurements. A novel model is proposed to explain the formation of anisotropic micelles and the effects of various parameters on the structure of micelles in an aqueous medium.

In vivo study on the histocompatibility and degradation behavior of biodegradable poly(trimethylene carbonate-co-D,L-lactide).

The aim of this study was to explore the in vivo behavior and histocompatibility of poly(trimethylene carbonate-co-D,L-lactide) (PDLLA/TMC) and its feasibility of manufacturing cardiovascular stents. Copolymers with 50/50 molar ratio were synthesized by ring-opening polymerization with TMC and D, L-LA, or TMC and L-LA. Poly(L-lactide) (PLLA) was synthesized as a control. The films of the three polymers were implanted into 144 Wistar rats. At different time points of implantation, polymer films were explanted for the evaluation of degradation characteristics and histocompatibility using size exclusion chromatography , nuclear magnetic resonance , environmental scanning electron microscope , and optical microscope. Results showed that there were differences in the percentage of mass loss, molecular weight, shape and appearance changes, and inflammation cell counts between different polymers. With the time extended, the film's superficial structure transformed variously, which was rather obvious in the polymer of PDLLA/TMC. In addition, there were relatively lower inflammation cell counts in the PDLLA/TMC and poly(trimethylene carbonate-co-L-lactide) (PLLA/TMC) groups at different time points in comparison with those in the PLLA group. The differences were of statistical significance (P< 0.05) in the group of PDLLA/TMC vs. PLLA, and the group of PLLA/TMC vs. PLLA, but not within the PDLLA/TMC and PLLA/TMC groups (P> 0.05). These results suggested that the polymer of PDLLA/TMC (50/50) with favorable degradation performance and histocompatibility is fully biodegradable and suitable for manufacturing implanted cardiovascular stents.

Evaluation of a novel paclitaxel-eluting stent with a bioabsorbable polymeric surface coating in the porcine artery injury model.

PURPOSE: Drug-eluting stents (DES) are unique in allowing sustained release after a single short intervention. The challenge with DES still remaining is the optimal combination of a biocompatible drug-eluting matrix including an antiproliferative drug. We studied the role of a novel paclitaxel-eluting stent with a bioabsorbable polymer coating in preventing vascular restenosis in the porcine artery injury model. MATERIAL AND METHODS: Bare metal stents (BMS); polymer-coated-only stents (POLY); and polymer-based paclitaxel-eluting stents (PACL) were randomly implanted in pig femoral arteries. The dose density of paclitaxel was 1 microg/mm2 with in vitro studies demonstrating a gradual elution over a course of 6 month. RESULTS: After 1-, 3- and 6-month follow-up, respectively, the animals underwent angiographic restudy and were terminated for histomorphometrical and histopathological analyses. At 1 month, the PACL group had the lowest histological percent stenosis when compared to the BMS and POLY groups (20 +/- 4% vs 39 +/- 6% and 41 +/- 6%, respectively, P < 0.05). At 3 months, the PACL group still presents the lowest level of histological percent stenosis among the three groups (27 +/- 6% vs 50 +/- 10% and 46 +/- 5%, respectively, P < 0.01). Six months later, the PACL group showed a similar histological percent stenosis as the BMS and POLY groups (44 +/- 9% vs 56 +/- 11% and 53 +/- 9%, respectively, P = 0.145). CONCLUSIONS: This study shows favourable vascular compatibility and efficacy for a novel DES to inhibit in-stent neointima formation and preserve lumen area in the porcine artery model.

[Biocompatibility evaluation of lactide--trimethylene carbonate copolymers].

Biocompatibility is the essential property of biomaterials, which is the essence of biomaterial evaluation as well as the foundation of the design and improvement of biomaterials. Several methods were carried out to evaluate the biocompatibility of poly(L-Lactide)-b-poly(trimethylene carbonate (PLLA-b-PTMC) and poly(D,L-Lactide)-b-poly(trimethylene carbonate) (PDLLA-b-PTMC) with poly(L-Lactide) (PLLA) and poly(trimethylene carbonate) (PTMC) as control, including extract liquid experiment, directly contact experiment of materials and cells, hemolytic ratio analysis and platelet adhesion investigation. The results revealed that all the materials exhibited an acceptable cytotoxicity, and proliferation of cells on the modified materials was less than that on the PLLA but more than that on PTMC. The results of hemocompatibility experiments showed that no significant hemolysis was detected when all the materials were in use; in addition, the numbers of platelets adhered on the surface of copolymers were smaller than that on the surface of PLLA, and the degree of platelet deformation was slighter. So, the biocompatibility of copolymers is similar to that of PLLA, the biocompatibility of PLLA is not remarkably changed by modification with PTMC, but rather is improved.

Bioinspired pH-sensitive riboflavin controlled-release alkaline hydrogels based on blue crab chitosan: Study of the effect of polymer characteristics.

Recently, the application of natural biocompatible polymeric hydrogels for the conception of drug delivery matrices has attracted widespread interest. Thus, in the present study, riboflavin pH-sensitive drug delivery hydrogels were developed based on blue crab chitosan (Cs), via direct dissolution in alkali/urea aqueous solution at low temperatures. First, the effect of Cs characteristics in terms of acetylation degree (AD) and molecular weight (Mw) on the structural, mechanical, thermal, swelling and in vitro biodegradation of Cs-based hydrogels were studied. Data from overall analysis revealed that Cs with low AD and high Mw exhibited improved mechanical properties, as evidenced by the compressive and rheological behaviors tests, thermal resistance, swelling behavior and in vitro degradation kinetics. However, hydrogels pore sizes were reduced with the AD decrease and Mw increase. Additionally, hydrogels in PBS (pH 5.5) underwent quicker degradation, compared to those immersed in PBS (pH 7.4). In the drug delivery model, the kinetics of Riboflavin release, through the Cs-based hydrogels were monitored. The Riboflavin release exhibited typical deliverance patterns, with significantly higher released amounts in more acidic systems. Therefore, drug encapsulation within the conceived pH-sensitive Cs-based hydrogels could provide suitable and promoting microenvironment for drugs delivery.

Novel Thermosensitive Polymer-Modified Liposomes as Nano-Carrier of Hydrophobic Antitumor Drugs.

Thermo-sensitive polymer-modified liposomes are able to achieve site-specific delivery of drugs. In this work, thermo-sensitive polymers were synthesized by atomic transfer radical polymerization of N-isopropyl acrylamide (NIPAAm) and N,N-dimethyl acrylamide (DMAAm) using bromoisobutyryl distearoyl phosphoethanolamine (DSPE-Br) as initiator. The resulting PNIPAAm-DSPE and P(NIPAAm-DMAAm)-DSPE polymers were characterized using proton nuclear magnetic resonance, Fourier transform infrared, and ultraviolet-visible spectroscopy. PNIPAAm-DSPE and P(NIPAAm-DMAAm)-DSPE exhibit a lower critical solution temperature of 34.0 and 46.9°C in water, and 29.8 and 38.8°C in phosphate buffered saline, respectively. Paclitaxel-loaded thermo-sensitive liposomes were prepared using film hydration method, followed by post-insertion of P(NIPAAm-DMAAm)-DSPE into the liposome bilayer. Drug release of traditional and thermosensitive liposomes was comparatively studied at 37 and 40°C. The total release and release rate of thermosensitive liposomes at 40°C were much higher than those at 37°C. And drug release is higher for thermosensitive liposomes than for traditional liposomes because insertion of thermo-sensitive polymer chains affects the system's stability. MTT assay showed that thermo-sensitive liposomes present no cytotoxicity to L929 cells at the tested concentrations, and paclitaxel-loaded liposomes have significant cytotoxicity against A549 cancer cells. Therefore, it is concluded that P(NIPAAm-DMAAm)-DSPE modified thermo-sensitive liposomes could be promising as nano-carrier of antitumor drugs.

Self-assembled micelles prepared from bio-based hydroxypropyl methyl cellulose and polylactide amphiphilic block copolymers for anti-tumor drug release.

Fully bio-based amphiphilic diblock copolymers were synthesized from hydroxypropyl methyl cellulose (HPMC) and amino-terminated poly(l-lactide) (PLLA) or poly(l-lactide-co-dl-lactide) (PLA) by reductive amination. The resulting HPMC-PLLA and HPMC-PLA copolymers with various hydrophobic block lengths were characterized by NMR, DOSY-NMR and FT-IR. Micelles were obtained by self-assembly of copolymers in aqueous medium. The micelles are spherical in shape, and the micelle size ranges from 150 to 180 nm with narrow distribution. The critical micelle concentration decreases with increasing PLA block length. Paclitaxel was loaded in micelles. Enhanced drug loading is obtained with increase of PLA block length. A biphasic release profile is observed with a burst of 40% followed by slower release up to 80%. MTT assay indicates the good cytocompatibility of HPMC-PLA micelles. SRB assay shows a significant cytotoxicity of paclitaxel-loaded micelles against SK-BR-3cells. It is thus concluded that bio-based HPMC-PLA block copolymers could be promising nano-carrier of anti-tumor drugs.

A novel blue crab chitosan/protein composite hydrogel enriched with carotenoids endowed with distinguished wound healing capability: In vitro characterization and in vivo assessment.

This work aimed to the development of chitosan and protein isolate composite hydrogels, for carotenoids-controlled delivery and wound healing. By increasing the concentration of the protein isolate, chitosan hydrogels were more elastic at a protein isolate concentration not exceeding 15% (w/w). Chitosan-protein isolate composite hydrogels revealed low cytotoxicity towards MG-63 osteosarcoma cells. Thanks to its appropriate structural, swelling and mechanical resistance properties, chitosan hydrogel (3%; w/v), reinforced with 15% (w/w) of protein isolate, was selected for the carotenoids in vitro release study. Release profiles, show delivery patterns, where carotenoids were more barely released at a pH 7.4 medium (p < .05), compared to more acidic microenvironments (pH 4.0 and pH 2.0). Thus, developed hydrogels could be applied as pH-sensitive intelligent carriers, for drugs-controlled release, with interesting antioxidant abilities. The in vivo healing potential of hydrogels in rats' models was further studied. Topical application of hydrogel-based patches allowed the acceleration of wound healing and the complete healing, for composite hydrogel enriched with carotenoids.

Novel biodegradable polylactide/poly(ethylene glycol) micelles prepared by direct dissolution method for controlled delivery of anticancer drugs.

PURPOSE: The aim of this study is to develop novel polylactide/poly(ethylene glycol) (PLA/PEG) micelles as carrier of hydrophobic drug (paclitaxel) by direct dissolution method without using any organic solvents. The in vitro and in vivo release properties were studied in comparison with micelles prepared by dialysis. METHODS: Drug encapsulation efficiency (EE) and loading content (LC) of the micelles were evaluated by high-performance liquid chromatography. Micelle diameters and structures were determined by dynamic light scattering and transmission electron microscopy. In vitro release was performed in phosphate-buffered saline (pH 7.4) at 37 degrees C, and in vivo experiments were realized in lung cancer-bearing mice. RESULTS: Similar EE and LC values were obtained for micelles by direct dissolution method and those by dialysis. L- and D-PLA/PEG mixed micelles present higher drug encapsulation ability than separate micelles due to stereocomplexation. Micelle diameters are enlarged by drug-loading. Faster drug release was obtained for micelles by direct dissolution than those by dialysis. Compared with current clinical formulation and micelles by dialysis, paclitaxel-loaded micelles by direct dissolution showed the highest antitumor ability. CONCLUSION: The L- and D-PLA/PEG mixed micelles by direct dissolution method present many advantages such as easy formulation and absence of toxic organic solvents, which shows great potential as carrier of hydrophobic drugs.

Effect of cellulose nanocrystals on scaffolds comprising chitosan, alginate and hydroxyapatite for bone tissue engineering.

In this study, chitosan/alginate/hydroxyapatite/nanocrystalline cellulose scaffolds were successfully fabricated by the using of freeze-drying method, followed by dicationic crosslinking using CaCl2. The chemical structure and morphology along with mechanical properties of the formed scaffolds respecting to various CNC contents were studied by Fourier-transform infrared spectroscopy (FTIR), X-Ray Diffraction (XRD), Scanning Electron Microscopy (SEM) and mechanical compression test. Chemical interaction and electrostatic attraction between chitosan (CS) and alginate with various CNC ratios were affirmed by FTIR spectroscopy. Results depicted that, scaffolds containing CNC exhibited remarkable improvement in both swelling ratio up to 110% compared without CNC (63%) and compressive strength when compared with other scaffolds. In addition, the average pore size increased, dramatically, with increasing of CNC up to 230 µm. Porosity was also obeyed the sequence and attainted a maximum value at 93.6%. The growth and cell attachment of fibroblast cells of the selected scaffold were examined prolonging to the cell viability by using Alamar Blue (AB) and then confirmed using SEM. The results indicated that the scaffold comprising CNC has a promising cell growth and cell adherence, and thus expected to have a potent possibility for applications in bone tissue culture.

Synthesis and self-assembly of AB2-type amphiphilic copolymers from biobased hydroxypropyl methyl cellulose and poly(L-lactide).

AB2-type amphiphilic (HPMC)2-PLA copolymers with various hydrophilic block lengths were synthesized using a three step procedure: ring-opening polymerization of L-lactide initiated by propynol, amination reduction of the aldehyde endgroup of HPMC, and thiol-click reaction. The resulted copolymers were characterized by NMR, DOSY-NMR, SEC and FT-IR. The cloud point (CP) was determined by UV-vis spectrometer. Data show that the HPMC block length has little effect on the Cp of the copolymers which is lower than that of HPMC. The self-assembly behavior of the copolymers was investigated from DLS, TEM, and critical micelle concentration (CMC) measurements. Spherical micelles are obtained by self-assembly of copolymers in aqueous solution. The micelle size and the CMC of copolymers increase with increasing HPMC block length. It is concluded that biobased and biodegradable (HPMC)2-PLA copolymers could be promising as nano-carrier of hydrophobic drugs.

Novel thermo-responsive micelles prepared from amphiphilic hydroxypropyl methyl cellulose-block-JEFFAMINE copolymers.

A series of amphiphilic and thermo-responsive block copolymers were synthesized by reductive amination between the aldehyde endgroup of hydrophilic HPMC and the amine group of monoamine, diamine, or triamine JEFFAMINE as hydrophobic block. The resulting diblock, triblock and three-armed copolymers with different hydrophilic/hydrophobic ratios and block lengths were characterized by NMR, FT-IR, DOSY-NMR and SEC. The cloud point (CP) of copolymers was determined by UV-visible spectrometer. Data show that both the geometrical structure and the molar mass of HPMC affect the CP of HPMC-JEF copolymers. The higher the hydrophilic/hydrophobic ratio, the higher the CP of copolymers which is lower than that of HPMC homopolymers. The self-assembly behavior of the copolymers was investigated from dynamic light scattering, transmission electron microscopy, and critical micelle concentration (CMC) measurements. Spherical nano-micelles are obtained by self-assembly of copolymers in aqueous solution, and the micelle size can be tailored by varying the block length of HPMC and the geometrical structure. Three-armed HPMC-JEF copolymers present lower CMC and smaller micelle size as compared to linear diblock and triblock ones. MTT assay evidenced the cytocompatibility of HPMC-JEF copolymers, indicating that they could be promising as drug carrier in drug delivery systems.

Bioresorbable filomicelles for targeted delivery of betulin derivative - In vitro study.

Filomicelles (worm-like micelles) possess high drug loading capacity and long circulation time in the bloodstream. A novel approach can be filomicelles with folic acid (FA) as a targeting moiety. Folate-drug delivery systems can target FA receptors (FAR) that are overexpressed in several human carcinomas, which can potentially maximize therapeutic efficacy while minimizing side effects. The aim of this study was to develop filomicelles from combination of poly(L-lactide)-Jeffamine-folic acid and poly(L-lactide)-poly(ethylene glycol) for delivery of betulin derivative. Phosphate derivative of betulin reveals high cytotoxicity against cancer cells, however its application is restricted due to poor solubility in water. Incorporation into hydrophobic core of micelles can effectively solubilize the drug. Three kinds of micelles were obtained with high drug loading capacity. Based on TEM analysis, the copolymers formed exclusively filomicelles or mixture of filomicelles and spherical micelles. All kinds of micelles provided release of betulin derivative for over 9 days and apart the very initial phase displayed similar release profile. The influence of PLA block on initial burst effect was revealed. The in vitro cytotoxicity of betulin derivative loaded micelles against FAR-positive HeLa cells was confirmed, which proves their usefulness for targeted delivery of cytostatic drug.

Relationship between enzyme adsorption and enzyme-catalyzed degradation of polylactides.

The adsorption of proteinase K on PLLA and PDLA films was studied by CA, surface tension, and microscopic measurements. ESEM clearly shows that proteinase K can irreversibly adsorb on PLLA film. In contrast, no enzyme adsorption was detected on PDLA film under the same conditions. The CA of PLLA film rapidly decreases after immersion in Tris buffer containing proteinase K, whereas that of PDLA remains unchanged. These findings indicate that enzyme adsorption may be a prerequisite for enzymatic degradation of polylactide substrates. Surface tension measurements allow calculation of the average area occupied per proteinase K molecule. The results show that the enzyme molecules exhibit a more compact conformation at higher temperature.