Monthly Archives: February 2016

PLGA-PEG-PLGA block thermogel investigated for glimepiride delivery system as diabetes treatment

PolySciTech division of Akina, Inc (www.polyscitech.com) provides a wide array of block copolymers including PLGA-PEG-PLGA thermogels (such as Polyvivo AK097). Recently, these kinds of polymers were used as part of an investigation for novel delivery systems for glimepiride, an anti-diabetic drug. This delivery system involved forming an inclusion complex between glimerpiride and zein (a corn-based protein with many uses) and these nanoparticles were subsequently embedded in thermogelling PLGA-PEG-PLGA for controlled drug delivery application. Read more: Ahmed, Osama Abdelhakim Aly, Ahmed Samir Zidan, and Maan Khayat. “Mechanistic analysis of Zein nanoparticles/PLGA triblock in situ forming implants for glimepiride.” International Journal of Nanomedicine 11 (2016): 543. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745829/

“Abstract: Objectives: The study aims at applying pharmaceutical nanotechnology and D-optimal fractional factorial design to screen and optimize the high-risk variables affecting the performance of a complex drug delivery system consisting of glimepiride–Zein nanoparticles and inclusion of the optimized formula with thermoresponsive triblock copolymers in in situ gel. Methods: Sixteen nanoparticle formulations were prepared by liquid–liquid phase separation method according to the D-optimal fractional factorial design encompassing five variables at two levels. The responses investigated were glimepiride entrapment capacity (EC), particle size and size distribution, zeta potential, and in vitro drug release from the prepared nanoparticles. Furthermore, the feasibility of embedding the optimized Zein-based glimepiride nanoparticles within thermoresponsive triblock copolymers poly(lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly(lactide-co-glycolide) in in situ gel was evaluated for controlling glimepiride release rate. Results: Through the systematic optimization phase, improvement of glimepiride EC of 33.6%, nanoparticle size of 120.9 nm with a skewness value of 0.2, zeta potential of 11.1 mV, and sustained release features of 3.3% and 17.3% drug released after 2 and 24 hours, respectively, were obtained. These desirability functions were obtained at Zein and glimepiride loadings of 50 and 75 mg, respectively, utilizing didodecyldimethylammonium bromide as a stabilizer at 0.1% and 90% ethanol as a common solvent. Moreover, incorporating this optimized formulation in triblock copolymers-based in situ gel demonstrated pseudoplastic behavior with reduction of drug release rate as the concentration of polymer increased. Conclusion: This approach to control the release of glimepiride using Zein nanoparticles/triblock copolymers-based in situ gel forming intramuscular implants could be useful for improving diabetes treatment effectiveness. Keywords: glimepiride, Zein, nanoparticles, quality by design, in situ implants”

Poly(lactide-co-glycolide) degradation rate relationship with surface area to volume

PolySciTech division of Akina, Inc. (www.polyscitech.com) provides a wide array of biodegradable polyesters including PLGA and others. These polyesters hydrolyze based on random chain scissions along the ester backbone which cut the polymer into smaller components down until they are returned to their original lactic acid and glycolic acid monomeric units. Because of this non-toxic biodegradation, PLGA is widely used for drug delivery and implant applications. One question remains: how long does this process take to occur? This is truly a multi-faceted and complex question relating to the type of PLGA used and its formulation properties. The key parameters which affect this are water access and reactivity. At neutral pH, the hydrolysis reaction is fairly slow but it is accelerated at low pH as well as at high pH. Additionally, the hydrophobic polymer chain itself and polymer characteristics such as crystallinity can act to sterically hinder water access which slows down the degradation rate. Recently, researchers at University of Texas investigated the effect of surface-area-to-volume ratio for PLGA degradation by making scaffolds at varying SVR (some which were very thick and others which were thin). They found, in this situation, that the buildup of low-pH acidic components contributed more significantly to the degradation rate than the restricted water access of the thicker polymer pieces. This is useful in understanding that thicker drug delivery systems are not always slower despite their reduced SVR. Read more about their research here: Chew, Sue Anne, Marco Arriaga, and Victor Hinojosa. “Effects of surface area to volume ratio of plga scaffolds with different architectures on scaffold degradation characteristics and drug release kinetics.” Journal of Biomedical Materials Research Part A (2016). http://onlinelibrary.wiley.com/doi/10.1002/jbm.a.35657/abstract

“Abstract: In this work, PLGA scaffolds with different architectures were fabricated to investigate the effects of surface area to volume ratio (SVR) (which resulted from the different architectures) on scaffold degradation characteristics and drug release kinetics with minocycline as the model drug. It was hypothesized that the thin strand scaffolds, which had the highest SVR, would degrade faster than the thick strand and globular scaffolds as the increase in surface area will allow more contact between water molecules and degradable ester groups in the polymer. However, it was found that globular scaffolds, which had the lowest SVR, resulted in the fastest degradation which demonstrated that the amount of degradation of the scaffolds does not only depend on the SVR but also on other factors such as the retention of acidic degradation byproducts in the scaffold and scaffold porosity. PLGA 50 : 50 globular scaffolds resulted in a biphasic release profile, with a burst release in the beginning and the middle of the release study which may be beneficial for some drug delivery applications. A clear correlation between SVR and release rates was not observed, indicating that besides the availability of more surface area for drug to diffuse out of the polymer matrix, other factors such as amount of scaffold degradation and scaffold porosity may play a role in determining drug release kinetics. Further studies, such as scanning electron microscopy, need to be performed in the future to further evaluate the porosity, morphology and structure of the scaffolds. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2016. Keywords: PLGA scaffolds;surface area to volume ratio;scaffold architecture;degradation characteristics;drug release kinetics”

PolySciTech P(NIPAM-Co-AM) (Polyvivo AO023) used for drop-on-demand (DOD) printing

PolySciTech division of Akina, Inc. (www.polyscitech.com) provides a wide array of thermogelling polymers including gels based of off poly(N-isopropylacrylamind-co-acrylamide) (AO023). One application of this is gel printing. Because it is possible to chill the printing head to dispense the cold liquid thermogel below the polymer LCST and then heat the receiver above the polymer LCST so the thermogel sets, there is the possibility to print gel structures. Eventually, this technology can allow for printing structures using thermogels which incorporate living cells into the printed component which could be used to generate living tissues. Recently, researchers at Purdue University utilized PNIPAM from Akina, along with a developed printing system to create a drop-on-demand system for studying the precise thermogel kinetics, dehydration parameters, and fluid-structure interactions for printing thermogels.  Read more: Han, Bumsoo, Gyu Young Yun, J. William Boley, Samuel Haidong Kim, Jun Young Hwang, George T-C. Chiu, and Kinam Park. “Dropwise gelation-dehydration kinetics during drop-on-demand printing of hydrogel-based materials.” International Journal of Heat and Mass Transfer 97 (2016): 15-25. http://www.sciencedirect.com/science/article/pii/S0017931015310565

“Abstract: The present study aims to characterize and understand the dropwise gelation-dehydration phenomena during drop-on-demand (DOD) printing of hydrogel-based soft materials. Functional soft materials have broader impacts on many medical and engineering applications, but constructing soft materials into three-dimensional (3D) configuration with spatially varying properties is still extremely challenging. In order to establish a mechanistic understanding, a hypothesis was postulated that the porosity of hydrogel printed is determined by dropwise gelation and dehydration phenomena during the printing process. The underlying rationale is that many functional properties of the printed hydrogels are closely associated with the structural characteristics at the sub-droplet and droplet scales, specifically porosity. The porosity of a hydrogel droplet is thought to be determined by intra-droplet fluid–structure interactions during gelation and dehydration. In this study, thus, we characterized the gelation-dehydration and consequent microstructure of thermally responsive poly(N-isopropylacrylamind-co-acrylamide) (PNIPAM) copolymer droplets as a model hydrogel material. The gelation kinetics was studied by differential scanning calorimetry. Both macroscopic and microscopic structures of DOD printed hydrogels were characterized by a 3D profiler and scanning electron microscopy. Furthermore, a theoretical model to explain this complex transport processes was also developed. The results showed that the gelation is a rapid process and its impact is mainly observed at the deposition of droplets. Significant structural shrinkage of the printed hydrogel droplets was induced by dehydration. This shrinkage resulted in spatially varying intra-droplet porosity. A computational model of intra-droplet fluid–structure interactions was developed to explain this spatial variation of intra-droplet porosity. In addition, a new dimensionless parameter is proposed to gauge the significance of evaporation and interstitial water transport in the fluid–structure interactions. Significance of gelation kinetics, dehydration and complex fluid–structure interaction within the droplets was discussed to design a DOD printing process for 3D additive manufacturing of hydrogel-based soft materials. Keywords: Evaporation; Interstitial water transport; Dilatation; Fluid–structure interaction; Consolidation”

PLGA from PolySciTech used as precursor for synthesis of poly(lactic-co-glycolic acid)-g-poly-1-vinylpyrrolidin-2-one copolymers

PolySciTech Division of Akina, Inc. (www.polyscitech.com) provides a wide array of biodegradable block copolymers and polyesters such as poly(lactide-co-glycolide) (PLGA). Recently, researchers at Consorzio Interuniversitario Nazionale per la Scienza e Tecnologia dei Materiali (INSTM) in Firenze, Italy have utilized PLGA from PolySciTech (Polyvivo AP059) as a chain transfer precursor for synthesizing a copolymer of poly(lactic-co-glycolic acid)-g-poly-1-vinylpyrrolidin-2-one. The resultant polymer produced a highly stable dispersion in water indicating its potential application towards solubilizing poorly soluble materials or aiding in drug-delivery. Read more: Ranucci, Elisabetta, Giovanna Capuano, Amedea Manfredi, and Paolo Ferruti. “One‐step synthesis of poly (lactic‐co‐glycolic acid)‐g‐poly‐1‐vinylpyrrolidin‐2‐one copolymers.” Journal of Polymer Science Part A: Polymer Chemistry (2016). http://onlinelibrary.wiley.com/doi/10.1002/pola.28049/full

 

“ABSTRACT: The radical polymerization of 1-vinylpyrrolidin-2-one (NVP) in poly(lactic-co-glycolic acid) (PLGA) 50:50 at 100 °C leads to amphiphilic PLGA-g-PVP copolymers. Their composition is determined by FT-IR spectroscopy. Thermogravimetric analyses agree with FT-IR determinations. Saponification of the PLGA-g-PVP polyester portion allows isolating the PVP side chains and measuring their molecular weight, from which the average chain transfer constant (CT) of the PLGA units is estimated. The MALDI-TOF spectra of PVP reveal the presence at one chain end of residues of either glycolic acid- or lactic acid- or lactic/glycolic acid dimers, trimers and one tetramer, the other terminal being hydrogen. This unequivocally demonstrates that grafting occurred. Accordingly, the orthogonal solvent pair ethyl acetate—methanol, while separating the components of PLGA/PVP intimate mixtures, fails to separate pure PVP or PLGA from the reaction products. All PLGA-g-PVP and PLGA/PLGA-g-PVP blends, but not PLGA/PVP blends, give long-time stable dispersions in water. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016”

Thermogel PLGA-PEG-PLGA investigated for cartilage regeneration as part of arthritis treatment

PolySciTech division of Akina, Inc. (www.polyscitech.com) provides a wide array of biodegradable block copolymers including thermogelling PLGA-PEG-PLGA. This type of polymer transitions from a liquid solution to a solid gel when it is heated from room temperature to body temperature. The benefit of this is it allows for an injected solution to form into a gel once it is introduced into the human body. This is useful for treatment of diseases such as arthritis which may require local delivery to the damaged site. In 2005, an estimated 1.5 million (0.6%) of US adults age ≥ 18 had rheumatoid arthritis which is a disease that attacks cartilage in joints leading to pain and immobility. Recently, researchers published the incorporation of kartogenin in PLGA-PEG-PLGA thermogel and its use in cartilidge repair. Kartogenin induces chondrogenesis by binding the actin-binding protein, filamin A. This disrupts its interaction with the transcription factor core-binding factor β subunit (CBFβ). When dissociated from filamin A, CBFβ translocates to the nucleus and forms a transcriptional complex with RUNX1 thus enabling chondrocyte differentiation. This drug was found to be effectively delivered by the PLGA-PEG-PLGA thermogel locally into the cartilage and this lead to a regerative repair of the cartilage tissue. Read more: Li, Xuezhou, Jianxun Ding, Zheng-Zheng Zhang, Modi Yang, Jia-Kuo Yu, J. C. Wang, Fei Chang, and Xuesi Chen. “Kartogenin-Incorporated Thermogel Supports Stem Cells for Significant Cartilage Regeneration.” ACS applied materials & interfaces (2016). http://pubs.acs.org/doi/pdfplus/10.1021/acsami.5b12212

“Abstract: Recently, cartilage tissue engineering (CTE) attracts increasing attention in cartilage defect repair. In this work, kartogenin (KGN), an emerging chondroinductive non-protein small molecule, was incorporated into a thermogel of poly(L-lactide-co-glycolide)−poly(ethylene glycol)−poly(L-lactide-co-glycolide) (PLGA−PEG−PLGA) to fabricate an appropriate microenvironment of bone marrow mesenchymal stem cells (BMSCs) for effective cartilage regeneration. More integrative and smoother repaired articular surface, more abundant characteristic glycosaminoglycans (GAGs) and collagen II (COL II), and less degeneration of normal cartilage were obtained in the KGN and BMSCs co-loaded thermogel group in vivo. In conclusion, the KGN-loaded PLGA−PEG−PLGA thermogel can be utilized as an alternative support for BMSCs to regenerate the damaged cartilage in vivo.”

Thermogelling PLA-PEG-PLA used in development of post-surgical adhesion prevention

PolySciTech Division of Akina, Inc. (www.polyscitech.com) provides a wide array of biodegradable block copolymers. These include thermogelling PolyVivo AK100 Poly(DL-lactide)-b-Poly(ethylene glycol)-b-Poly(DL-lactide) (P(DL)LA-PEG-P(DL)LA). Recently, researchers at Sichuan University investigated a similar polymer for its use in adhesion prevention. These thermogelling polymers are liquid at room temperature and then transition into a solid gel when the temperature is increased to 37C. This has many uses for applications such as depot drug delivery, vaccine delivery, and prevention of post-surgical adhesion. Post-surgical adhesion is a normal injury response of peritoneal surfaces during surgery which can cause significant morbidity, including bowel obstruction, female infertility, and chronic abdominal and pelvic pain (Diamond MP, Freeman ML. Clinical implications of postsurgical adhesions. Hum Reprod Update 2001; 7:567.) Nationally, about 5.7% of readmissions are due to adhesion with 3.8% requiring operation to fix the problem (Ellis H, Moran BJ, Thompson JN, et al. Adhesion-related hospital readmissions after abdominal and pelvic surgery: a retrospective cohort study. Lancet 1999; 353:1476.) so there is a great need to reduce these adhesions. The researchers found that P(DL)LA-PEG-P(DL)LA presented minimal cytotoxicity or hemolysis, due to its biocompatible nature. They also found that the thermogel polymer led to a significant post-operative adhesion in a rat sidewall defect bowel abrasion model. These results indicate the potential for use of these types of polymers to prevent surgical adhesion. Read more: Shi, K., Wang, Y.L., Qu, Y., Liao, J.F., Chu, B.Y., Zhang, H.P., Luo, F. and Qian, Z.Y., 2016. Synthesis, characterization, and application of reversible PDLLA-PEG-PDLLA copolymer thermogels in vitro and in vivo. Scientific reports, 6. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707506/

“Abstract: In this study, a series of injectable thermoreversible and thermogelling PDLLA-PEG-PDLLA copolymers were developed and a systematic evaluation of the thermogelling system both in vitro and in vivo was performed. The aqueous PDLLA-PEG-PDLLA solutions above a critical gel concentration could transform into hydrogel spontaneously within 2 minutes around the body temperature in vitro or in vivo. Modulating the molecular weight, block length and polymer concentration could adjust the sol-gel transition behavior and the mechanical properties of the hydrogels. The gelation was thermally reversible due to the physical interaction of copolymer micelles and no crystallization formed during the gelation. Little cytotoxicity and hemolysis of this polymer was found, and the inflammatory response after injecting the hydrogel to small-animal was acceptable. In vitro and in vivo degradation experiments illustrated that the physical hydrogel could retain its integrity as long as several weeks and eventually be degraded by hydrolysis. A rat model of sidewall defect-bowel abrasion was employed, and a significant reduction of post-operative adhesion has been found in the group of PDLLA-PEG-PDLLA hydrogel-treated, compared with untreated control group and commercial hyaluronic acid (HA) anti-adhesion hydrogel group. As such, this PDLLA-PEG-PDLLA hydrogel might be a promising candidate of injectable biomaterial for medical applications.”

PLGA used for development of nanoparticle based chlamydia vaccine delivery

PolySciTech (www.polyscitech.com) provides a wide array of biodegradable polyesters including PLGA. Recently, researchers are Alabama State University, used this kind of polymer for the delivery of rMOMP-187 peptide to elicit a genital mucosal Th1 response. The researchers established that this delivery system induced macrophages to display an immune response thus showing potential for prevention of chlamydia. This research has the potential to provide for an effective vaccine against chlamydia. This is particularly valuable as the incidence of chlamydia infections as of 2008 was 105.7 million cases and rising (WHO, Global incidence and prevalents of selected curable sexually transmitted infections – 2008). Read more about this research here: Taha, M., S. R. Singh, C. Butler, E. Nyairo, and V. A. Dennis. “Characterization of rMOMP-187 Peptide Encapsulated in PLGA 50: 50 Nanoparticles.” une 13 (2016): 15. http://www.nsti.org/procs/Nanotech2011v3/3/T6.321

“Abstract: The design of an immunization regimen capable of inducing sustained genital mucosal Th1 response is the current goal for a vaccine for humans to control the severe complications of genital infection by C. trachomatis. In this research, gene fragments of the MOMP gene containing T and B-cell epitopes (corresponding to amino acids 187 – 344) were expressed in E. coli cells, purified and encapsulated in PLGA 50:50 nanoparticles. The efficacy of rMOMP-187–PLGA nanoparticles was evaluated in vitro in J774 macrophages. Our data shows that rMOMP-187 encapsulated in PLGA 50:50 nanoparticles has the potential to induce immune responses in vivo and hence further studies are underway to confirm its usefulness as a promising vaccine candidate against Chlamydia. The anticipated results will provide the foundation for full- scale research on the antibody immunity characteristics of recombinant MOMP-PLGA as a potential candidate against Chlamydia. Keywords: Chlamydia, rMOMP, PLGA”

PolySciTech PLGA used as part of development of bio-adhesive

PolySciTech division of Akina, Inc. (www.polyscitech.com) provides a wide array of biodegradable block copolymers and polyesters. Recently, researchers used PLGA from PolySciTech as a control article as part of the development of an mussel-inspired bioadhesive. Read more: Guo, J., Wang, W., Hu, J., Xie, D., Gerhard, E., Nisic, M., Shan, D., Qian, G., Zheng, S. and Yang, J., 2016. Synthesis and characterization of anti-bacterial and anti-fungal citrate-based mussel-inspired bioadhesives. Biomaterials. http://www.sciencedirect.com/science/article/pii/S0142961216000958

“Abstract: Bacterial and fungal infections in the use of surgical devices and medical implants remain a major concern. Traditional bioadhesives fail to incorporate anti-microbial properties, necessitating additional anti-microbial drug injection. Herein, by the introduction of the clinically used and inexpensive anti-fungal agent, 10-undecylenic acid (UA), into our recently developed injectable citrate-based mussel-inspired bioadhesives (iCMBAs), a new family of anti-bacterial and anti-fungal iCMBAs (AbAf iCs) was developed. AbAf iCs not only showed strong wet tissue adhesion strength, but also exhibited excellent in vitro cyto-compatibility, fast degradation, and strong initial and considerable long-term anti-bacterial and anti-fungal ability. For the first time, the biocompatibility and anti-microbial ability of sodium metaperiodate (PI), an oxidant used as a cross-linking initiator in the AbAf iCs system, was also thoroughly investigated. Our results suggest that the PI-based bioadhesives showed better anti-microbial properties compared to the unstable silver-based bioadhesive materials. In conclusion, AbAf iCs family can serve as excellent anti-bacterial and anti-fungal bioadhesive candidates for tissue/wound closure, wound dressing, and bone regeneration, especially when bacterial or fungal infections are a major concern. Keywords: wound closure; antibacterial; antifungal; citric acid; sodium metaperiodate; silver nanoparticles”

PolyVivo PLGA used in nanoparticle development for contraceptives

PolySciTech Division of Akina, Inc. (www.polyscitech.com) provides a wide array of biodegradable polymers including PLGA. Recently, our PLGA product PolyVivo AP081 was used as part of development of a nanoparticle delivery system of male contraceptive FSHR vaccine to allow for reduction in spermatogenesis without causing side-effects. Read more: Xu, Pingping, Shuai Tang, Luping Jiang, Lihua Yang, Dinglin Zhang, Shibin Feng, Tingting Zhao et al. “Nanomaterial-dependent immunoregulation of dendritic cells and its effects on biological activities of contraceptive nanovaccines.” Journal of Controlled Release (2016). http://www.sciencedirect.com/science/article/pii/S0168365916300396

“Abstract: Nanovehicles are promising delivery systems for various vaccines. Nevertheless, different biophysicochemical properties of nanoparticles (NPs), dominating their in vitro and in vivo performances for vaccination, remain unclear. We attempted to elucidate the effects of NPs and their pH-sensitivity on in vitro and in vivo efficacy of resulting prophylactic nanovaccines containing a contraceptive peptide (FSHR). To this end, pH-responsive and non-responsive nanovaccines were produced using acetalated β-cyclodextrin (Ac-bCD) and poly(lactic-co-glycolic acid) (PLGA), respectively. Meanwhile, FSHR derived from an epitope of the follicle-stimulating hormone receptor was used as the model antigen. FSHR-containing Ac-bCD and PLGA NPs were successfully prepared by a nanoemulsion technique, leading to well-shaped nanovaccines with high loading efficiency. The pH-sensitivity of Ac-bCD and PLGA nanovaccines was examined by in vitro hydrolysis and antigen release studies. Nanovaccines could be effectively engulfed by dendritic cells (DCs) via endocytosis in both dose and time dependent manners, and their intracellular trafficking was closely related to the pH-sensitivity of the carrier materials. Furthermore, nanovaccines could induce the secretion of inflammatory cytokines by DCs and T cells co-cultured with the stimulated DCs. In vivo evaluations demonstrated that nanovaccines were more potent than that based on the complete Freund’s adjuvant, with respect to inducing anti-FSHR antibody, reducing the sperm count, inhibiting the sperm motility, and increasing the teratosperm rate. Immunization of male mice with nanovaccines notably decreased the parturition incidence of the mated females. Consequently, both in vitro and in vivo activities of FSHR could be considerably augmented by NPs. More importantly, our studies indicated that the pH-responsive nanovaccine was not superior over the non-responsive counterpart for the examined peptide antigen. Keywords: Nanoparticle; Peptide antigen; pH-responsive; Cyclodextrin; Dendritic cell; Intracellular delivery”

Image: http://4.bp.blogspot.com/-fKTmLnWI8II/Vq9-TTudwyI/AAAAAAAACCY/TqFssXKJJd0/s1600/Xu%252C%2B2016%2Bcontraceptive%2Bnanoparticle.png