Monthly Archives: March 2016

PolyVivo polymers and reactive intermediates investigated for delivery of magnetic nanoparticles and quantum dots as part of cancer theranostics

PolySciTech division of Akina, Inc. (www.polyscitech.com) provides a wide variety of block copolymers and reactive intermediates. Recently, two PolySciTech polymers PolyVivo AK051 (mPEG-PLGA 5000-5000Da) and PolyVivo AI075 (Maleimide-PEG-PLGA 5000-5000Da) were used to generate targeted nanoparticles as part of delivery system of quantum dots to tumor cells. This allows for the simultaneous therapy and diagnostic approaches to cancer, known as theranostics. Read more: Zhu, Xiaoshan. “Magnetofluorescent Nanocomposites Integrating Magnetic Nanoparticles and Near Infrared Quantum Dots for Tumor Cell Targeting.” In Materials Science Forum, vol. 856. 2016. http://search.ebscohost.com/login.aspx?direct=true&profile=ehost&scope=site&authtype=crawler&jrnl=16629752&AN=113640126&h=JADHJX1brxin1jyiZ%2FBR%2Fosqe0jGI7nRrK4hC8EZHTOX7EqIuT6eiCX2nhW2jByFd4SNxUtKv60KWP4A62eZEw%3D%3D&crl=c

“Abstract: In this work, we report the preparation of MFNCs integrating MnFe2O4 magnetic nanoparticles (MNPs), near infrared CuInS2/ZnS quantum dots (QDs) and poly(ethylene glycol)-b- poly(lactide-co-glycolide) (PEG-PLGA) in a tetrahydrofuran (THF)/water solvent system. It is found that the MFNCs possess high (Mn + Fe) recovery rates, and the optical properties and magnetic relaxivity of the MFNCs are tunable according to the MNP:QD mass ratios. Furthermore, the MFNCs present excellent capability for tumor cell targeting once they are conjugated with bioprobes specific to tumor cells. This study opens an avenue for the MFNCs to be employed in broad biological or biomedical applications.”

PLGA from PolySciTech investigated for in-situ delivery of doxorubicin for treatment of liver cancer

PolySciTech division of Akina, Inc (www.polyscitech.com) provides a wide array of biodegradable block copolymers and polyesters. This includes PLGA (PolyVivo AP031) which has recently been used in a study relating to localized delivery of doxorubicin to a tumor site. There are many advantages to providing localized delivery, especially for chemotherapeutics, as this reduces systemic toxicity to whole body while maintaining a therapeutic concentration directly at the tumor site. One means of doing this is to dissolve a biodegradable polymer (such as PLGA) in a water-miscible, biocompatible organic solvent such as N-methyl-2-pyrrolidinone (NMP) along with the drug to be delivered. When this solution is introduced into the body, the NMP extracts out quickly with the surrounding bodily fluids leaving a solid PLGA form containing the drug. This is referred to as an ‘in-situ implant’ because the solid implant is actually formed inside the body itself. From this point forward, the drug leaches slowly out of the PLGA by diffusion and degradation, providing an extended delivery system which provides drug directly to the local tissues. A major advantage to using this system is direct, local application of the medicine. This is unlike systemic application. The majority of medicine which is administered systemically (for example, a traditional IV injection) never reaches the location of action. Instead, the body’s natural screening mechanisms, remove the drug from the blood by the kidneys and it ends up in the urine, or it is removed by other pathways.  Recently, researchers used in-situ formation technique to deliver PLGA encapsulated doxorubicin to model liver-cancer tumors. Liver cancer is normally resistant to traditional chemotherapy. They found that the tumors had significantly reduced progression after 21 days from this doxorubicin delivery method which holds promise as a treatment method. Read more: Solorio, Luis, Hanping Wu, Christopher Hernandez, Mihika Gangolli, and Agata A. Exner. “Ultrasound-guided intratumoral delivery of doxorubicin from in situ forming implants in a hepatocellular carcinoma model.” Therapeutic Delivery 7, no. 4 (2016): 201-212. http://www.future-science.com/doi/abs/10.4155/tde-2015-0008

“Abstract: Background: Hepatocellular carcinomas are frequently nonresponsive to systemically delivered drugs. Local delivery provides an alternative to systemic administration, maximizing the dose delivered to the tumor, achieving sustained elevated concentrations of the drug, while minimizing systemic exposure. Results: Ultrasound-guided deposition of doxorubicin (Dox)-eluting in situ forming implants (ISFI) in an orthotopic tumor model significantly lowers systemic drug levels. As much as 60 µg Dox/g tumors were observed 21 days after ISFI injection. Tumors treated with Dox implants also showed a considerable reduction in progression at 21 days. Conclusion: Dox-eluting ISFIs provide a promising platform for the treatment of hepatocellular carcinomas by which drug can be delivered directly into the lesion, bypassing distribution and elimination by the circulatory system.”

New NIR fluorescent dyes available for in-vivo imaging applications

PolySciTech division of Akina, Inc (www.polyscitech.com) provides a wide array of research products including Flamma Fluor dyes. Recently, 3 new dyes have been added to our local inventory available for 1 business-day shipping to anywhere in USA. These include FKI-749, a non-reactive hydrophobic near-IR (abs/em 746 nm/773 nm), FKI-749 dichlorotirazine, an amine and hydroxyl reactive near-IR dye (abs/em 749 nm/774 nm), and D-0013 (abs/em 739 nm/768 nm). Because of their near-IR fluorescence spectra, these dyes have the capability to operate in a region of light which passes easily through bodily tissues. The benefit to this is that these can be applied to in-vivo imaging, which is imaging of a structure or dyed component in an animal model while the animal is alive. This is particularly useful for research and other applications. Read more about in-vivo imaging here: Gibbs, Summer L. “Near infrared fluorescence for image-guided surgery.” Quantitative imaging in medicine and surgery 2, no. 3 (2012): 177-187. Full-Text: http://www.amepc.org/qims/article/view/1078/1373

“Abstract: Near infrared (NIR) image-guided surgery holds great promise for improved surgical outcomes. A number of NIR image-guided surgical systems are currently in preclinical and clinical development with a few approved for limited clinical use. In order to wield the full power of NIR image-guided surgery, clinically available tissue and disease specific NIR fluorophores with high signal to background ratio are necessary. In the current review, the status of NIR image-guided surgery is discussed along with the desired chemical and biological properties of NIR fluorophores. Lastly, tissue and disease targeting strategies for NIR fluorophores are reviewed. Key words: Near infrared (NIR); image-guided surgery”

mPEG-PLGA nanoparticles investigated as part of dual-drug chemotherapeutic treatment of brain cancer

PolySciTech division of Akina, Inc. (www.polyscitech.com) provides a wide array of research products including biodegradable block copolymer mPEG-PLGA. Recently, this polymer was used for generating nanoparticles loaded with two chemotherapeutic drugs. These include paclitaxel, an anti-mitotic drug derived from the Pacific yew tree commonly used in treatment of cancer, and Temozolomide, a drug which acts to damage DNA of tumor cells making it unreadable and triggering cell-death.  The co-delivery of these chemotherapeutic agents in a nanoparticle system was found to significantly reduce brain tumor cell growth and proliferation in mice. Read more: Xu, Y., M. Shen, Y. Li, Y. Sun, Y. Teng, Y. Wang, and Y. Duan. “The synergic antitumor effects of paclitaxel and temozolomide co-loaded in mPEG-PLGA nanoparticles on glioblastoma cells.” Oncotarget (2016).  http://europepmc.org/abstract/med/26956046

“Abstract: To get better chemotherapy efficacy, the optimal synergic effect of Paclitaxel (PTX) and Temozolomide (TMZ) on glioblastoma cells lines was investigated. A dual drug-loaded delivery system based on mPEG-PLGA nanoparticles (NPs) was developed to potentiate chemotherapy efficacy for glioblastoma. PTX/TMZ-NPs were prepared with double emulsification solvent evaporation method and exhibited a relatively uniform diameter of 206.3 ± 14.7 nm. The NPs showed sustained release character. Cytotoxicity assays showed the best synergistic effects were achieved when the weight ratios of PTX to TMZ were 1:5 and 1:100 on U87 and C6 cells, respectively. PTX/TMZ-NPs showed better inhibition effect to U87 and C6 cells than single drug NPs or free drugs mixture. PTX/TMZ-NPs (PTX: TMZ was 1:5(w/w)) significantly inhibited the tumor growth in the subcutaneous U87 mice model. These results indicate that coordinate administration of PTX and TMZ combined with NPs is an efficient method for glioblastoma.”

Polymers from PolySciTech investigated for optimizing magnesium skeletal implant coatings

PolySciTech division of Akina, Inc (www.polyscitech.com) provides a wide array of biodegradable polyesters including PLGA, PLLA, and PCL. Recently, researchers at University of California at Riverside utilized a PLGA (PolyVivo AP052), a PLLA (PolyVivo AP065) and PCL (PolyVivo AP009) from PolySciTech to design a system for coating magnesium substrates.  Read more about this study: Johnson, Ian, Sebo Michelle Wang, Christine Silken, and Huinan Liu. “A Systemic Study on Key Parameters Affecting Nanocomposite Coatings on Magnesium Substrates.” Acta Biomaterialia (2016). http://www.sciencedirect.com/science/article/pii/S1742706116301209

“Abstract: Nanocomposite coatings offer multiple functions simultaneously to improve the interfacial properties of magnesium (Mg) alloys for skeletal implant applications, e.g., controlling the degradation rate of Mg substrates, improving bone cell functions, and providing drug delivery capability. However, the effective service time of nanocomposite coatings may be limited due to their early delamination from the Mg-based substrates. Thus, the objective of this study was to address the delamination issue of nanocomposite coatings, improve the coating properties for reducing the degradation of Mg-based substrates, and thus improve their cytocompatibility with bone marrow derived mesenchymal stem cells (BMSCs). The surface conditions of the substrates, polymer component type of the nanocomposite coatings, and post-deposition processing are the key parameters that contribute to the efficacy of the nanocomposite coatings in regulating substrate degradation and bone cell responses. Specifically, the effects of metallic surface versus alkaline heat-treated hydroxide surface of the substrates on coating quality were investigated. For the nanocomposite coatings, nanophase hydroxyapatite (nHA) was dispersed in three types of biodegradable polymers, i.e., poly(lactic-co-glycolic acid) (PLGA), poly(L-lactic acid) (PLLA), or poly(caprolactone) (PCL) to determine which polymer component could provide integrated properties for slowest Mg degradation. The nanocomposite coatings with or without post-deposition processing, i.e., melting, annealing, were compared to determine which processing route improved the properties of the nanocomposite coatings most significantly. The results showed that optimizing the coating processes addressed the delamination issue. The melted then annealed nHA/PCL coating on the metallic Mg substrates showed the slowest degradation and the best coating adhesion, among all the combinations of conditions studied; and, it improved the adhesion density of BMSCs. This study elucidated the key parameters for optimizing nanocomposite coatings on Mg-based substrates for skeletal implant applications, and provided rational design guidelines for the nanocomposite coatings on Mg alloys for potential clinical translation of biodegradable Mg-based implants. Keywords: Magnesium; hydroxyapatite (HA) nanoparticles; Nanocomposites; poly(lactic-co-glycolic acid) (PLGA); poly(L-lactic acid) (PLLA); poly(caprolactone) (PCL); Biodegradable polymers; revised simulated body fluid (rSBF); bone marrow derived mesenchymal stem cells (BMSCs); Internal stress; Residual stress; Bioresorbable skeletal implants”

PLGA nanoparticles studied for curcumin delivery as Alzheimer’s treatment

PolySciTech Division of Akina Inc. (www.polyscitech.com) provides a wide array of biodegradable polymers including PLGA. Recently researchers have investigated the role of PLGA in regards to its application in aiding the uptake of curcumin, a naturally derived potent neuroprotective agent, into neural brain cells. Read more: Paka, Ghislain Djiokeng, Sihem Doggui, Ahlem Zaghmi, Ramia Safar, Lé Dao, Andreas Reisch, Andrey Klymchenko, V. Gaëlle Roullin, Olivier Joubert, and Charles Ramassamy. “Neuronal Uptake and Neuroprotective Properties of Curcumin-Loaded Nanoparticles on SK-N-SH Cell Line: Role of Poly (lactide-co-glycolide) Polymeric Matrix Composition.” Molecular Pharmaceutics 13, no. 2 (2016). https://hal-univ-lorraine.archives-ouvertes.fr/hal-01281133/

“Abstract : Curcumin, a neuroprotective agent with promising therapeutic approach has poor brain bioavailability. Herein, we demonstrate that curcumin-encapsulated poly(lactide-co-glycolide) (PLGA) 50:50 nanoparticles (NPs-Cur 50:50) are able to prevent the phosphorylation of Akt and Tau proteins in SK-N-SH cells induced by H2O2 and display higher anti-inflammatory and antioxidant activities than free curcumin. PLGA can display various physicochemical and degradation characteristics for controlled drug release applications according to the matrix used. We demonstrate that the release of curcumin entrapped into a PLGA 50:50 matrix (NPs-Cur 50:50) is faster than into PLGA 65:35. We have studied the effects of the PLGA matrix on the expression of some key antioxidant- and neuroprotective-related genes such as APOE, APOJ, TRX, GLRX, and REST. NPs-Cur induced the elevation of GLRX and TRX while decreasing APOJ mRNA levels and had no effect on APOE and REST expressions. In the presence of H2O2, both NPs-Cur matrices are more efficient than free curcumin to prevent the induction of these genes. Higher uptake was found with NPs-Cur 50:50 than NPs-Cur 65:35 or free curcumin. By using PLGA nanoparticles loaded with the fluorescent dye Lumogen Red, we demonstrated that PLGA nanoparticles are indeed taken up by neuronal cells. These data highlight the importance of polymer composition in the therapeutic properties of the nanodrug delivery systems. Our study demonstrated that NPs-Cur enhance the action of curcumin on several pathways implicated in the pathophysiology of Alzheimer’s disease (AD). Overall, these results suggest that PLGA nanoparticles are a promising strategy for the brain delivery of drugs for the treatment of AD.”

PLGA microparticle drug delivery elucidated by in-depth mechanistic study

PolySciTech division of Akina, Inc (www.polyscitech.com) provides a wide array of biodegradable polyesters including poly(lactide-co-glycolide) PLGA and related polymers. One of the common usages for this polymer is to use it for encapsulating a medicinal molecule inside and generating a micron sized spheres of PLGA (microspheres or microparticles) which can be directly injected into a patient via typical syringe and needle either intra-muscular or subcutaneous. Over time, the PLGA microparticles slowly releases the medicine into the patient’s blood-stream ideally maintaining the medicinal concentration within the therapeutic window (above the effective dose but below the toxic dose) over an extended course of time (weeks to months). Afterwards, the PLGA degrades into its nontoxic components lactic and glycolic acid and is naturally metabolized by the body. This delivery system is currently used for a variety of clinical formulations (Risperdal Consta®, Trelstar ®, and several others) so that there is no need for the patient to receive daily injections to maintain a therapeutic dose. The release mechanism is known to be a combination of diffusion of the drug through the PLGA matrix out into the blood-stream as well as the degradation of the polymer which contributes to drug release from PLGA microparticles. However, not all of these complex and overlapping processes are fully understood in a mechanistic sense. Without this understanding, development to drug delivery microparticles still require a great deal of trial-and-error. Recently, one of the most in-depth mechanistic studies to date regarding the PLGA controlled delivery of medicines has been reported by researchers at the University of Connecticut. Here they trapped the PLGA microspheres in a PVA hydrogel and imaged them in sequence during drug release and degradation. They correlated these results to polymer physicochemical properties to elucidate parameters which affect release in a micro-environment setting. They managed to track several complex and overlapping interactions including pore-formation and closure, microclimate acidification, water uptake, and microdialysis. You can learn more about these fascinating processes that affect PLGA microparticle performance here: Gu, Bing, Xuanhao Sun, Fotios Papadimitrakopoulos, and Diane J. Burgess. “Seeing is believing, PLGA microsphere degradation revealed in PLGA microsphere/PVA hydrogel composites.” Journal of Controlled Release (2016). http://www.sciencedirect.com/science/article/pii/S0168365916301353

“Abstract: The aim of this study was to understand the polymer degradation and drug release mechanism from PLGA microspheres embedded in a PVA hydrogel. Two types of microspheres were prepared with different molecular weight PLGA polymers (approximately 25 and 7 kDa) to achieve different drug release profiles, with a 9-day lag phase and without a lag phase, respectively. The kinetics of water uptake into the microspheres coincided with the drug release profiles for both formulations. For the 25 kDa microspheres, minimal water uptake was observed in the early part of the lag phase followed by substantial water uptake at the later stages and in the drug release phase. For the 7 kDa microspheres, water uptake occurred simultaneously with drug release. Water uptake was approximately 2-3 times that of the initial microsphere weight for both formulations. The internal structure of the PLGA microspheres was evaluated using low temperature scanning electron microscopy (cryo-SEM). Burst drug release occurred followed by pore forming from the exterior to the core of both microspheres. A well-defined hydrogel/microsphere interface was observed. For the 25 kDa microspheres, internal pore formation and swelling occurred before the second drug release phase. The surface layer of the microspheres remained intact whereas swelling, and degradation of the core continued throughout the drug release period. In addition, microsphere swelling reduced glucose transport through the coatings in PBS media and this was considered to be a as a consequence of the increased thickness of the coatings. The combination of the swelling and microdialysis results provides a fresh understanding on the competing processes affecting molecular transport of bioanalytes (i.e. glucose) through these composite coatings during prolonged exposure in PBS. Keywords: swelling; release mechanism; heterogeneous degradation; outside-in pore formation; cryo-SEM; glucose diffusion”

PEG-PLGA nanoparticles investigated for delivery of orlistat and antisense miRNA for triple-negative breast cancer therapy

PolySciTech division of Akina, Inc. (www.polyscitech.com) provides a wide array of biodegradable research polymers including PEG-PLGA block copolymers for drug-delivery applications. Recently, these types of polymers were used to generate nanoparticles loaded with Orlistat along with doxorubicin or antisense-miR-21. Orlistat is traditionally used to treat obesity, as it acts as a gastric lipase inhibitor. However, it also inhibits the thioesterase domain of fatty acid synthase, which is an enzyme involved in cancer cell proliferation. When this drug was delivered via nanoparticles it more effectively inhibited growth of breast-cancer cells than when delivered as loose drug. When it was co-delivered in a PEG-PLGA nanoparticle formulation along with conventional chemotherapeutic doxorubicin or antisense miR-21, an inhibitor of microRNA-21 which is a cancer-related RNA sequence that affects cancer migration, apoptosis, and growth, the combined drugs had a powerful synergistic effect against cancer proliferation. Read more: Bhargava-Shah, Aarohi, Kira Foygel, Rammohan Devulapally, and Ramasamy Paulmurugan. “Orlistat and antisense-miRNA-loaded PLGA-PEG nanoparticles for enhanced triple negative breast cancer therapy.” Nanomedicine 0 (2016). http://www.futuremedicine.com/doi/abs/10.2217/nnm.15.193

“Abstract: Background: This study explores the use of hydrophilic poly(ethylene glycol)-conjugated poly(lactic-co-glycolic acid) nanoparticles (PLGA-PEG-NPs) as delivery system to improve the antitumor effect of antiobesity drug orlistat for triple-negative breast cancer (TNBC) therapy by improving its bioavailability. Materials & methods: PLGA-PEG-NPs were synthesized by emulsion-diffusion-evaporation method, and the experiments were conducted in vitro in MDA-MB-231 and SKBr3 TNBC and normal breast fibroblast cells. Results: Delivery of orlistat via PLGA-PEG-NPs reduced its IC50 compared with free orlistat. Combined treatment of orlistat-loaded NPs and doxorubicin or antisense-miR-21-loaded NPs significantly enhanced apoptotic effect compared with independent doxorubicin, anti-miR-21-loaded NPs, orlistat-loaded NPs or free orlistat treatments. Conclusion: We demonstrate that orlistat in combination with antisense-miR-21 or current chemotherapy holds great promise as a novel and versatile treatment agent for TNBC.”

PolyVivo AK109: Thermogelling PLCL-PEG-PLCL for long-term delivery

PolySciTech division of Akina, Inc. (www.polyscitech.com) provides a wide array of biodegradable block copolymers including thermogelling PLCL-PEG-PLCL AK109. This polymer has a similar LCST property to its PLGA based counter-parts but, unlike PLGA, a much slower degradation time due to slow-degrading PLCL blocks.  Since a 20% w/v aqueous solution of this polymer is liquid it can easily be combined with microparticles or API directly. Then the solution can be injected where body heat solidifies the gel trapping the pharmaceutical so that it elutes out slowly for long term controlled release. You can learn more about in-situ thermogels and their usage in drug delivery in a well-written review article here: He, Chaoliang, Sung Wan Kim, and Doo Sung Lee. “In situ gelling stimuli-sensitive block copolymer hydrogels for drug delivery.” Journal of controlled release 127, no. 3 (2008): 189-207. http://www.sciencedirect.com/science/article/pii/S0168365908000436

“Abstract: Stimuli-sensitive block copolymer hydrogels, which are reversible polymer networks formed by physical interactions and exhibit a sol–gel phase-transition in response to external stimuli, have great potential in biomedical and pharmaceutical applications, especially in site-specific controlled drug-delivery systems. The drug may be mixed with a polymer solution in vitro and the drug-loaded hydrogel can form in situ after the in vivo administration, such as injection; therefore, stimuli-sensitive block copolymer hydrogels have many advantages, such as simple drug formulation and administration procedures, no organic solvent, site-specificity, a sustained drug release behavior, less systemic toxicity and ability to deliver both hydrophilic and hydrophobic drugs. Among the stimuli in the biomedical applications, temperature and pH are the most popular physical and chemical stimuli, respectively. The temperature- and/or pH-sensitive block copolymer hydrogels for biomedical applications have been extensively developed in the past decade. This review focuses on recent development of the preparation and application for drug delivery of the block copolymer hydrogels that respond to temperature, pH or both stimuli, including poly(N-substituted acrylamide)-based block copolymers, poloxamers and their derivatives, poly(ethylene glycol)-polyester block copolymers, polyelectrolyte-based block copolymers and the polyelectrolyte-modified thermo-sensitive block copolymers. In addition, the hydrogels based on other stimuli-sensitive block copolymers are discussed. Keywords: Stimuli sensitive; Hydrogel; Block copolymer; Drug delivery; Response”

Kito-10 Thiolated Chitosan available from PolySciTech: Akina, Inc.

The Polyscitech division of Akina, Inc. (www.polyscitech.com) now provides thiolated chitosan as an iminothiolane conjugate (Kitopure: Kito-10). This pH sensitive and bioadhesive polysaccharide has loose thiol units available which can form disulfide bonds under appropriate conditions thereby creating a gel for drug delivery or cell-scaffolding applications. Additionally, this polymer improves bioavailability. Read more about this class of polymers here: Sreenivas, S. A., and K. V. Pai. “Thiolated chitosans: novel polymers for mucoadhesive drug delivery–a review.” Tropical Journal of Pharmaceutical Research 7, no. 3 (2008): 1077-1088. http://www.ajol.info/index.php/tjpr/article/view/14694

“Abstract: Chitosan is a natural polycationic copolymer consisting of glucosamine and N-acetylglucosamine units. The polymer has valuable properties as a biomaterial because it is considered to be biocompatible, biodegradable and non-toxic. The purpose of this review article is to provide detailed information about thiolated chitosans which are gaining popularity because of their high mucoadhsiveness and extended drug release properties. The derivatization of the primary amino groups of chitosan with coupling reagents bearing thiol functions leads to the formation of thiolated chitosans. Various properties of chitosan are improved by the immobilization of thiol groups. Due to the formation of disulfide bonds with mucus glycoproteins, mucoadhesiveness is augmented. The permeation of paracellular markers through mucosa can be enhanced by utilizing thiolated instead of unmodified chitosan. Moreover, thiolated chitosans display in situ gelling features due to the pH-dependent formation of inter- as well as intra-molecular disulfide bonds. This latter process provides, strong cohesion and stability of carrier matrices, being based on thiolated chitosans. The in situ gel formation within the pH range of 5 to 6.8 makes the application of thiolated chitosans on vaginal, nasal and ocular mucosa also possible. Thiolated chitosans can guarantee prolonged controlled release of embedded therapeutic ingredients. Keywords: Thiolated chitosan,Thiomers, Mucoadhesion, Permeation enhancement, In situ gelation”