Monthly Archives: May 2016

PLGA-PEG-PLGA investigated for intratympanic delivery of antiviral medicines as cytomegalovirus treatment

PolySciTech division of Akina, Inc (www.polyscitech.com) provides a wide array of biodegradable block copolymers including PLGA-PEG-PLGA. This biodegradable thermogel is a free-flowing solution at room temperature and stiffens to a gel when warmd to body temperature. One common cause of hearing loss is a cytomegalovirus (CMV) which is a viral infection that leads to progressive deterioration of the inner ear and eventual hearing loss in children. The two most common antivirals used to treat this (Ganciclovir and Cidofovir) are effective against the virus but have significant toxicity when delivered systemically especially towards kidneys. One way to avoid system side effects is to provide for a localized delivery of the medicine to the exact location needed so that overall systemic dose is very low while the local dose is about the therapeutic threshhold. Recently, researchers in Cincinnati have combined these antivirals with thermogelling PLGA-PEG-PLGA along with anti-inflammatory dexamethasone to generate a system that can be injected into the intratympanic space and deliver these medicines there. This research may be useful for treating a disease which leads to hearing loss in the future. Read more: Sidell, Douglas, Jonette A. Ward, Angad Pordal, Carson Quimby, Michel Nassar, and Daniel I. Choo. “Combination therapies using an intratympanic polymer gel delivery system in the guinea pig animal model: A safety study.” International journal of pediatric otorhinolaryngology 84 (2016): 132-136. http://www.sciencedirect.com/science/article/pii/S0165587616001038

“Abstract: Objectives: High dose antivirals have been shown to cause hearing loss when applied via the intratympanic route. The aim of this study was to determine if a combination therapy using dexamethasone (DXA) with either Cidofovir (CDV) or Ganciclovir (GCV), in solution or in PLGA-PEG-PLGA (PPP) hydrogel, is innocuous to the inner ear. Methods: Cytomegalovirus (CMV)-free guinea pigs were separated into four principal study groups and treated via intratympanic injection (IT) of CDV/DXA solution, CDV/DXA Hydrogel, GCV/DXA solution and GCV/DXA hydrogel. Hearing thresholds were evaluated with pretreatment ABR and post injection weekly ABRs for a total follow up of 28 days. Temporal bone tissue was harvested and stained with Hematoxylin and Eosin for histologic analysis. Results: ABR analysis revealed that GCV/DXA in solution and in hydrogel led to a mild hearing loss at days 7–21 but returned to baseline by day 28 When administered via PPP hydrogel, CDV/DXA demonstrated mild persistent hearing loss at 32 kHz at 28 days. An inflammatory response was identified in the cochlear specimen of the CDV/DXA/PPP hydrogel group, in concert with mild hearing loss, at days 21 and 28. Conclusion: Results of this study support the safe intratympanic use of higher concentrations of antivirals when combined with DXA, both in solution and when applied via PPP hydrogel. Keywords: Antiviral; Hydrogel; Intratympanic; Dexamethasone; Cidofovir; Ganciclovir”

History of PLGA in FDA approved products.

Since PLGA is sold at PolySciTech (www.polyscitech.com), I often receive questions about what products have PLGA in them that have been approved by FDA. Below is a quick list of these. As can be seen, there is a long and successful history of using PLGA as a safe and effective drug carrier system.

 

Product Name Drug Type Duration Dose Approved
Zoladex Goserelin Solid implant 1,3 months 3.6 mg/month 1989
Lurpon Leuprolide Microparticle 1-4 months 7.5 mg/month 1989
Sandostatin Octreotide Microparticle 1 month 20 mg/month 1998
Atridox Doxycycline In situ gel 1 week 42.5 mg/week 1998
Nutropin Somatotropin Microparticle 1 month 13.5 mg/month 1999
Trelstar Triptorelin Microparticle 1-6 months 3.75 mg/month 2000, 2010
Superfact Buserelin Solid implant 2,3 months 3.15 mg/month 2000
Somatuline Lanreotide Microparticle 1 month 60 mg/month 2000
Arestin Minocycline Microparticle 2 weeks 0.5 mg/week 2001
Eligard Leuprolide In situ gel 1-6 months 7.5 mg/month 2002
RisperidalConsta Risperidone Microparticle 2 weeks 12.5 mg/week 2003
Vivitrol Naltrexone Microparticle 1 month 380 mg/month 2006
Ozurdex Dexamethasone Solid implant 3 months 0.23 mg/month 2009
Propel Mometasone Solid implant 1 month 370 mg/month 2011
Bydureon Exenatide Microparticles 1 week 2 mg/week 2012
Lupaneta Pack Leuprolide Microparticles 3 months 3.75 mg/month 2012

PLGA-PEG-NH2 from PolySciTech used as part of development of a carrier for crossing the blood-brain-barrier.

PolySciTech division of Akina, Inc (www.polyscitech.com) provides, amongst other products, a wide variety of endcap reactive block copolymers including PLGA-PEG-NH2. One of the challenges for drug delivery is that the human immune and clearance systems do not discriminate between medicine and poison. Any compound introduced into the body is treated by the body in a similar manner in that it is typically up-taken by the liver for metabolic destruction, or screened out by the kidneys to remove into the urine. This is a valuable survival mechanism in the situation of accidental poisoning, but creates challenges for medicinal delivery as a substantial portion of administered medicine is cleared by these and other pathways before it has a chance to act where it is needed. The brain, in particular, is understandably very discriminatory about what is allowed to cross over from the blood stream into the brain tissue. This phenomenon is referred to as the blood-brain-barrier and prevents medicinal delivery to brain tissues. Recently, researchers have utilized PLGA-PEG-NH2 from PolySciTech (PolyVivo AI-058) to generate SiRNA loaded PLGA-PEG nanoparticles decorated with a transferrin receptor to allow for delivery across the blood-brain-barrier. This research holds promise to provide for treatment of a wide variety of neural diseases. Read more: Gomes, Maria João, Carlos Fernandes, Susana Martins, Fernanda Borges, and Bruno Sarmento. “Tailoring Lipid and Polymeric Nanoparticles as siRNA Carriers towards the Blood-Brain Barrier–from Targeting to Safe Administration.” Journal of Neuroimmune Pharmacology (2016): 1-13. http://link.springer.com/article/10.1007/s11481-016-9685-6

“Abstract: Blood-brain barrier is a tightly packed layer of endothelial cells surrounding the brain that acts as the main obstacle for drugs enter the central nervous system (CNS), due to its unique features, as tight junctions and drug efflux systems. Therefore, since the incidence of CNS disorders is increasing worldwide, medical therapeutics need to be improved. Consequently, aiming to surpass blood-brain barrier and overcome CNS disabilities, silencing P-glycoprotein as a drug efflux transporter at brain endothelial cells through siRNA is considered a promising approach. For siRNA enzymatic protection and efficient delivery to its target, two different nanoparticles platforms, solid lipid (SLN) and poly-lactic-co-glycolic (PLGA) nanoparticles were used in this study. Polymeric PLGA nanoparticles were around 115 nm in size and had 50 % of siRNA association efficiency, while SLN presented 150 nm and association efficiency close to 52 %. Their surface was functionalized with a peptide-binding transferrin receptor, in a site-oriented manner confirmed by NMR, and their targeting ability against human brain endothelial cells was successfully demonstrated by fluorescence microscopy and flow cytometry. The interaction of modified nanoparticles with brain endothelial cells increased 3-fold compared to non-modified lipid nanoparticles, and 4-fold compared to non-modified PLGA nanoparticles, respectively. These nanosystems, which were also demonstrated to be safe for human brain endothelial cells, without significant cytotoxicity, bring a new hopeful breath to the future of brain diseases therapies. Keywords: Blood-brain barrier Functionalization Nanoparticles siRNA Targeting TfR-peptide”

PEG-PLGA from PolySciTech use in development of drug delivery system described in recent patent

The PolySciTech division of Akina Inc. (www.polyscitech.com) provides a wide array of biodegradable block copolymers including non-reactive mPEG-PLGA and end-cap reactive Maleimide-PEG-PLGA. These allow for the generation of nanoparticles that can perform drug-delivery functions such as enhanced circulation time of poorly soluble drugs or targeted delivery to specific binding sites. Recently, researchers at John Hopkins University, as disclosed in a patent, utilized products from PolySciTech as part of their development efforts relating to a novel delivery platform for the delivery of peptides which prevent overgrowth of blood vessels (angiogenesis). Angiogenesis is involved in tumor development as tumors require more blood flow than normal tissue to sustain their rapid growth. Also, angiogenesis is involved in other diseases such as certain types of macular degeneration in which abnormally high blood vessel growth under the macula leads to bleeding and leakage. This research holds promise for treating a wide variety of diseases ranging from cancer to wet AMD. Read more here: Popel, Aleksander S., Niranjan B. Pandey, Esak Lee, Jordan J. Green, and Ron B. Shmueli. “A Biomimetic Peptide And Biodegradable Delivery Platform For The Treatment Of Angiogenesis-And Lymphangiogenesis-Dependent Diseases.” U.S. Patent 20,160,122,390, issued May 5, 2016. http://www.freepatentsonline.com/y2016/0122390.html

“Abstract: Mimetic peptides having anti-angiogenic and anti-tumorigenic properties and methods of their use for treating cancer, ocular diseases, such as age-related macular degeneration, and other-angiogenesis-dependent diseases are disclosed. More particularly, an isolated peptide comprising the amino acid sequence LRRFSTAPFAFIDINDVINF, which exhibits anti-angiogenic activity in endothelial cell proliferation, migration, adhesion, and tube formation assays, anti-migratory activity in human breast cancer cells in vitro, anti-angiogenic and anti-tumorigenic activity in vivo in breast cancer xenograft models, and age-related macular degeneration models is disclosed. The isolate peptide also exhibits anti-lymphangiogenic and directly anti-tumorigenic properties.”

Fluorescently-endcapped PLGA from Akina, Inc. used as part of oral-insulin delivery research for experimental diabetes treatment

PolySciTech division of Akina, Inc. (www.polyscitech.com) provides a wide-array of biodegradable polymers including fluorescently endcapped polymers in the PolyVivo AV*** series. The dye’s conjugated to these polymers absorb a certain wavelength of light and subsequently emit a different wavelength of light allowing for them to be imaged in a manner which eliminates surrounding tissues or other components by applying sharp-cut wavelength filters to the provided light-source and the observation platform (eye piece or camera). A common process simply referred to as fluorescence microscopy. The advantage of these is that nanoparticles or other structures formed using these systems can be imaged and tracked using fluorescence microscopy. Recently PolyVivo AV008 (PLGA-FPR648 MW ~20,000; Abs: 648 nm /Em: 672 nm) was used to track insulin loaded nanoparticles and their penetration into model intestinal cells as part of research to develop an oral (as opposed to the current injection-based systems) insulin delivery system. This system holds the promise for a less-painful treatment option for diabetes. Read more about this exciting research here: Sheng, Jianyong, Huining He, Limei Han, Jing Qin, Sunhui Chen, Ge Ru, Ruixiang Li, Pei Yang, Jianxin Wang, and Victor C. Yang. “Enhancing insulin oral absorption by using mucoadhesive nanoparticles loaded with LMWP-linked insulin conjugates.” Journal of Controlled Release (2016). http://www.sciencedirect.com/science/article/pii/S0168365916302784

“Abstract: Although significant progress has been made, effective oral delivery of protein drugs such as insulin by nanoparticle-based carrier systems still faces certain formidable challenges. Considerable amount of protein drug is released from the nanoparticles (NPs) in the gastrointestinal (GI) tract. Because of their low permeability through the intestinal mucosa, the released protein would be soon degraded by the large amount of proteases in the GI tract. Herein, we report an oral insulin delivery system that can overcome the above-mentioned problems by mucoadhesive NPs (MNPs) loaded with cell penetrating peptide-linked insulin conjugates. On one hand, after conjugation with low molecular weight protamine (LMWP), a cell penetrating peptide (CPP), insulin showed greatly improved permeability through intestinal mucus layer and epithelia. On the other hand, the mucoadhesive N-trimethyl chitosan chloride-coated PLGA nanoparticles (MNPs) that were loaded with conjugates enhanced the retention in the intestinal mucus layer. By adopting this delivery strategy, the LMWP-insulin conjugates released from NPs could be deprived from enzymatic degradation, due to the short distance in reaching the epithelia and the high permeation of the conjugates through epithelia. The oral delivery system of insulin designed by us showed a long-lasting hypoglycemia effect with a faster onset in diabetic rats, with an oral insulin pharmacological availability being 17.98 ± 5.61% relative to subcutaneously injected insulin solution, as well as a 2-fold higher improvement over that by MNPs loaded with native insulin. Our results suggested that conjugation with CPP followed by encapsulation in MNPs provides an effective strategy for oral delivery of macromolecular therapeutics. Keywords: Nanoparticles; Cell-penetrating peptide; Low molecular weight protamine; Insulin; Oral delivery; Mucoadhesion”

Image: https://3.bp.blogspot.com/-2-t5kq0CSog/VznYJrShDYI/AAAAAAAAEl4/PHgMLwI5X5AGPMqwrsnKuWSvI_aTVj4qQCLcB/s1600/Shen%2B2016%2Boral%2Binsulin%2Bdiabetes.png

 

mPEG-PLGA investigated for delivery of syringopicroside and hydroxytyrosol as chemotherapy

PolySciTech division of Akina, Inc. (www.polyscitech.com) provides a wide array of biodegradable block copolymers including mPEG-PLGA polymers for several biomedical applications. Recently, this type of polymer was reported for the co-delivery of syringopicroside and hydroxytyrosol with enhanced circulation. Read more: Guan, Qingxia, Shuang Sun, Xiuyan Li, Shaowa Lv, Ting Xu, Jialin Sun, Wenjing Feng, Liang Zhang, and Yongji Li. “Preparation, in vitro and in vivo evaluation of mPEG-PLGA nanoparticles co-loaded with syringopicroside and hydroxytyrosol.” Journal of Materials Science: Materials in Medicine 27, no. 2 (2016): 1-13. http://link.springer.com/article/10.1007/s10856-015-5641-x

“Abstract: This study investigated the therapeutic efficiency of monomethoxy polyethylene glycol-poly(lactic-co-glycolic acid) (mPEG-PLGA) co-loaded with syringopicroside and hydroxytyrosol as a drug with effective targeting and loading capacity as well as persistent circulation in vivo. The nanoparticles were prepared using a nanoprecipitation method with mPEG-PLGA as nano-carrier co-loaded with syringopicroside and hydroxytyrosol (SH-NPs). The parameters like in vivo pharmacokinetics, biodistribution in vivo, fluorescence in vivo endomicroscopy, and cellular uptake of SH-NPs were investigated. Results showed that the total encapsulation efficiency was 32.38 ± 2.76 %. Total drug loading was 12.01 ± 0.42 %, particle size was 91.70 ± 2.11 nm, polydispersity index was 0.22 ± 0.01, and zeta potential was −24.5 ± 1.16 mV for the optimized SH-NPs. The nanoparticle morphology was characterized using transmission electron microscopy, which indicated that the particles of SH-NPs were in uniformity within the nanosize range and of spherical core shell morphology. Drug release followed Higuchi kinetics. Compared with syringopicroside and hydroxytyrosol mixture (SH), SH-NPs produced drug concentrations that persisted for a significantly longer time in plasma following second-order kinetics. The nanoparticles moved gradually into the cell, thereby increasing the quantity. ALT, AST, and MDA levels were significantly lower on exposure to SH-NPs than in controls. SH-NPs could inhibit the proliferation of HepG2.2.15 cells and could be taken up by HepG2.2.15 cells. The results confirmed that syringopicroside and hydroxytyrosol can be loaded simultaneously into mPEG-PLGA nanoparticles. Using mPEG-PLGA as nano-carrier, sustained release, high distribution in the liver, and protective effects against hepatic injury were observed in comparison to SH.”

PolyVivo PLGA-PEG-NH2 uses as part of investigation of drug-tumor penetration model

PolySciTech division of Akina, Inc. (www.polyscitech.com) provides a wide array of biodegradable block copolymers and reactive intermediates such as PLGA-PEG-NH2 (PolyVivo AI058). Recently, this polymer was used by researchers at The University of Utah and Fuji Research Laboratories as part of developing a tumor model for tracking intra-cellular transportation of drug molecules and delivery systems. This research holds promise for developing advanced chemotherapeutics in the future which allow for higher drug uptake into the tumor cells than what is currently available. Read more about this here: Suzuki, Hidenori, and You Han Bae. “Evaluation of drug penetration with cationic micelles and their penetration mechanism using an in vitro tumor model.” Biomaterials (2016). http://www.sciencedirect.com/science/article/pii/S0142961216301569

“Abstract: Elevated interstitial fluid pressure (IFP) and abnormal extracellular matrix (ECM) are major factors causing significant barriers to penetration of nanomedicines in solid tumors. To better understand the barriers, various in vitro tumor models including multicellular spheroids and multilayered cell cultures (MCCs) have been developing. Recently, we have established a unique in vitro tumor model composed of a MCC and an Ussing chamber system which is modified to add a hydraulic pressure gradient through the MCC. In this study, we evaluated the drug penetration ability of cationic micelles using the unique in vitro tumor model. The doxorubicin (DOX)-loaded cationic micelles, which are formed from a triblock copolymer of poly(D,L-lactide-co-glycolide)-block-branched polyethyleneimine-block-poly(D,L-lactide-co-glycolide), deeply penetrated and released the DOX throughout the MCC against convectional flow caused by a hydraulic pressure gradient. The studies using endocytosis markers and inhibitors showed that the micelles utilized mainly macropinocytosis as an internalization pathway. Furthermore, the penetration was apparently inhibited by treatment with exocytosis inhibitor Exo1. These results suggest that the active penetration of the cationic micelles is induced by iterative transcytosis via macropinocytosis and exocytosis. Our findings could be beneficial information to improve intratumoral penetration in new nanomedicines for solid tumors.  Keywords: intratumoral; penetration; multilayered cell culture; micelle; cationic surface; transcytosis”