John Garner's Technical Blog
John GarnerJohn Garner, Manager

What's New and on the Manager's Mind

A blog dedicated to answering technical questions in an open format relating to products from PolySciTech, a division of Akina, Inc.


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PLA from PolySciTech used in development of nanoparticle-based triple-negative breast cancer therapy

Wednesday, November 15, 2017, 7:44 PM ET

Most forms of breast cancer respond well to conventional therapies, such as doxorubicin. There is, however, a specific type of breast cancer that is referred to as ‘triple-negative’ (named this because it does not have receptors for estrogen, progesterone, or HER2) breast cancer. It is highly resistant to conventional chemotherapy and very invasive. Recently, researchers at University of Cincinnati utilized polylactide (AP128) from PolySciTech (www.polyscitech.com) to develop chemotherapy particles which released gefitinib followed by sequential release of doxorubicin. These particles were found to be significantly more effective at treating triple-negative breast cancer than . This research holds promise for developing more effective chemotherapy strategies to treat breast cancer. Read more: Zhou, Zilan, Mina Jafari, Vishnu Sriram, Jinsoo Kim, Joo-Youp Lee, Sasha J. Ruiz-Torres, and Susan E. Waltz. "Delayed Sequential Co-Delivery of Gefitinib and Doxorubicin for Targeted Combination Chemotherapy." Molecular Pharmaceutics (2017). http://pubs.acs.org/doi/abs/10.1021/acs.molpharmaceut.7b00669

“There are an increasing number of studies showing the order of drug presentation plays a critical role in achieving optimal combination therapy. Here, a nanoparticle design is presented using ion pairing and drug-polymer conjugate for the sequential delivery of gefitinib (Gi) and doxorubicin (Dox) targeting epidermal growth factor receptor (EGFR) signaling applicable for the treatment of triple negative breast cancers. To realize this nanoparticle design, Gi complexed with dioleoyl phosphatidic acid (DOPA) via ion paring was loaded onto the nanoparticle made of Dox-conjugated poly(l-lactide)-block-polyethylene glycol (PLA-b-PEG) and with an encapsulation efficiency of ∼90%. The nanoparticle system exhibited a desired sequential release of Gi followed by Dox, as verified through release and cellular uptake studies. The nanoparticle system demonstrated approximate 4-fold and 3-fold increases in anticancer efficacy compared to a control group of Dox–PLA-PEG conjugate against MDA-MB-468 and A549 cell lines in terms of half maximal inhibitory concentration (IC50), respectively. High tumor accumulation of the nanoparticle system was also substantiated for potential in vivo applicability by noninvasive fluorescent imaging. Keywords: combination therapy; controlled delivery; doxorubicin; EGFR inhibitor; nanoparticles; sequential delivery”

PLGA and PLGA-rhodamine from PolySciTech used in study on chemotherapeutic delivery by nanoparticles

Wednesday, November 15, 2017, 7:41 PM ET

For conventional, loose-drug, chemotherapy, less than 1% of the injected medicine actually makes it to the tumor site. The clinical method for solving this problem has been to inject massive doses of chemotherapeutic agents to the patient, in the hopes that at least some of the medicine makes it to the tumor. This is not a good solution to this problem and leads to substantial morbidity from the side-effects of chemotherapy (hair loss, immune-system damage, etc.). Nanoparticle-based technologies have been developed in the hopes of creating a system in which the drug is encapsulated in a small particle that flows through the blood until it is entrapped by the tumor. Although coating the particle with PEG improves its circulation time, it can also hinder uptake by the tumor. Recently, researchers from Purdue University and Eli Lilly and Company used PLGA (PolyVivo AP020) and Rhodamine-labelled PLGA (Polyvivo AV011) from PolySciTech (www.polyscitech.com) to develop chitosan-coated nanoparticles with preferential tumor attraction over PEGylated nanoparticles. They found, however, that although the particles were preferentially absorbed by the polymer, the drug itself (in the study, ICG tracer-dye was used) leached out too quickly to be of any use. This highlights how critical the drug-entrapment strategy is to the overall design of a nanoparticle formulation. This research holds promise to provide for improved chemotherapeutic strategies with reduced side-effects. Read more: Park, Jinho, Yihua Pei, Hyesun Hyun, Mark A. Castanares, David S. Collins, and Yoon Yeo. "Small molecule delivery to solid tumors with chitosan-coated PLGA particles: A lesson learned from comparative imaging." Journal of Controlled Release (2017). http://www.sciencedirect.com/science/article/pii/S0168365917309367

“Abstract: For polymeric nanoparticles (NPs) to deliver more drugs to tumors than free drug solution, it is critical that the NPs establish interactions with tumor cells and avoid removal from the tumors. Since traditional polyethylene glycol (PEG) surface layer interferes with the cell-NP interaction in tumors, we used a water-soluble and blood-compatible chitosan derivative called zwitterionic chitosan (ZWC) as an alternative surface coating for poly(lactic-co-glycolic acid) (PLGA) NPs. The ZWC-coated PLGA NPs showed pH-dependent surface charge profiles and differential cellular interactions according to the pH of the medium. The in vivo delivery of ZWC-coated NPs was evaluated in mice bearing LS174T-xenografts using magnetic resonance (MR) imaging and fluorescence whole body imaging, which respectively tracked iron oxide particles and indocyanine green (ICG) encapsulated in the NPs as tracers. MR imaging showed that ZWC-coated NPs were more persistent in tumors than PEG-coated NPs, in agreement with the in vitro results. However, the fluorescence imaging indicated that the increased NP retention in tumors by the ZWC coating did not significantly affect the ICG distribution in tumors due to the rapid release of the dye. This study shows that stable drug retention in NPs during circulation is a critical prerequisite to successful translation of the potential benefits of surface-engineered NPs. Keywords: pH-responsive Drug delivery PLGA nanoparticles Small molecules In vivo imaging Encapsulation stability”

PLGA-PEG-NHS from PolySciTech used as part of nanoparticle-protected-islets based treatment of diabetes

Thursday, November 9, 2017, 4:52 PM ET

Type 1 Diabetes is a chronic disease brought on by loss of function of pancreatic islets, groups of cells that produce insulin to regulate the blood sugar content. Recently, transplantation of pancreatic islets has been considered as a long-term treatment for type 1 diabetes that does not require the patient to take daily injections of insulin. Immune-system rejection of the transplant, however, creates difficult for this treatment method as the body attacks the newly transplanted cells. One means of preventing this is to encapsulate the cells in a material which is non-immunogenic so as to protect them from macrophages. Recently, researchers at Yeungnam University, Seoul National University, and Keimyung University (Korea) utilized PolyVivo AI111 (PLGA-PEG-NHS) from PolySciTech (www.polyscitech.com) to create pegylated nanoparticles which attach to the islet cells and prevent them from being attacked by the immune system. This research holds promise to provide for a long-term treatment of diabetes which does not require the patient to continuously inject insulin. Read more: Pham, Tung Thanh, Tiep Tien Nguyen, Shiva Pathak, Shobha Regmi, Hanh Thuy Nguyen, Tuan Hiep Tran, Chul Soon Yong et al. "Tissue adhesive FK506–loaded polymeric nanoparticles for multi–layered nano–shielding of pancreatic islets to enhance xenograft survival in a diabetic mouse model." Biomaterials (2017). http://www.sciencedirect.com/science/article/pii/S014296121730707X

“Abstract: This study aims to develop a novel surface modification technology to prolong the survival time of pancreatic islets in a xenogenic transplantation model, using 3,4–dihydroxyl–l–phenylalanine (DOPA) conjugated poly(lactide–co–glycolide)–poly(ethylene glycol) (PLGA–PEG) nanoparticles (DOPA–NPs) carrying immunosuppressant FK506 (FK506/DOPA–NPs). The functionalized DOPA–NPs formed a versatile coating layer for antigen camouflage without interfering the viability and functionality of islets. The coating layer effectively preserved the morphology and viability of islets in a co–culture condition with xenogenic lymphocytes for 7 days. Interestingly, the mean survival time of islets coated with FK506/DOPA–NPs was significantly higher as compared with that of islets coated with DOPA–NPs (without FK506) and control. This study demonstrated that the combination of surface camouflage and localized low dose of immunosuppressant could be an effective approach in prolonging the survival of transplanted islets. This newly developed platform might be useful for immobilizing various types of small molecules on therapeutic cells and biomaterial surface to improve the therapeutic efficacy in cell therapy and regenerative medicine. Keywords: Surface modification; FK506; Islets transplantation; Local delivery; Diabetes mellitus”

PLGA-PEG-PLGA from PolySciTech used for localized propranolol delivery system

Wednesday, November 1, 2017, 9:12 PM ET

Hemangioma (red or purple colored birthmarks) is a benign childhood tumor generated by excessive growth of blood vessels. Although external hemangioma’s typically only affect aesthetics, the growth of internal hemangiomas, especially near liver, brain, or other critical organs, can cause severe pain and morbidity. Treatment options include corticosteroids and beta-blockers, however applying such treatments to infants and children throughout the whole body in a systemic fashion can create problems with controlling the dose and side-effects. Recently, researchers at Henan Provincial People’s Hospital and the Second Military Medical University (China) used PLGA-PEG-PLGA (PolyVivo AK016) from PolySciTech (www.polyscitech.com) to generate microparticles as part of a local propranolol delivery system. These particles were found to be effective at delivering propranolol (a beta blocker) locally without requiring a large systemic dose. This research holds promise for treating a variety of conditions where excessive angiogenesis is a problem. Read more: Guo, Xiaonan, Xiaoshuang Zhu, Dakan Liu, Yubin Gong, Jing Sun, and Changxian Dong. "Continuous delivery of propranolol from liposomes-in-microspheres significantly inhibits infantile hemangioma growth." International Journal of Nanomedicine 12 (2017): 6923. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609781/

“Purpose: To reduce the adverse effects and high frequency of administration of propranolol to treat infantile hemangioma, we first utilized propranolol-loaded liposomes-in-microsphere (PLIM) as a novel topical release system to realize sustained release of propranolol. Methods: PLIM was developed from encapsulating propranolol-loaded liposomes (PLs) in microspheres made of poly(lactic-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) copolymers (PLGA-PEG-PLGA). The release profile of propranolol from PLIM was evaluated, and its biological activity was investigated in vitro using proliferation assays on hemangioma stem cells (HemSCs). Tumor inhibition was studied in nude mice bearing human subcutaneous infantile hemangioma. Results: The microspheres were of desired particle size (~77.8 μm) and drug encapsulation efficiency (~23.9%) and achieved sustained drug release for 40 days. PLIM exerted efficient inhibition of the proliferation of HemSCs and significantly reduced the expression of two angiogenesis factors (vascular endothelial growth factor-A [VEGF-A] and basic fibroblast growth factor [bFGF]) in HemSCs. Notably, the therapeutic effect of PLIM in hemangioma was superior to that of propranolol and PL in vivo, as reflected by significantly reduced hemangioma volume, weight, and microvessel density. The mean hemangioma weight of the PLIM-treated group was significantly lower than that of other groups (saline =0.28 g, propranolol =0.21 g, PL =0.13 g, PLIM =0.03 g; PLIM vs saline: P<0 .001="" a="" and="" approach="" conclusion:="" controlled="" deliver="" density="" efficiently="" findings="" group="" groups="" hemangioma.="" hemangioma="" infantile="" inhibition="" is="" keywords:="" leading="" liposomes="" locally="" lower="" mean="" microsphere="" microvessel="" mm2="" o:p="" of="" other="" our="" p="" pl:="" pl="25" plim-treated="" plim="" promising="" propranolol:="" propranolol="" release="" saline:="" saline="40" show="" significant="" significantly="" site="" than="" that="" the="" to="" very="" vessels="" vs="" was="">

PLGA-Glucose from PolySciTech used in cancer glucose-targeting nanoparticle development for cancer therapy

Tuesday, October 31, 2017, 9:18 PM ET

Cancer cells are typically be considered to act ‘hungry,’ as they consume glucose and oxygen at much faster rates than normal cells. For this, they have over-expressed glucose uptake moieties to absorb more of this energy filled sugar. This provides one method of targeting cancer which is to focus on their over-uptake of glucose as a targeting strategy. Recently, researchers at Seoul National University and Kangwon National University (Korea) utilized PLGA and PLGA-glucose from PolySciTech (www.polyscitech.com) (PolyVivo AP027 (PLGA-glucose) and AP041 (PLGA)) to create nanoparticles which target to the glucose uptake transporters of cancer cells. This research holds promise for improved cancer treatments by targeted delivery. Read more: Park, Ju-Hwan, Hyun-Jong Cho, and Dae-Duk Kim. "Poly ((D, L) lactic-glycolic) acid–star glucose nanoparticles for glucose transporter and hypoglycemia-mediated tumor targeting." International Journal of Nanomedicine 12 (2017): 7453. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5644567/

“Poly((D,L)lactic-glycolic)acid–star glucose (PLGA-Glc) polymer-based nanoparticles (NPs) were fabricated for tumor-targeted delivery of docetaxel (DCT). NPs with an approximate mean diameter of 241 nm, narrow size distribution, negative zeta potential, and spherical shape were prepared. A sustained drug release pattern from the developed NPs was observed for 13 days. Moreover, drug release from PLGA-Glc NPs at acidic pH (endocytic compartments and tumor regions) was significantly improved compared with that observed at physiological pH (normal tissues and organs). DCT-loaded PLGA-Glc NPs (DCT/PLGA-Glc NPs) exhibited an enhanced antiproliferation efficiency rather than DCT-loaded PLGA NPs (DCT/PLGA NPs) in Hep-2 cells, which can be regarded as glucose transporters (GLUTs)-positive cells, at ≥50 ng/mL DCT concentration range. Under glucose-deprived (hypoglycemic) conditions, the cellular uptake efficiency of the PLGA-Glc NPs was higher in Hep-2 cells compared to that observed in PLGA NPs. Cy5.5-loaded NPs were prepared and injected into a Hep-2 tumor-xenografted mouse model for in vivo near-infrared fluorescence imaging. The PLGA-Glc NPs group exhibited higher fluorescence intensity in the tumor region than the PLGA NPs group. These results imply that the PLGA-Glc NPs have active tumor targeting abilities based on interactions with GLUTs and the hypoglycemic conditions in the tumor region. Therefore, the developed PLGA-Glc NPs may represent a promising tumor-targeted delivery system for anticancer drugs. Keywords: PLGA-Glc, nanoparticles, glucose transporter, hypoxia, tumor targeting”

PLGA and PLCL from PolySciTech used in development of biodegradable foam for advanced wound treatment

Tuesday, October 24, 2017, 6:49 PM ET

One means to encourage wound healing, in either chronic or traumatic wounds, is to reduce the pressure across the wound surface to encourage local blood-flow, stimulate healing, and draw out excess fluids. This requires placing a sterile foam over the top of the wound and connecting the foam to a vacuum pump with an air-tight cover to apply vacuum to the wound. Conventionally, this is done with a non-degradable polyurethane-type foam. During this treatment, tissue often grows into the foam, which creates significant problems upon changing the dressing as fresh-grown tissue can be damaged. Recently, researchers at Wake Forest University utilized multiple PLGA, PLCL, and PCL products (PolyVivo AP037, AP081, AP036, AP073, AP013, and AP015) from PolySciTech (www.polyscitech.com) to develop a degradable, compressible foam for wound therapy. This research holds promise for development of improved wound-therapy methods using foams that simply resorb into the body rather than have problems with in-growth. Read more: Warner, Harleigh J., and William D. Wagner. "Fabrication of biodegradable foams for deep tissue negative pressure treatments." Journal of Biomedical Materials Research Part B: Applied Biomaterials. http://onlinelibrary.wiley.com/doi/10.1002/jbm.b.34007/full

“ABSTRACT: Devices for negative pressure wound therapy (NPWT) rely on compressible foams operating at the tissue-device interface. Clinically used foams are nonabsorbable and if used on deep wounds or left in place for an extended period of time, excessive cell ingrowth and formation of granulation tissue into the foam may require a surgical procedure to remove the foam. Foams with fast degradation and with low immunogenicity and fibrotic response are required. Foams composed of combinations of poly(lactide-co-glycolide) (PLGA), poly(lactide-co-caprolactone) (PLCL), and polycaprolactone (PCL) were created by combined salt leaching and solvent displacement protocols. In vitro and in vivo degradation studies and mechanical properties of foams were evaluated and compared to clinically used poly(vinyl alcohol) (PVA) foam and PCL foams. Foams composed of PLGA (50:50 lactide:glycolide) of low molecular weight blended with PCL maintained mechanical properties and degraded significantly after 21 days of subcutaneous implantation in rats. The most ideal formulations for use in NPWT were identified as copolymeric PLGA (Mn 3000 Da) at a lactide:glycolide ratio of 50:50 combined with PCL at either a 75:25 or 50:50 ratio, and copolymeric PLGA (Mn 7500 Da) at a lactide:glycolide ratio of 50:50 combined with PCL at a 50:50 ratio. KeyWords: polyester, polycaprolactone, poly(lactic-co-glycolic acid), foams, negative pressure wound therapy”

PLGA-PEG-PLGA thermogel from PolySciTech used in development of delivery system for ovarian cancer treatment

Monday, October 23, 2017, 9:08 PM ET

Ovarian cancer is particularly difficult to treat in a clinical setting as it has relatively few symptoms before progressing to an advanced stage. Chemotherapeutic agents tend to work well initially, but the cancer can become resistant quickly. One means to counter this is to apply drugs through the intraperitoneal route, a direct injection into the abdominal cavity. This allows for maximum exposure of the cancer to the chemotherapeutics. This, however, requires a thermogel delivery system which can trap the drug and allow for slow, controlled release of the compounds after the injection. Recently, researchers at University of Wisconsin-Madison and Mokpo National University (Korea), purchased PLGA-PEG-PLGA (PolyVivo AK012) from PolySciTech (www.polyscitech.com). They utilized this polymer to generate a thermogel and deliver chemotherapeutic agents epothilone B (EpoB), rapamycin, and tanespimycin. They found good pre-clinical results in reducing the growth of ovarian cancer cells by delivering these agents. This research holds promise for improved ovarian cancer treatment options. Read more: Shin, Dae Hwan, and Glen S. Kwon. "Pre-clinical evaluation of a themosensitive gel containing epothilone B and mTOR/Hsp90 targeted agents in an ovarian tumor model." Journal of Controlled Release (2017). http://www.sciencedirect.com/science/article/pii/S0168365917309069

“Abstract: Despite clinical remission of epithelial ovarian cancer (EOC) after surgical resection and first-line chemotherapy, about 60% of patients will re-develop peritoneal metastasis and about 50% will relapse with chemoresistant disease. Clinical studies suggest that intra-peritoneal (i.p.) chemotherapy effectively treats residual EOC after cyto-reduction by gaining direct access into the peritoneal cavity, enabling elevated drug levels versus intravenous (i.v.) injection. However, chemoresistant disease is still problematic. To overcome resistance against microtubule stabilizing agents such as taxanes, epothilone B (EpoB) has merit, especially in combination with molecular targeted agents that inhibit heat shock protein 90 (Hsp90) and/or mammalian target of rapamycin (mTOR). In this paper, we report on the successful loading and solubilization of EpoB in a poly(d,l-lactic-co-glycolic acid)-block-poly(ethylene glycol)-block-poly(d,l-lactic-co-glycolic acid) (PLGA-b-PEG-b-PLGA) thermosensitive gel (g-E). Further, we report on successful co-loading of 17-AAG (Hsp90) and rapamycin (mTOR) (g-EAR). After i.p. injection in mice, g-EAR showed gelation in the peritoneum and sustained, local-regional release of EpoB, 17-AAG, and rapamycin. In a luciferase-expressing ES-2 (ES-2-luc) ovarian cancer xenograft model, single i.p. injections of g-E and g-EAR delayed bioluminescence from metastasizing ES-2-luc cells for 2 and 3 weeks, respectively, despite fast drug release for g-EAR in vivo versus in vitro. In summary, a PLGA-b-PEG-b-PLGA sol-gel has loading and release capacities for EpoB and its combinations with 17-AAG and rapamycin, enabling a platform for i.p. delivery, sustained multi-drug exposure, and potent antitumor efficacy in an ES-2-luc, ovarian cancer i.p. xenograft model. Keywords: Drug combination; Epothilone B; Intraperitoneal injection; Ovarian cancer; Peritoneal carcinomatosis; Thermogel”

PLGA-cholesterol from PolySciTech used in development of bone-targeting nanoparticles as treatment for bone-marrow diseases

Friday, October 20, 2017, 9:20 PM ET

Delivery of medicinal molecules to bone tissue is very difficult as bone tissue is dense and poorly vascularized. Diseases of bone-marrow are particularly difficult to treat and can lead to death if they progress into leukemia. Recently, researchers working at Houston Methodist Research Institute, Weill Cornell Medical College, Harbin Medical University, and Huazhong University of Science and Technology (China) used cholesterol-endcapped from PolySciTech (www.polyscitech.com) (PolyVivo AP097) to develop a bone-targeting nanoparticle loaded with decitabine and arsenic trioxide, medicines which are effective at treating bone-marrow disorders. This particle was found to have preferential uptake into bone tissue and restored blood counts in a mouse model. This research holds promise for improved treatments for leukemia and other bone-marrow related diseases. Read more: Wu, Xiaoyan, Zhenhua Hu, Sara Nizzero, Guodong Zhang, R. Maricela Ramirez, Ce Shi, Jin Zhou, Mauro Ferrari, and Haifa Shen. "Bone-targeting nanoparticle to co-deliver decitabine and arsenic trioxide for effective therapy of myelodysplastic syndrome with low systemic toxicity." Journal of Controlled Release (2017). http://www.sciencedirect.com/science/article/pii/S016836591730901X

“Abstract: Myelodysplastic syndromes (MDS) are a diverse group of bone marrow disorders and clonal hematopoietic stem cell disorders characterized by abnormal blood cells, or reduced peripheral blood cell count. Recent clinical studies on combination therapy of decitabine (DAC) and arsenic trioxide (ATO) have demonstrated synergy on MDS treatment, but the treatment can cause significant side effects to patients. In addition, both drugs have to be administered on a daily basis due to their short half-lives. In addressing key issues of reducing toxic side effects and improving pharmacokinetic profiles of the therapeutic agents, we have developed a new formulation by co-packaging DAC and ATO into alendronate-conjugated bone-targeting nanoparticles (BTNPs). Our pharmacokinetic studies revealed that intravenously administered BTNPs increased circulation time up to 3 days. Biodistribution analysis showed that the BTNP facilitated DAC and ATO accumulation in the bone, which is 6.7 and 7.9 times more than untargeted NP. Finally, MDS mouse model treated with BTNPs showed better restoration of complete blood count to normal level, and significantly longer median survival as compared to free drugs or untargeted NPs treatment. Our results support bone-targeted co-delivery of DAC and ATO for effective treatment of MDS. Keywords: Myelodysplastic syndrome; Bone marrow; Delivery; Nanoparticle; Decitabine; Arsenic trioxide”

PLGA-PEG-NHS from PolySciTech used to generate peptide-functionalized nanoparticles in development of breast-cancer therapy

Wednesday, October 18, 2017, 4:12 PM ET

One of the requirements for cancer growth is increased blood-flow to the region where cancer affects the body. Most cancers induce angiogenesis, an excessive increase in the growth of blood-vessels in the region immediately surrounding the cancer, as a means to support their excessive growth. One strategy to eliminate cancer is to prevent angiogenesis, thus cutting off cancer from its supply of nutrients and oxygen which starves the tumor to death. There are several agents which can do this, but it is critical to control the exact targeting as prevention of growth of blood-vessels throughout the rest of the body can lead to toxic side-effects. Recently, researchers from AsclepiX Therapeutics and Johns Hopkins University utilized PLGA-PEG-NHS from PolySciTech (www.polyscitech.com) (PolyVivo AI111) to create nanoparticles with a biomimetic targeting moiety to improve nanoparticle targeting and tumor uptake for improved delivery of a novel anti-angiogenic peptide. These particles were found to preferentially bind to cancer, even to aggressive triple-negative breast cancer, and reduce available blood-flow to these tumors in an animal model. This research holds promise to provide for improved therapy of breast cancer. Read more: Kim, Jayoung, Eric Bressler, Ron Shmueli, Adam Mirando, Niranjan Pandey, Aleksander S. Popel, and Jordan J. Green. Biomaterials.org "Biodegradable polymeric nanoparticles targeted by a novel biomimetic peptide to human breast cancer." http://2017.biomaterials.org/sites/default/files/abstracts/0797.pdf

“Progression of tumor requires angiogenesis in order to achieve the increased need for oxygen and nutrients. Anti-angiogenesis is a widely investigated approach to prevent tumor growth (Bhise NS.Expert Opin Drug Deliv 2011; 8(4): 485-504). We have discovered a biomimetic peptide that shows potent anti-angiogenic activity in vitro and in vivo (Karagiannis ED.PNAS 2008; 105(37): 13775-13780). Nanoparticle (NP) formulations can be used for efficient systemic delivery and controlled release of such peptides at the target site to significantly enhance bioavailability while minimizing side effects. However, unmodified or poly(ethyleneglycol) (PEG)-coated polymeric NPs can suffer from a high rate of clearance and a low level of tumor accumulation (Wilhelm S. Nat. Rev. Mater. 2016; 1: 1-12). To overcome these limitations, we have designed a targeted poly(lactic-co-glycolic acid) (PLGA) NP with a biomimetic peptide as a novel targeting agent. In this study, we test PLGA NPs coated and loaded with peptide for the dual functionality of actively targeting human breast cancer and inducing anti-angiogenesis.”

Meet Akina, Inc at Purdue Research Park Vendor Fair Oct 18th

Monday, October 16, 2017, 1:35 PM ET

Akina, Inc. (www.akinainc.com) will be hosting a booth at the Purdue Research Park Vendor Fair is at Kurz Purdue Technology Center October 18th from 11AM-1PM. We will be answering questions about the company and our offerings as well as handing out 3DCellMaker T-shirts (while supplies last). Please join us for this event.

PLGA from PolySciTech used in development of novel micro-manufacturing technique for drug-delivery applications

Tuesday, October 10, 2017, 9:23 PM ET

Conventional emulsion-based methods can be used to create microparticles for drug delivery applications, however these have some drawbacks. There is little control over the distribution, structure, and spatial orientation of the particles and generally the formed particles are always spherical or nearly so. Most manufacturing techniques, such as 3D printing, lack the resolution capabilities to make micro-structured components. Recently, researchers at the Massachusetts Institute of Technology (MIT) utilized PLGA (PolyVivo AP045) from PolySciTech (www.polyscitech.com) to create a series of uniquely manufactured microstructures using a novel manufacturing technique. In this technique, the PLGA is heated and carefully pressed against a micropatterned mold to form the structure. Subsequent pressings can be applied to create more complex structures in micron dimensions. This research holds promise to generate new avenues for drug delivery by creating microparticles and structures which have precisely controlled time-release properties or functions based on shape and orientation. Read more: McHugh, Kevin J., Thanh D. Nguyen, Allison R. Linehan, David Yang, Adam M. Behrens, Sviatlana Rose, Zachary L. Tochka et al. "Fabrication of fillable microparticles and other complex 3D microstructures." Science 357, no. 6356 (2017): 1138-1142. http://science.sciencemag.org/content/357/6356/1138.abstract

“Abstract: Three-dimensional (3D) microstructures created by microfabrication and additive manufacturing have demonstrated value across a number of fields, ranging from biomedicine to microelectronics. However, the techniques used to create these devices each have their own characteristic set of advantages and limitations with regards to resolution, material compatibility, and geometrical constraints that determine the types of microstructures that can be formed. We describe a microfabrication method, termed StampEd Assembly of polymer Layers (SEAL), and create injectable pulsatile drug-delivery microparticles, pH sensors, and 3D microfluidic devices that we could not produce using traditional 3D printing. SEAL allows us to generate microstructures with complex geometry at high resolution, produce fully enclosed internal cavities containing a solid or liquid, and use potentially any thermoplastic material without processing additives. Putting the pieces together: One route to improving the delivery of existing drugs is by encapsulation inside a protective but slowly degrading shell. Such slow-release capsules improve drug availability in vivo, reduce side effects, and allow for more constant dose delivery. McHugh et al. leverage a number of existing fabrication techniques to make tiny (400-µm), hollow injectable microparticles that can be filled with fluid containing the therapeutic agent. By adjusting the degradation rate of the microparticle material (in this case, a lactic/glycolic copolymer), the cargo in the internal reservoir can be released at a desired time, ranging from a few days to 2 months.”

PLGA-PEG-COOH from PolySciTech used in development of nanoparticle targeted delivery system

Monday, October 9, 2017, 10:53 AM ET

Most medicine applied today has no specific targeting system. Both most oral formulations and free-drug injections simply flood the entire blood-stream with a medicinal molecule such that the area of action receives enough dose to be therapeutic. This can be problematic in the situation of side-effects. Use of a delivery system, however, can ensure localization of the drug to a specific area. Recently, researchers utilized PLGA-PEG-COOH (PolyVivo AI034) from PolySciTech (www.polyscitech.com) to generate nanoparticles for targeted delivery of propranolol. Typically, propranolol is used to treat high blood pressure in a systemic application. However, with targeted application, it can be applied for treating hemangioma. This research holds promise to find new applications for existing medicines through targeted delivery. Read more: Guo, Xiaonan, Xiaoshuang Zhu, Jie Gao, Dakan Liu, Changxian Dong, and Xing Jin. "PLGA nanoparticles with CD133 aptamers for targeted delivery and sustained release of propranolol to hemangioma." Future Medicine (2017). https://www.futuremedicine.com/doi/abs/10.2217/nnm-2017-0130

“Aim: To develop propranolol-loaded poly(lactic-co-glycolic acid) nanoparticle with CD133 aptamers (PPN-CD133) to treat infantile hemangioma. Materials & methods: The antihemangioma activity and mechanism of PPN-CD133 were evaluated. Results & conclusion: PPN-CD133 are of desired size (143.7 nm), drug encapsulation efficiency (51.8%) and sustained drug release for 8 days. PPN-CD133 could effectively bind to CD133+ hemangioma stem cells, resulting in enhanced cytotoxic effect and reduced expression of angiogenesis factors in hemangioma stem cells. The therapeutic effect of PPN-CD133 in hemangioma was superior to that of untargeted PPN and propranolol in vivo, as reflected by reduced hemangioma volume, weight and microvessel density. PPN-CD133 represents a very promising approach to locally and efficiently deliver propranolol leading to significant inhibition of infantile hemangioma. Keywords: aptamer, biomaterials, cell biology, controlled release, nanoparticles, remove.”

Akina Happenings: Office of Generic Drugs Public Workshop presentation, shipping improvements.

Thursday, October 5, 2017, 2:51 PM ET

hese are busy times at PolySciTech division of Akina, Inc (www.polyscitech.com). Tomorrow, several employees will be at the FDA public workshop “Demonstrating Equivalence of Generic Complex Drug Substances and Formulations” October 6, 2017 (8:00 a.m. – 4:00 p.m.), FDA White Oak Campus (https://www.fda.gov/Drugs/NewsEvents/ucm552461.htm) with both a presentation by Dr. Kinam Park as well as three scientific poster presentations detailing research from collaborative work between the FDA and Akina, Inc. for development of a variety of assay techniques and methodologies. Also, Akina, Inc. is upgrading the packaging process for biodegradable polymers. In order to improve shipping condition, our products are now argon-flushed as part of the packaging process. Flushing the bottle with this chemically inert gas provides for an added layer protection during transport, by removing components that the polymer could potentially react with such as water and oxygen. This is in addition to the other precautions already taken (ice packs, desiccant) as part of shipping to ensure high product quality upon arrival.

PLA from PolySciTech used as part of polylysine based pancreatic cancer therapy development

Monday, September 25, 2017, 9:37 PM ET

Pancreatic cancer is a form of cancer which is very difficult to treat and can often be fatal. Peptides, such as polylysine, have been found to slow the growth of cancer however delivering them to the cancer site is difficult. Recently, researchers working at Universidad Nacional de Mar del Plata, Universidad Nacional de Cordoba (Argentina) University of Nebraska-Lincoln, and University of Sao Paulo (Brazil), utilized PLA (Polyvivo # AP078) from PolySciTech (www.polyscitech.com) as part of a microparticle system for delivery of polylysine as a treatment of pancreatic cancer. This research holds promise for providing treatment options for this fatal disease. Read more: Merari T. Chevalier, Mónica C. García, Daniela Gonzalez, Sandro M. Gomes-Filho, Daniela S. Bassères, Hernan Farina & Vera A. Alvarez (2017): Preparation, characterization and in vitro evaluation of ε-polylysine-loaded polymer blend microparticles for potential pancreatic cancer therapy, Journal of Microencapsulation, DOI: 10.1080/02652048.2017.1370028 (http://dx.doi.org/10.1080/02652048.2017.1370028)

“Peptide active ingredients show great promise regarding the treatment of various health-endangering diseases. It is reported that L-lysine inhibits the proliferation of several tumour lines in vitro and in vivo. However, proteins and peptide drugs possess certain disadvantages such as in vivo instability and short biological half-life. On the grounds that drug delivery systems can overcome a wide spectrum of bioactive compounds issues, a biopolymeric blend-based microparticulated system capable of delivering ε-polylysine (PLL) was developed. PLL-loaded poly((L)Lactic acid)/poly(D,L-Lactide)-co-poly(ethylene glycol)-based microparticles (PLL-PB-MPs) were prepared and fully characterised exhibiting a narrow size distribution (1.2 ± 0.12 µm), high loading efficiency (81%) and improved thermal stability (Td from 250 °C to 291 °C). The cytotoxicity and antiproliferative effect of PLL-PB-MPs in pancreatic adenocarcinoma cell lines BxPC3 and MIA PaCa-2 were confirmed. Due to their physicochemical and biopharmaceutical properties, PB-MPs constitute a promising carrier to deliver bioactive peptides. Keywords: Biopolymers, ε-polylysine, microparticles, polylactic acid”

PLGA-PEG-Mal from PolySciTech used in the development of Fn14-targeting nanoparticle system for brain cancer treatment

Monday, September 11, 2017, 1:21 PM ET

Glioblastoma accounts for 12-15% of all intracranial (brain) tumors. This particular form of brain-cancer is resistant to conventional therapies and tends to be rapidly growing, which makes this form of cancer particularly difficult to treat. Recently, researchers at the University of Maryland used mPEG-PLGA (PolyVivo# AK010) PLGA-PEG-Maleimide (PolyVivo# AI053), and PLGA-Rhodamine B (PolyVivo# AV011) from PolySciTech (www.polyscitech.com) to develop nanoparticles which bind strongly to the Fn14 receptor that is found in brain-cancer. This research holds promise to provide for additional treatment options to this deadly disease. Read more: Wadajkar, Aniket S., Jimena G. Dancy, Nathan B. Roberts, Nina P. Connolly, Dudley K. Strickland, Jeffrey A. Winkles, Graeme F. Woodworth, and Anthony J. Kim. "Decreased non-specific adhesivity, receptor targeted (DART) nanoparticles exhibit improved dispersion, cellular uptake, and tumor retention in invasive gliomas." Journal of Controlled Release (2017). http://www.sciencedirect.com/science/article/pii/S0168365917308295

“Abstract: The most common and deadly form of primary brain cancer, glioblastoma (GBM), is characterized by significant intratumoral heterogeneity, microvascular proliferation, immune system suppression, and brain tissue invasion. Delivering effective and sustained treatments to the invasive GBM cells intermixed with functioning neural elements is a major goal of advanced therapeutic systems for brain cancer. Previously, we investigated the nanoparticle characteristics that enable targeting of invasive GBM cells. This revealed the importance of minimizing non-specific binding within the relatively adhesive, ‘sticky’ microenvironment of the brain and brain tumors in particular. We refer to such nanoformulations with decreased non-specific adhesivity and receptor targeting as ‘DART’ therapeutics. In this work, we applied this information toward the design and characterization of biodegradable nanocarriers, and in vivo testing in orthotopic experimental gliomas. We formulated particulate nanocarriers using poly(lactic-co-glycolic acid) (PLGA) and PLGA-polyethylene glycol (PLGA-PEG) polymers to generate sub-100 nm nanoparticles with minimal binding to extracellular brain components and strong binding to the Fn14 receptor – an upregulated, conserved component in invasive GBM. Multiple particle tracking in brain tissue slices and in vivo testing in orthotopic murine malignant glioma revealed preserved nanoparticle diffusivity and increased uptake in brain tumor cells. These combined characteristics also resulted in longer retention of the DART nanoparticles within the orthotopic tumors compared to non-targeted versions. Taken together, these results and nanoparticle design considerations offer promising new methods to optimize therapeutic nanocarriers for improving drug delivery and treatment for invasive brain tumors. Graphical abstract: Fn14-targeted nanoparticles bind specifically to Fn14 receptor but not to brain ECM and are retained in invasive intracranial tumors over significantly longer periods than non-targeted nanoparticles. Keywords: Glioblastoma; Invasive malignant glioma; Biodegradable nanoparticles; Targeted therapeutics; Fibroblast growth factor-inducible 14; Multiple particle tracking; Surface plasmon resonance”

PLGA-PEG-Mal from PolySciTech used in development of curcumin nanoparticles for brain-cancer treatment

Wednesday, September 6, 2017, 9:48 PM ET

Curcumin is a powerful anti-inflammatory agent found in turmeric that prevents cancer metastasis and can aid in treatment of cancer. Due to its extremely poor absorption and low water solubility, simply eating turmeric or taking curcumin as a supplement will not provide adequate curcumin levels to cancerous cells to be of any therapeutic effect. Pairing this agent with a delivery system, however, can leverage its potential as an anticancer compound. Recently, researchers at Yantai University, Luye Pharmaceutical Co, Lunan Pharmaceutical Group, and Binzhou Medical University (China) utilized PLGA-PEG-Mal (PolyVivo AI020) from PolySciTech (www.polyscitech.com) to create a targeted delivery nanoparticle for curcumin to glioma cells. This research holds promise to provide for additional treatment options for brain-cancer. Read more: Zhang, Xuemei, Xuejuan Li, Hongchen Hua, Aiping Wang, Wanhui Liu, Youxin Li, Fenghua Fu, Yanan Shi, and Kaoxiang Sun. "Cyclic hexapeptide-conjugated nanoparticles enhance curcumin delivery to glioma tumor cells and tissue." International Journal of Nanomedicine 12 (2017): 5717. http://pubmedcentralcanada.ca/pmcc/articles/PMC5557616/

“Glioma has one of the highest mortality rates among primary brain tumors. The clinical treatment for glioma is very difficult due to its infiltration and specific growth locations. To achieve improved drug delivery to a brain tumor, we report the preparation and in vitro and in vivo evaluation of curcumin nanoparticles (Cur-NPs). The cyclic hexapeptide c(RGDf(N-me) VK)-C (cHP) has increased affinity for cells that overexpress integrins and was designed to target Cur-NPs to tumors. Functional polyethyleneglycol-modified poly(d,l-lactide-co-glycolide) (PEG-PLGA) conjugated to cHP was synthesized, and targeted Cur-NPs were prepared using a self-assembly nanoprecipitation process. The physicochemical properties and the in vitro cytotoxicity, accuracy, and penetration capabilities of Cur-NPs targeting cells with high levels of integrin expression were investigated. The in vivo targeting and penetration capabilities of the NPs were also evaluated against glioma in rats using in vivo imaging equipment. The results showed that the in vitro cytotoxicity of the targeted cHP-modified curcumin nanoparticles (cHP/Cur-NPs) was higher than that of either free curcumin or non-targeted Cur-NPs due to the superior ability of the cHP/Cur-NPs to target tumor cells. The targeted cHP/Cur-NPs, c(RGDf(N-me)VK)-C-modified Cur-NPs, exhibited improved binding, uptake, and penetration abilities than non-targeting NPs for glioma cells, cell spheres, and glioma tissue. In conclusion, c(RGDf(N-me)VK)-C can serve as an effective targeting ligand, and cHP/Cur-NPs can be exploited as a potential drug delivery system for targeting gliomas. Keywords: glioma targeting, integrin targeting, c(RGDf(N-me)VK)-C peptide, curcumin nanoparticles, in vitro and in vivo evaluation”

PASP from PolySciTech used in SiRNA delivery research

Wednesday, September 6, 2017, 9:47 PM ET

Silencing RNA (siRNA) is short segments of RNA which bind to formed RNA and prevent specific genes from being expressed. This is a powerful tool in gene therapy however the siRNA is very delicate and susceptible to degradation. For this reason, it requires advanced delivery systems. Recently, researchers at Hoshi University and Osaka University (Japan) utilized poly-(α,β)-dl-aspartic acid (PolyVivo Cat# AO005) from PolySciTech (www.polyscitech.com) as part of their investigation into the biodistribution of siRNA drug-delivery systems in-vivo. This research holds promise to enable therapeutic effects of this technology. Read more: Hattori, Yoshiyuki, Ayako Nakamura, Shiori Hanaya, Yuta Miyanabe, Yuki Yoshiike, Takuto Kikuchi, Kei-ichi Ozaki, and Hiraku Onishi. "Effect of chondroitin sulfate on siRNA biodistribution and gene silencing effect in mice after injection of siRNA lipoplexes." Journal of Drug Delivery Science and Technology (2017). http://www.sciencedirect.com/science/article/pii/S1773224717305051

“Abstract: Previously, we found that intravenous injection of chondroitin sulfate (CS), followed by intravenous injection of siRNA/cationic liposome complexes (siRNA lipoplexes) could deliver siRNAs to the liver and suppress expression of target genes. Here, we examined the effect of injection order of CS and siRNA lipoplexes on the biodistribution of siRNA and gene silencing in the liver after sequential injection. When siRNA lipoplexes were injected intravenously into mice, the siRNA largely accumulated in the lungs. However, injection of siRNA lipoplexes, followed by injection of CS, reduced siRNA accumulation in the lungs and increased it in the liver. In addition, agglutinates of erythrocytes caused by the addition of siRNA lipoplexes were re-dispersed by the addition of CS, indicating that the agglutinates accumulating in the lungs by injection of siRNA lipoplexes were broken up by CS injection. However, injection of apolipoprotein B (ApoB) siRNA lipoplexes, followed by injection of CS did not suppress ApoB mRNA levels in the liver. From there results on sequential injection, the injection order of CS and siRNA lipoplexes was important for gene silencing effects in the liver, although the sequential injection could deliver siRNA efficiently into the liver regardless of the injection order of CS and siRNA lipoplexes. Keywords: siRNA delivery; Liposome; Chondroitin sulfate; Liver; Gene silencing”

Whitepaper available on speeding up thermogel dissolution in cold water.

Friday, September 1, 2017, 5:11 PM ET

One drawback of using PLGA-PEG-PLGA and other thermogels is the long time necessary to dissolve them in water. Often, this can be upwards of two days. Recent testing at Akina has found that this time can be cut from 2 days down to around 2 hours by mixing these polymers with PEG-400 biocompatible solvent. Read more here (http://akinainc.com/pdf/WhitePaper-Thermogel-additives-dissolution-effects.pdf).

mPEG-PLLA from PolySciTech used in development of phosphovalproic acid based pancreatic cancer treatment

Friday, September 1, 2017, 4:56 PM ET

The word “cancer” actually describes a broad range of diseases that can affect many different parts of the body. Some cancers, such as skin cancer, respond well to treatment by conventional therapies and have a good prognosis. Other cancers, notably pancreatic, are very difficult to treat and often prove fatal. Recently, researchers working at Stony Brook University, University of Louisiana, and University of California utilized PEG-PLLA (Polyvivo AK004) from PolySciTech (www.polyscitech.com) as part of developing a nanoparticle-based phosphovalproic acid delivery system for treating pancreatic cancer. The developed system showed promise in an animal model for preventing the growth of pancreatic cancer. This research holds promise for a treatment to this lethal disease. Read more: Mattheolabakis, George, Ruixue Wang, Basil Rigas, and Gerardo G. Mackenzie. "Phospho-valproic acid inhibits pancreatic cancer growth in mice: enhanced efficacy by its formulation in poly-(L)-lactic acid-poly (ethylene glycol) nanoparticles." International Journal of Oncology. https://www.spandidos-publications.com/10.3892/ijo.2017.4103/download

“Pancreatic cancer (PC) is one of the most difficult cancers to treat. Since the current chemotherapy is inadequate and various biological approaches have failed, the need for agents that have a potential to treat PC is pressing. Phospho-valproic acid (P-V), a novel anticancer agent, is efficacious in xenograft models of human PC and is apparently safe. In the present study, we evaluated whether formulating P-V in nanoparticles could enhance its anticancer efficacy. In a mouse model of Kras/pancreatitis-associated PC, P-V, orally administered, inhibited the incidence of acinar-to-ductal metaplasia by 60%. To improve its efficacy, we formulated P-V in five different polymeric nanoparticles. Poly-(L)-lactic acid- poly(ethylene glycol) (PLLA-PEG) nanoparticles proved the optimal formulation. PLLA-PEG improved P-V's pharmacokinetics in mice enhancing the levels of P-V in blood. Compared to control, P-V formulated in PLLA-PEG suppressed the growth of MIA PaCa-2 xenografts by 81%, whereas P-V alone reduced it by 51% (p<0 .01="" 87="" a="" acinar-to-ductal="" activated="" against="" agent="" and="" at="" both="" by="" conclusion="" disease="" efficacy="" enhances="" font="" formulated="" formulation="" furthermore="" improving="" in="" inhibited="" is="" it="" its="" kras="" metaplasia="" mice="" models="" molecular="" nanoparticles="" of="" p-v.="" p-v="" p="" pc="" pharmacokinetics.="" phosphorylation="" pivotal="" plla-peg="" promising="" reducing="" residues="" ser727="" stat3="" suppressed="" target="" the="" tyr705="" with="">

PLA from PolySciTech used in development of triple-negative breast cancer nanoparticle-based treatment

Wednesday, August 23, 2017, 3:52 PM ET

Triple negative breast cancer is a specific type of cancer which does not have estrogen, progesterone, or HER2 receptors. This type of breast cancer is typically resistant to receptor-targeted treatments and tends to be more highly invasive than other kinds of breast cancer. One powerful form of treatment for this cancer requires sequential treatment with chemotherapeutics to maximize the effectiveness of the administered drugs. Recently, researchers at University of Cincinnati and The Cincinnati Veteran’s Hospital utilized PLA (PolyVivo AP128) from PolySciTech (www.polyscitech.com) as part of their work in generating nanoparticles which provide for time-controlled release of Erlotinib and Doxorubicin to treat triple-negative breast cancer. These nanoparticles release the Erlotinib as an initial burst followed by sustained release of the Doxorubicin. This research holds promise to treat this highly invasive form of breast cancer. Read more: Zhou, Zilan, Carly Kennell, Mina Jafari, Joo-Youp Lee, Sasha J. Ruiz-Torres, Susan E. Waltz, and Jing-Huei Lee. "Sequential Delivery of Erlotinib and Doxorubicin for Enhanced Triple Negative Breast Cancer Treatment Using Polymeric Nanoparticle." International Journal of Pharmaceutics (2017). (http://www.sciencedirect.com/science/article/pii/S0378517317306944)

“Abstract: Recent studies of signaling networks point out that an order of drugs to be administrated to the cancerous cells can be critical for optimal therapeutic outcomes of recalcitrant metastatic and drug-resistant cell types. In this study, a development of a polymeric nanoparticle system for sequential delivery is reported. The nanoparticle system can co-encapsulate and co-deliver a combination of therapeutic agents with different physicochemical properties [i.e. epidermal growth factor receptor (EGFR) inhibitor, erlotinib (Ei), and doxorubicin (Dox)]. Dox is hydrophilic and was complexed with anionic lipid, 1,2-dioleoyl-sn-glycero-3-phosphate (DOPA), via ion pairing to form a hydrophobic entity. Then it was co-encapsulated with hydrophobic Ei in a poly(L-lactide)-b-polyethylene glycol (PLA-b-PEG) nanoparticle by nanoprecipitation. The complexation of Dox with DOPA greatly helps the encapsulation of Dox, and substantially reduces the release rate of Dox. This nanoparticle system was found to burst the release of Ei with a slow and sustained profile of Dox, which is an optimal course of administration for these two drugs as previously reported. The efficacy of this sequential delivery nanoparticle system was validated in vitro and its in vivo potential applicability was substantiated by fluorescent imaging of high tumor accumulation. Keywords: Nanoparticle, Combination therapy, Sequential delivery, Triple negative breast cancer, EGFR, inhibitor, Erlotinib, Doxorubicin”

PolySciTech mPEG-PLGA/PLGA-rhodamine used in the development of nanoparticle-based intracellular MRSA treatment

Tuesday, August 15, 2017, 4:07 PM ET

MRSA is a bacterial infection that is highly resistant to conventional antibiotic treatments or other therapies. It is still affected by vancomycin, but the bacterial spores have the capability to ‘hide’ inside of cells making it very difficult to treat. One means around this is to use nanoparticles for delivery of the antibiotic to the cells to ensure suitable vancomycin in a local concentration to kill off the bacteria. Recently, researchers at Purdue University used mPEG-PLGA (Polyvivo AK030) and rhodamine-B labelled PLGA (PolyVivo AV011) from PolySciTech (www.polyscitech.com) to create pH sensitive nanoparticles designed for intracellular delivery of vancomycin. This research holds promise to improve treatments of this deadly bacterial infection. Read more: Pei, Yihua, Mohamed F. Mohamed, Mohamed N. Seleem, and Yoon Yeo. "Particle engineering for intracellular delivery of vancomycin to methicillin-resistant Staphylococcus aureus (MRSA)-infected macrophages." Journal of Controlled Release (2017). http://www.sciencedirect.com/science/article/pii/S0168365917307745

“Abstract: Methicillin-resistant Staphylococcus aureus (MRSA) infection is a serious threat to the public health. MRSA is particularly difficult to treat when it invades host cells and survive inside the cells. Although vancomycin is active against MRSA, it does not effectively kill intracellular MRSA due to the molecular size and polarity that limit its cellular uptake. To overcome poor intracellular delivery of vancomycin, we developed a particle formulation (PpZEV) based on a blend of polymers with distinct functions: (i) poly(lactic-co-glycolic acid) (PLGA, P) serving as the main delivery platform, (ii) polyethylene glycol-PLGA conjugate (PEG-PLGA, p) to help maintain an appropriate level of polarity for timely release of vancomycin, (iii) Eudragit E100 (a copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate, E) to enhance vancomycin encapsulation, and (iv) a chitosan derivative called ZWC (Z) to trigger pH-sensitive drug release. PpZEV NPs were preferentially taken up by the macrophages due to its size (500–1000 nm) and facilitated vancomycin delivery to the intracellular pathogens. Accordingly, PpZEV NPs showed better antimicrobial activity than free vancomycin against intracellular MRSA and other intracellular pathogens. When administered intravenously, PpZEV NPs rapidly accumulated in the liver and spleen, the target organs of intracellular infection. Therefore, PpZEV NPs is a promising carrier of vancomycin for the treatment of intracellular MRSA infection. Keywords: Nanoparticles, Intracellular drug delivery, pH-sensitive, Macrophages, Intracellular MRSA, Vancomycin”

Improved targeted-delivery system using oriented antibody fragments developed using PLGA-PEG-Azide from PolySciTech.

Monday, August 14, 2017, 2:43 PM ET

A powerful tool for medicinal delivery is the use of a nanoparticle with a surface covered in a specific antibody or targeting ligand. Because these antibodies and ligands bind specifically to certain protein factors these can be tailored to target to specific cells, notably cancer cells. Since antibody bonding is a stereochemical process, shape and orientation of the antibody matters in terms of its capability to bind. If the active site of the ligand is facing inwards, towards the nanoparticle, it may not work well at all. Recently, researchers working at Queen's University Belfast, University College London, (UK) and Universidade de Lisboa (Portugal) used PLGA-PEG-Azide from PolySciTech (www.polyscitech.com, PolyVivo AI085) to generate nanoparticles which had very precisely controlled antibody orientation on their surface allowing for improved functionality and targeting. They tested this system for its ability to bind to HER2 (a factor that is overexpressed in cancer cells) and found it had substantially higher binding than a randomly oriented nanoparticle system. This research holds promise for developing a wide-array of targeted delivery systems for treating a variety of diseases, most notably cancer. Read more: M. Greene, D. A. Richards, J. Nogueira, K. Campbell, P. Smyth, M. Fernandez, C. J. Scott and V. Chudasama “Generating Next-Generation Antibody-Nanoparticle Conjugates through the Oriented Installation of Non-Engineered Antibody Fragments” Chem. Sci., 2017, DOI: 10.1039/C7SC02747H. (http://pubs.rsc.org/en/Content/ArticleLanding/2017/SC/C7SC02747H#!divAbstract)

“Abstract: The successful development of targeted nanotherapeutics is contingent upon the conjugation of therapeutic nanoparticles to target-specific ligands, with particular emphasis being placed on antibody-based ligands. Thus, new methods that enable the covalent and precise installation of targeting antibodies to nanoparticle surfaces are greatly desired, especially those which do not rely on costly and time-consuming antibody engineering techniques. Herein we present a novel method for the highly controlled and oriented covalent conjugation of non-engineered antibody F(ab) fragments to PLGA-PEG nanoparticles using disulfide-selective pyridazinedione linkers and strain-promoted alkyneazide click chemistry. Exemplification of this method with trastuzumab and cetuximab showed significant improvements in both conjugation efficiency and antigen binding capability, when compared to commonly employed strategies for antibody-nanoparticle construction. This new approach paves the way for the development of antibody-targeted nanomedicines with improved paratope availability, reproducibility and uniformity to enhance both biological activity and ease of manufacture.”

PolySciTech PLGA-NH2 used in research thesis on nanoparticle-surface interactions with living cells

Friday, August 11, 2017, 3:35 PM ET

Nanoparticles have been around for many years but we are still, as a species, just scratching at the surface of understanding them. Of course, the surface is the most important part of a nanoparticle since, due to their incredibly small size, they have an incredible surface area to volume ratio. For example, 1g of PLGA nanoparticles (100 nm) would have a surface area of 7.8 square meters (a little larger than a typical parking space for a car). For this reason, the surface and how it interacts with living organisms is the most important aspect of nanoparticle technology. Recently, Angie (Morris) Thorn at University of Iowa published a PhD thesis which details efforts to broaden our understanding of nanoparticle surface interactions with cells. This includes work with PLGA-NH2 (PolyVivo AI063) from PolySciTech (www.polyscitech.com) to generate nanoparticles covered with either chitosan (for mucoadhesion) or TPP (mitochondria-targeting) to create targeted nanoparticles as drug-delivery vectors. Read more: Thorn, Angie Sue Morris. "The impact of nanoparticle surface chemistry on biological systems." (2017). http://ir.uiowa.edu/etd/5659/

“Abstract: The unique properties of nanomaterials, such as their small size and large surface area-to-volume ratios, have attracted tremendous interest in the scientific community over the last few decades. Thus, the synthesis and characterization of many different types of nanoparticles has been well defined and reported on in the literature. Current research efforts have redirected from the basic study of nanomaterial synthesis and their properties to more application-based studies where the development of functionally active materials is necessary. Today such nanoparticle-based systems exist for a range of biomedical applications including imaging, drug delivery and sensors. The inherent properties of the nanomaterial, although important, aren’t always ideal for specific applications. In order to optimize nanoparticles for biomedical applications it is often desirable to tune their surface properties. Researchers have shown that these surface properties (such as charge, hydrophobicity, or reactivity) play a direct role in the interactions between nanoparticles and biological systems can be altered by attaching molecules to the surface of nanoparticles. In this work, the effects of physicochemical properties of a wide variety of nanoparticles was investigated using in vitro and in vivo models. For example, copper oxide (CuO) nanoparticles were of interest due to their instability in biological media. These nanoparticles undergo dissolution when in an aqueous environment and tend to aggregate. Therefore, the cytotoxicity of two sizes of CuO NPs was evaluated in cultured cells to develop a better understanding of how these propertied effect toxicity outcomes in biological systems. From these studies, it was determined that CuO NPs are cytotoxic to lung cells in a size-dependent manner and that dissolved copper ions contribute to the cytotoxicity however it is not solely responsible for cell death. Moreover, silica nanoparticles are one of the most commonly used nanomaterials because they are easy to synthesize and their properties (such as size, porosity and surface chemistry) can be fine-tuned. Silica nanoparticles can be found in thousands of commercially available products such as toothpastes, cosmetics and detergents and are currently being developed for biomedical applications such as drug delivery and biomedical imaging. Our findings herein indicate that the surface chemistry of silica nanoparticles can have an effect on lung inflammation after exposure. Specifically, amine-modified silica NPs are considered to be less toxic compared to bare silica nanoparticles. Together, these studies provide insight into the role that material properties have on toxicity and allow for a better understanding of their impact on human and environmental health. The final aim of this thesis was to develop surface-modified nanoparticles for drug delivery applications. For this, biodegradable, polymeric NPs were used due to their inert nature and biocompatibility. Furthermore, polymeric NPs are excellent for loading drugs and using them as drug delivery vehicles. In this work, poly (lactic-co-glycolic acid) (PLGA) NPs were loaded with a therapeutic peptide. These NPs were then coated with chitosan (a mucoadhesive polymer) for the treatment of allergic asthma or coated with a small cationic mitochondrial targeting agent for the treatment of ischemia/reperfusion injury. Taken as a whole, this thesis sheds light on the impact of NPs on human health. First by providing useful toxological data for CuO and silica NPs as well as highlighting the potential of surface-modified polymeric NPs to be used in drug delivery-based applications. Keywords: Cell Culture, Nanoparticle, Toxicity”

PEG-PLGA/PLGA from PolySciTech used by Precision NanoSystems, Inc. as part of microfluidics NanoAssemblr™ method optimization and testing

Friday, July 28, 2017, 3:09 PM ET

Microfluidics references the use of systems which have extremely small fluid-channels on the order of magnitude of microns in scale. Precision NanoSystems, Inc. is a company which has developed an array of microfluidic instruments and machines designed for a variety of applications including the synthesis of micro and nanoparticles. For generating micro/nano-particles of polymers, the typical process is to dissolve the polymer in an organic solvent and then mix it with water so that the polymer (which is not water soluble) precipitates out into sub-micron sized particles. Unlike simple emulsion, where the solvent and water are randomly mixed together, the mixing of the organic phase with the water phase in a microfluidics system is highly controlled which allows for the generation of very precise micro/nanoparticles. Recently, Precision Nanosystems, Inc. used a series of mPEG-PLGA’s from PolySciTech (www.polyscitech.com, PolyVivo AK010, AK037, AK106) to make a series of test pegylated nanoparticles with highly controlled properties. They reported these results in a scientific poster presented at controlled release society (CRS) 2017 meeting. This research holds promise for a wide array of applications involving the use of nanoparticles/microparticles as drug delivery systems. Read more here: S.M. Garg, M. Parmar, A. Thomas, E. Ouellet, M. Deleonardis, P. Johnson, A. Armstead, S. Ip, T.J. Leaver, A.W. Wild, R.J. Taylor, E.C. Ramsay “Microfluidics-based Manufacture of PEG-b-PLGA Block Copolymer Nanoparticles for the Delivery of Small Molecule Therapeutics” Controlled Release Society 2017 Poster Session. (https://www.precisionnanosystems.com/resources/?_sf_s=PEG-b-PLGA&_sft_resource-type=poster)

“(Poster introduction): Purpose: In recent years, numerous methods have been developed for the production of block copolymer nanoparticles as drug delivery vehicles. However, these methods pose numerous challenges in maintaining consistent nanoparticle quality, tuning size depending on the application, optimization for scale-up, and reproducibility. The NanoAssemblr™ platform is an automated microfluidics-based system that eliminates user variability and is capable of reproducible, and scalable manufacture of nanoparticles. Here, we describe the use of microfluidic mixing to manufacture PEG-b-PLGA nanoparticles using the NanoAssemblr™ Benchtop instrument. We further describe optimization strategies and investigate the physical encapsulation of a hydrophobic model drug coumarin-6.Results: Microfluidic mixing enabled the rapid and consistent manufacturing of PEG-b-PLGA nanoparticles having diameters below 100 nm. Instrument parameters such as aqueous:organic Flow Rate Ratio and Total Flow Rate had a significant impact on the size of the resulting nanoparticles. Increasing the molecular weight of the PLGA block from 10000 - 95000 Da resulted in an increase in the size of the nanoparticles from 40 - 80 nm. However, changes in the total flow rate of the instrument enabled all the nanoparticles to be tuned to a similar size of 60 nm which is difficult to control using conventional techniques. Coumarin-6 was successfully loaded into PEG-b-PLGA nanoparticles with an encapsulation efficiency of 52% w/w which was significantly higher than that obtained by co-solvent evaporation technique (34% w/w). The size of the nanoparticles prepared using the NanoAssemblr platform were tunable over a broad range while co-solvent evaporation does not provide a reliable means to tune size.”

In addition to this poster, Precision Nanosystems, Inc. has utilized PLGA from PolySciTech (PolyVivo AP121) in generating a wide array of technical data relevant to their microfluidic system. You can see these technical whitepapers here (https://www.precisionnanosystems.com/resources/?_sf_s=plga&_sft_resource-type=tech-bulletins-and-white-papers)

PLA-amine from PolySciTech used in development of atherosclerosis-targeted nanoparticles for treatment of heart disease

Tuesday, July 25, 2017, 2:27 PM ET

Heart disease, typically due to atherosclerotic lesions, is one of the leading causes of death in USA. Most treatments for this disease focus on surgical interventions (e.g. stent placement), which is often utilized in acute situations, or on systemic medicines such as statins, which are typically applied as a preventative. There is a need for therapies to be applied in non-emergency situations but where atherosclerotic lesions are known to be present. Conventionally, nanoparticles have been applied for use against cancer, however they can be targeted to lesions by using appropriate targeting moieties. Recently, researchers working jointly at Harvard Medical School, New York University, Technical University of Denmark, Korea Institute of Ceramic Engineering and Technology, Korea Advanced Institute of Science and Technology, and King Abdulaziz University used PLA-NH2 (PolyVivo AI041, www.polyscitech.com) from PolySciTech as a reactive precursor for generating a fluorescently-conjugated tracer as part of a novel nanoparticle-based system for treatment of artherosclerosis. Read more: Yu, Mikyung, Jaume Amengual, Arjun Menon, Nazila Kamaly, Felix Zhou, Xiaoding Xu, Phei Er Saw et al. "Targeted Nanotherapeutics Encapsulating Liver X Receptor Agonist GW3965 Enhance Antiatherogenic Effects without Adverse Effects on Hepatic Lipid Metabolism in Ldlr−/− Mice." Advanced Healthcare Materials (2017). http://onlinelibrary.wiley.com/doi/10.1002/adhm.201700313/full

“Abstract: The pharmacological manipulation of liver X receptors (LXRs) has been an attractive therapeutic strategy for atherosclerosis treatment as they control reverse cholesterol transport and inflammatory response. This study presents the development and efficacy of nanoparticles (NPs) incorporating the synthetic LXR agonist GW3965 (GW) in targeting atherosclerotic lesions. Collagen IV (Col IV) targeting ligands are employed to functionalize the NPs to improve targeting to the atherosclerotic plaque, and formulation parameters such as the length of the polyethylene glycol (PEG) coating molecules are systematically optimized. In vitro studies indicate that the GW-encapsulated NPs upregulate the LXR target genes and downregulate proinflammatory mediator in macrophages. The Col IV-targeted NPs encapsulating GW (Col IV–GW–NPs) successfully reaches atherosclerotic lesions when administered for 5 weeks to mice with preexisting lesions, substantially reducing macrophage content (≈30%) compared to the PBS group, which is with greater efficacy versus nontargeting NPs encapsulating GW (GW–NPs) (≈18%). In addition, mice administered the Col IV–GW–NPs do not demonstrate increased hepatic lipid biosynthesis or hyperlipidemia during the treatment period, unlike mice injected with the free GW. These findings suggest a new form of LXR-based therapeutics capable of enhanced delivery of the LXR agonist to atherosclerotic lesions without altering hepatic lipid metabolism.”

These posts are syndicated from John Garner's blog at http://jgakinainc.blogspot.com/.

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