Monthly Archives: August 2015

mPEG-PLA used for gemcitabine-resistant pancreatic cancer treatment

PolySciTech (www.polyscitech.com) provides a wide array of biodegradable block copolymers including mPEG-PLA which can be used as a delivery system for a wide variety of therapeutic compounds. Recently this polymer has been found to assist in the delivery of salinomycin to pancreatic cancer cells leading to significantly increased cell-death. Read more: Daman, Zahra, Hamed Montazeri, Masoumeh Azizi, Faegheh Rezaie, Seyed Nasser Ostad, Mohsen Amini, and Kambiz Gilani. “Polymeric Micelles of PEG-PLA Copolymer as a Carrier for Salinomycin Against Gemcitabine-Resistant Pancreatic Cancer.” Pharmaceutical research (2015): 1-12. http://link.springer.com/article/10.1007/s11095-015-1737-8

“ABSTRACT: Purpose: Resistance to gemcitabine in pancreatic cancer (PC) may account for the failure of conventional treatments. Recently, salinomycin (SAL) has been identified as selective inhibitor of cancer stem cells (CSCs). In our study, we aimed to deliver SAL to gemcitabine-resistant PC by the aid of poly ethylene glycol-b-poly lactic acid (PEG-b-PLA) polymeric micelles (PMs). Methods: SAL-loaded PMs were prepared and investigated in terms of pharmaceutical properties. MTT and Annexin V/PI assays were used to study cell proliferation and apoptosis in AsPC-1 cells in response to treatment with SAL micellar formulations. Alterations in CSC phenotype, invasion strength, and mRNA expression of epithelial mesenchymal transition (EMT) markers were also determined in the treated cells. In vivo antitumor study was performed in Balb/c AsPC-1 xenograft mice. Results: PM formulations of SAL were prepared in suitable size and loading traits. In gemcitabine-resistant AsPC-1 cells, SAL was found to significantly increase cell mortality and apoptosis. It was also observed that SAL micellar formulations inhibited invasion and harnessed EMT in spite of induced expression of Snail. The in vivo antitumor experiment showed significant tumor eradication and the highest survival probability in mice treated with SAL PMs. Conclusions: The obtained results showed the efficacy of SAL nano-formulation against PC tumor cells. KEY WORDS: cancer stem cells epithelial mesenchymal transition pancreatic cancer polymeric micelles salinomycin”

3D tumor spheroids more accurate model for cancer research than conventional 2D

In addition to polymer products, Akina, Inc. also offers thermogelling matrices for growth of cells in 3-dimensional structures under the brand-name 3DCellMaker (www.3dcellmaker.com). 3D tumor models present many advantages over 2D models in that they accurately represent in-vivo cancer conditions such as microenvironment parameters and cell-cell interactions. This makes these models more reliable in terms of predicting whether a therapeutic strategy will actually be effective in the clinic. Read more: Fitzgerald, Kathleen A., Meenakshi Malhotra, Caroline M. Curtin, Fergal J. O’Brien, and Caitriona M. O’Driscoll. “Life in 3D is never flat: 3D models to optimise drug delivery.” Journal of Controlled Release 215 (2015): 39-54. http://www.sciencedirect.com/science/article/pii/S016836591530033X

“Abstract: The development of safe, effective and patient-acceptable drug products is an expensive and lengthy process and the risk of failure at different stages of the development life-cycle is high. Improved biopharmaceutical tools which are robust, easy to use and accurately predict the in vivo response are urgently required to help address these issues. In this review the advantages and challenges of in vitro 3D versus 2D cell culture models will be discussed in terms of evaluating new drug products at the pre-clinical development stage. Examples of models with a 3D architecture including scaffolds, cell-derived matrices, multicellular spheroids and biochips will be described. The ability to simulate the microenvironment of tumours and vital organs including the liver, kidney, heart and intestine which have major impact on drug absorption, distribution, metabolism and toxicity will be evaluated. Examples of the application of 3D models including a role in formulation development, pharmacokinetic profiling and toxicity testing will be critically assessed. Although utilisation of 3D cell culture models in the field of drug delivery is still in its infancy, the area is attracting high levels of interest and is likely to become a significant in vitro tool to assist in drug product development thus reducing the requirement for unnecessary animal studies. Keywords: 3D cell culture; In vitro biopharmaceutical tool; Drug delivery; Biomaterials; The 3 Rs”

PEG-PLGA polymers used for ultrasound/fluorescent/MRI contrast agent delivery

PolySciTech (www.polyscitech.com) provides a wide array of biodegradable block copolymers such as PEG-PLGA. Recetnly these types of polymers have been used to deliver superparamagnetic iron oxide nanoparticles and fluorescent dye proving their value for applications as ultrasound contrast agents. Read more: Luo, Binhua, Huajie Zhang, Xuhan Liu, Rong Rao, Yun Wu, and Wei Liu. “Novel DiR and SPIO nanoparticles embedded PEG-PLGA nanobubbles as a multimodalimaging contrast agent.” Bio-Medical Materials and Engineering 26, no. s1 (2015): 911-916. http://content.iospress.com/articles/bio-medical-materials-and-engineering/bme1384

“Abstract: Fluorescence dye DiR and superparamagnetic iron oxide nanoparticles (SPIONs) embedded in PEG-PLGA nanobubbles (DiR-SPIO-NBs) were produced using double emulsion method on a membrane of Shirasu porous glass (SPG). The nanobubbles encapsulated with DiR and SPIONs had a liquid core (perfluoropentane) and a PEG-PLGA shell. DiR-SPIO-NBs showed biocompatibility based on MTT cytotoxicity and hemolysis studies. The PFP encapsulated in the nanobubbles experienced phase transition under ultrasonic irradation. Nanobubbles dispersed well in saline over 3 months, and the relaxivity was 127.9 mM−1s−1, suggesting that it could be used as a contrast agent in MRI. The MR and fluorescence images in vivo demonstrated that the signal intensity in the spleen and liver was significantly enhanced with the treatment of nanobubbles. In addition, results of ultrasound images suggested that the nanobubbles had persistent contrast ability. In conclusion, nanobubbles could be utilized as an US/MRI/fluorescence contrast agent.”

PolySciTech PLGA used for anti-HIV drug delivery by electrospun scaffold

PolySciTech (www.polyscitech.com) provides a wide array of biodegradable polymer products including PLGA. Recently, researchers at the University of Washington have focused their efforts on generating an electrospun scaffold for the delivery of anti-HIV medicines using PolySciTech PLGA (PolyVivo AP060). These meshes can be used for a variety of applications including vaginal anti-HIV medicinal delivery for treatment and prevention. By varying the blend of PLGA with another biodegradable polyester, PCL, the research group was able to control the release rate of the medicines. Read more: Carson, Daniel, Yonghou Jiang, and Kim A. Woodrow. “Tunable Release of Multiclass Anti-HIV Drugs that are Water-Soluble and Loaded at High Drug Content in Polyester Blended Electrospun Fibers.” Pharmaceutical Research (2015): 1-12. http://link.springer.com/article/10.1007/s11095-015-1769-0

“Abstract: Objectives: Sustained release of small molecule hydrophilic drugs at high doses remains difficult to achieve from electrospun fibers and limits their use in clinical applications. Here we investigate tunable release of several water-soluble anti-HIV drugs from electrospun fibers fabricated with blends of two biodegradable polyesters. Methods: Drug-loaded fibers were fabricated by electrospinning ratios of PCL and PLGA. Fiber morphology was imaged by SEM, and DSC was used to measure thermal properties. HPLC was used to measure drug loading and release from fibers. Cytotoxicity and antiviral activity of drug-loaded fibers were measured in an in vitro cell culture assay. Results: We show programmable release of hydrophilic antiretroviral drugs loaded up to 40 wt%. Incremental tuning of highly-loaded drug fibers within 24 h or >30 days was achieved by controlling the ratio of PCL and PLGA. Fiber compositions containing higher PCL content yielded greater burst release whereas fibers with higher PLGA content resulted in greater sustained release kinetics. We also demonstrated that our drug-loaded fibers are safe and can sustain inhibition of HIV in vitro. Conclusions: These data suggest that we were able to overcome current limitations associated with sustained release of small molecule hydrophilic drugs at clinically relevant doses. We expect that our system represents an effective strategy to sustain delivery of water-soluble molecules that will benefit a variety of biomedical applications.”

New Fluorescent dye conjugated block copolymers available from PolySciTech

PolySciTech (www.polyscitech.com) provides a wide array of biodegradable block copolymers including fluorescently conjugated block copolymers. These types of polymers are particularly useful for researchers who are performing studies where visualizing and tracking the polymer is of value. Most notably, this is particularly useful for nanoparticles since they are small and difficult to see under a microscope. With a fluorescent dye conjugated onto the polymer, tracking nanoparticle formulations made of these materials is an easy way to confirm valuable parameters relevant to targeted delivery such as accumulation and cellular uptake. These new polymers are available online as PolyVivo AV19, AV20, and AV21 (https://akinainc.com/polyscitech/products/polyvivo/sequential.php#PolymerVisualization). Similar, lab-made, polymers have been used previously to track nanoparticles and you can read about this usage here: Wang, Hai, Ying Zhao, Yan Wu, Yu-lin Hu, Kaihui Nan, Guangjun Nie, and Hao Chen. “Enhanced anti-tumor efficacy by co-delivery of doxorubicin and paclitaxel with amphiphilic methoxy PEG-PLGA copolymer nanoparticles.” Biomaterials 32, no. 32 (2011): 8281-8290. http://www.sciencedirect.com/science/article/pii/S0142961211008039

PolySciTech PLGA-Fluorescein used for nanoparticle tracking and cellular uptake assay

PolySciTech (www.polyscitech.com) provides a wide variety of biodegradable research polymers. These include fluorescently conjugated PLGA to assist in imaging nanoparticles and other polymer structures by microscopy and other techniques. Recently PolyVivo AV01 (PLGA-Fluorescein) was combined with other polymer to generate a functionalized nanoparticle and the uptake of this particle by cells was monitored. This technique holds promise for cellular delivery of drug payloads which could be used as a means of cancer therapy. Read more:  Park, Joonyoung, Tarsis F. Brust, Hong Jae Lee, Sang Cheon Lee, Val J. Watts, and Yoon Yeo. “Polydopamine-based simple and versatile surface modification of polymeric nano drug carriers.” ACS nano 8, no. 4 (2014): 3347-3356. http://pubs.acs.org/doi/abs/10.1021/nn405809c

“Abstract: The surface of a polymeric nanoparticle (NP) is often functionalized with cell-interactive ligands and/or additional polymeric layers to control NP interaction with cells and proteins. However, such modification is not always straightforward when the surface is not chemically reactive. For this reason, most NP functionalization processes employ reactive linkers or coupling agents or involve prefunctionalization of the polymer, which are complicated and inefficient. Moreover, prefunctionalized polymers can lose the ability to encapsulate and retain a drug if the added ligands change the chemical properties of the polymer. To overcome this challenge, we use dopamine polymerization as a way of functionalizing NP surfaces. This method includes brief incubation of the preformed NPs in a weak alkaline solution of dopamine, followed by secondary incubation with desired ligands. Using this method, we have functionalized poly(lactic-co-glycolic acid) (PLGA) NPs with three representative surface modifiers: a small molecule (folate), a peptide (Arg-Gly-Asp), and a polymer [poly(carboxybetaine methacrylate)]. We confirmed that the modified NPs showed the expected cellular interactions with no cytotoxicity or residual bioactivity of dopamine. The dopamine polymerization method is a simple and versatile surface modification method, applicable to a variety of NP drug carriers irrespective of their chemical reactivity and the types of ligands. Keywords: polymeric nanoparticles; drug delivery; surface modification; dopamine polymerization; cell−nanoparticle interactions”

PLGA from PolySciTech used in developing metronomic delivery of PTX to treat ovarian cancer

PolySciTech (www.polyscitech.com) provides a wide array of PLGA and related products. PLGA degradation speed depends on lactide:glycolide ratio as well as molecular weight. PLGA’s with lower lactide ratios, down to 50%, and lower molecular weights tend to degrade faster as water easily gains access to the relatively short polymer chain and cleaves it into little pieces. Recently one of Akina’s fastest degrading polymers AP037 (PLGA 50:50 Mn 1000-5000) was combined with a very slow degrading PLGA with high molecular weight to create a nanoparticle which had controlled release properties of paclitaxel. This system was found to be less susceptible to cells developing resistance as there was less drug-free time periods in between doses. Read more: Amoozgar, Zohreh, Lei Wang, Tania Brandstoetter, Samuel S. Wallis, Erin M. Wilson, and Michael S. Goldberg. “Dual-layer surface coating of PLGA-based nanoparticles provides slow-release drug delivery to achieve metronomic therapy in a paclitaxel-resistant murine ovarian cancer model.” Biomacromolecules 15, no. 11 (2014): 4187-4194. http://pubs.acs.org/doi/abs/10.1021/bm5011933

“Abstact: Development of drug resistance is a central challenge to the treatment of ovarian cancer. Metronomic chemotherapy decreases the extent of drug-free periods, thereby hindering development of drug resistance. Intraperitoneal chemotherapy allows for treatment of tumors confined within the peritoneum, but achieving sustained tumor-localized chemotherapy remains difficult. We hypothesized that modulating the surface properties of poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles could enhance their drug retention ability and extend their release profile, thereby enabling metronomic, localized chemotherapy in vivo. Paclitaxel was encapsulated in particles coated with a layer of polydopamine and a subsequent layer of poly(ethylene glycol) (PEG). These particles achieved a 3.8-fold higher loading content compared to that of nanoparticles formulated from linear PLGA–PEG copolymers. In vitro release kinetic studies and in vivo drug distribution profiles demonstrate sustained release of paclitaxel. Although free drug conferred no survival advantage, low-dose intraperitoneal administration of paclitaxel-laden surface-coated nanoparticles to drug-resistant ovarian tumor-bearing mice resulted in significant survival benefits in the absence of any apparent systemic toxicity”

PLGA-Rhodamine from PolySciTech used as part of colorectal cancer therapy development

PolySciTech (www.polyscitech.com) provides a wide array of fluorescently conjugated nanoparticles. Recently PLGA-Rhodamine (AV11) from PolySciTech was used to track death-receptor 5 targeted nanoparticles for colorectal cancer therapy. Using the death-receptor, which is typically targeted to initiate apoptosis, as a target for nanotherapy represents a novel method of delivery chemotherapeutics to cancer cells. Read more: Schmid, Daniela, Francois Fay, Donna M. Small, Jakub Jaworski, Joel S. Riley, Diana Tegazzini, Cathy Fenning et al. “Efficient Drug Delivery and Induction of Apoptosis in Colorectal Tumors Using a Death Receptor 5-Targeted Nanomedicine.” Molecular Therapy (2014). http://www.nature.com/mt/journal/vaop/ncurrent/full/mt2014137a.html

“Abstract: Death Receptor 5 (DR5) is a pro-apoptotic cell-surface receptor that is a potential therapeutic target in cancer. Despite the potency of DR5-targeting agents in preclinical models, the translation of these effects into the clinic remains disappointing. Herein, we report an alternative approach to exploiting DR5 tumor expression using antibody-targeted, chemotherapy-loaded nanoparticles. We describe the development of an optimized polymer-based nanotherapeutic incorporating both a functionalized polyethylene glycol (PEG) layer and targeting antibodies to limit premature phagocytic clearance whilst enabling targeting of DR5-expressing tumor cells. Using the HCT116 colorectal cancer model, we show that following binding to DR5, the nanoparticles activate caspase 8, enhancing the anti-tumor activity of the camptothecin payload both in vitro and in vivo. Importantly, the combination of nanoparticle-induced DR5 clustering with camptothecin delivery overcomes resistance to DR5-induced apoptosis caused by loss of BAX or overexpression of anti-apoptotic FLIP. This novel approach may improve the clinical activity of DR5-targeted therapeutics while increasing tumor-specific delivery of systemically toxic chemotherapeutics.”

Delivery of paclitaxel to glioblastomas using Mal-PEG-PLA decorated nanoparticles

PolySciTech (www.polyscitech.com) provides a wide array of biodegradable block copolymers and activated precursors including Maleimide endcapped Mal-PEG-PLA. A recent report used this type of polymer and conjugated the Maleimide end to a peptide that targets mammary-derived growth factor which is over-expressed in cancerous glioma cells. This technique was found to provide targeted delivery in a glioma mouse model. Read more: Feng, Xingye, Xiaoling Gao, Ting Kang, Di Jiang, Jianhui Yao, Yixian Jing, Qingxiang Song, Xinguo Jiang, Jianying Liang, and Jun Chen. “Mammary-derived growth inhibitor targeting peptide-modified PEG-PLA nanoparticles for enhanced targeted glioblastoma therapy.” Bioconjugate Chemistry (2015). http://pubs.acs.org/doi/abs/10.1021/acs.bioconjchem.5b00379

“Targeting delivery of chemotherapeutics to neovasculature represents a promising means for tumor therapy since angiogenesis has been a featured hallmark of glioblastma. However, anti-angiogenic therapy would induce the occurrence of metastatic tumor and even neoplasm recurrence. Simultaneous targeting of tumor cells and neovasculature perfectly overcome such defects and has been proven to be an efficacious strategy for suppressing tumor growth. In the present study, a tumor homing peptide CooP selective binding to mammary-derived growth inhibitor that overexpressed in glioma cells and blood vessel endothelial cells was decorated on the surface of paclitaxel-loading PEG–PLA nanoparticles (NP-PTX) to obtain the dual targeting nanovector CooP-NP-PTX. In vitro antiproliferation study showed that HUVEC cells and U87MG cells were much more sensitive to CooP-NP-PTX than NP-PTX. In vivo imaging demonstrated that CooP-NP accumulated more selectively and penetrated deeper into the tumor site. In addition, the glioma-bearing mice treated with CooP-NP-PTX achieved the longest survival time compared to NP-PTX and Taxol. The findings observed above indicated that CooP peptide-functionalized anti-neoplastic agent-loaded nanoparticles might possess promising potential for glioblastoma therapy.”

PEG-PLGA from PolySciTech used to generate nanoparticles for chemoradiotherapy

PolySciTech (www.polyscitech.com) provides a wide variety of PEG-PLGA block copolymers. Recently researchers at University of North Carolina utilized PEG-PLGA from PolySciTech to generate nanoparticles which sequentially release wortmannin followed by docetaxel. Wortmannin acts to inhibit Phosphoinositide 3-kinase activity which reduces cancer metastasis (capability of cancer cells to float freely) and angiogenesis (capability of cancer cells to grow new blood vessels). Docetaxel acts to prevent cellular reproduction and as such has strong chemotherapeutic activity. It was found that delivering both together in sequence increased the effectiveness of the treatment as well as the efficiency of radiotherapy. Read more: Au, Kin Man, Yuanzeng Min, Xi Tian, Longzhen Zhang, Virginia Perello, Joseph M. Caster, and Andrew Z. Wang. “Improving Cancer Chemoradiotherapy Treatment by Dual Controlled Release of Wortmannin and Docetaxel in Polymeric Nanoparticles.” (2015). http://pubs.acs.org/doi/abs/10.1021/acsnano.5b02913

“Abstract: Combining molecularly targeted agents and chemotherapeutics is an emerging strategy in cancer treatment. We engineered sub-50 nm diameter di-block copolymer nanoparticles (NPs) that can sequentially release wortmannin (Wtmn, a cell signaling inhibitor) and docetaxel (Dtxl, genotoxic anticancer agent) to cancer cells. These NPs were studied in chemoradiotherapy, an important cancer treatment paradigm, in the preclinical setting. We demonstrated that Wtmn enhanced the therapeutic efficacy of Dtxl and increased the efficiency of radiotherapy (XRT) in H460 lung cancer and PC3 prostate cells in culture. Importantly, we showed that NPs containing both Wtmn and Dtxl release the drugs in a desirable sequential fashion to therapeutic efficacy in comparison to administering each drug alone. An in vivo toxicity study in a murine model validated that NPs containing both Dtxl and Wtmn do not have a high toxicity profile. Lastly, we demonstrated that Dtxl/Wtmn co-encapsulated NPs are more efficient than each single drug loaded NPs or combination of both single drug loaded NPs in chemoradiotherapy using xenograft models. Histopathological studies and correlative studies support that the improved therapeutic efficacy is through changes in signaling pathways (Wtmn) and increased tumor cell apoptosis. Our findings suggest that our nanoparticle system led to a dynamic rewiring of cellular apoptotic pathways and thus a higher therapeutic efficiency.”