Monthly Archives: January 2015

PEG-PLGA used for HIF1a siRNA/gemcitabine delivery as part of pancreatic cancer treatment

PolySciTech (www.polyscitech.com) provides a wide array of biodegradable block copolymers. These include diblock mPEG-PLGA polymers. Recently, these types of polymers have been used to develop a delivery system of HIF1a/gemcitabine which is effective against drug resistant tumors. Read more: Zhao, Xiao, Feng Li, Yiye Li, Hai Wang, He Ren, Jing Chen, Guangjun Nie, and Jihui Hao. “Co-delivery of HIF1α siRNA and gemcitabine via biocompatible lipid-polymer hybrid nanoparticles for effective treatment of pancreatic cancer.” Biomaterials 46 (2015): 13-25. http://www.sciencedirect.com/science/article/pii/S0142961214012782

“Abstract: Hypoxia-inducible factor 1α (HIF1α) has emerged as a promising new target for pancreatic cancer treatment over the past decade. High expression of HIF-1α increases the drug resistance of the current first line chemotherapeutic drug, gemcitabine (Gem). Here we employed biocompatible lipid-polymer hybrid nanoparticles to co-deliver HIF1α siRNA (si-HIF1α) and Gem for pancreatic cancer treatment in subcutaneous and orthotopic tumor models. The cationic ε-polylysine co-polymer (ENPs) can effectively absorb negatively charged si-HIF1α on the surface and encapsulate Gem to the hydrophilic core. Further coating of ENPs with PEGylated lipid bilayer resulted formation of LENPs, with reversed surface charge. The lipid bilayer of LENPs prevented nanoparticle aggregation and si-HIF1α degradation in serum, as well as Gem leakage. Those characteristics endow LENPs encapsulating drug prolonged lifetime in bloodstream and improved drug release via the enhanced tumor vasculature effect in tumor tissues. LENPs can co-deliver Gem and si-HIF1α (LENP-Gem-si-HIF1α) into tumor cells and effectively suppress the HIF1α expression both in vitro and in vivo. LENP-Gem-siHIF1α exhibited significant synergistic antitumor effects. Furthermore, LENP-Gem-si-HIF1α showed excellent capability to inhibit tumor metastasis in orthotopic tumor model. Keywords: siRNA delivery; Hypoxia-inducible factor 1α; Lipid-polymer hybrid nanoparticles; Combination therapy; Pancreatic cancer; Orthotopic tumor model”

PEG-PLGA- anti-EpCAM RNA aptamer used for targeted delivery of doxorubicin to breast cancer cells

PolySciTech (www.polyscitech.com) provides a wide array of biodegradable block copolymers. Recently aptamer linked PLGA-PEG nanoparticles were investigated as a potential medicinal delivery treatment method for breast cancer by the Mashhad University of Medical Sciences in Iran. Read more: Alibolandi, Mona, Mohammad Ramezani, Fatemeh Sadeghi, Khalil Abnous, and Farzin Hadizadeh. “Epithelial cell adhesion molecule aptamer conjugated PEG–PLGA nanopolymersomes for targeted delivery of doxorubicin to human breast adenocarcinoma cell line in vitro.” International journal of pharmaceutics 479, no. 1 (2015): 241-251. http://www.sciencedirect.com/science/article/pii/S0378517314009326

“Abstract: Targeted delivery of anti-cancer agents exclusively to tumor cells introduces an attractive strategy because it increases the therapeutic index compared with untargeted drugs. Aptamer conjugated nanoparticles that can specifically bind to the proteins on a tumor cell surface are capable nanoscale delivery systems for enhancing cellular uptake of chemotherapeutic agents. The epithelial cell adhesion molecule (EpCAM) as a cancer stem cell marker emerges as a versatile target for aptamer-based cancer therapy due to its high expression level in various adenocarcinoma cell lines and its very low expression level in normal cells. We developed EpCAM-targeted PEG–PLGA nanopolymersomes by covalently coupling the EpCAM aptamer to the surface of nanopolymersomes loaded with the anticancer agent doxorubicin via pH gradient method. The results indicated that doxorubicin was entrapped in PEG–PLGA nanopolymersomes with encapsulation efficiency and loading content of 91.25 ± 4.27% and 7.3 ± 0.34%, respectively. Over a period of 5 days, up to 8% of the DOX was released through this system. The doxorubicin-loaded aptamer conjugated nanopolymersomes exhibited efficient cell uptake and internalization, and were significantly more cytotoxic (P < 0.01) toward EpCAM-positive tumor cells (MCF-7) than non-targeted nanopolymersomes. Our data suggest that EpCAM-targeted nanopolymersomes will lead to an improved therapeutic index of doxorubicin to EpCAM positive cancer cells. Keywords: PEG–PLGA; Nanopolymersomes; EpCAM; Aptamer; Targeted drug delivery”

Ramezani, 2015 PLGA-PEG doxorubicin

New Product PolyVivo AK92 (PLGA-PEG-PLGA) with optimized gelation properties

PolySciTech (www.polyscitech.com) provides a wide array of thermogelling triblocks. Recently a thermogel has been generated which has optimized gelation properties to form a strong gel at body temperature (37C). You can see this one here https://akinainc.com/polyscitech/products/polyvivo/catalogue.php?highlight=AK92#h

PolyVivo AK92 thermogel

PLGA-PEG-PLGA used to control release of protein from microparticles

PolySciTech (www.polyscitech.com) provides a wide array of block copolymers such as PLGA-PEG-PLGA triblock. Recently these polymers were formulated with PLGA and lysozyme to generate microparticles with modulated protein release. Read more: Qodratnama, Roozbeh, Lorenzo Pio Serino, Helen C. Cox, Omar Qutachi, and Lisa J. White. “Formulations for modulation of protein release from large-size PLGA microparticles for tissue engineering.” Materials Science and Engineering: C 47 (2015): 230-236. http://www.sciencedirect.com/science/article/pii/S0928493114007048

“Abstract: In this study we present an approach to pre-program lysozyme release from large size (100–300 μm) poly(dl-lactic acid-co-glycolic acid) (PLGA) microparticles. This approach involved blending in-house synthesized triblock copolymers with a PLGA 85:15. In this work it is demonstrated that the lysozyme release rate and the total release are related to the mass of triblock copolymer present in polymer formulation. Two triblock copolymers (PLGA–PEG1500–PLGA and PLGA–PEG1000–PLGA) were synthesized and used in this study. In a like-for-like comparison, these two triblock copolymers appeared to have similar effects on the release of lysozyme. It was shown that blending resulted in the increase of the total lysozyme release and shortened the release period (70% release within 30 days). These results demonstrated that blending PLGA–PEG–PLGA triblock copolymer with PLGA 85:15 can be used as a method to pre-program protein release from microparticles. These microparticles with modulated protein release properties may be used to create microparticle-based tissue engineering constructs with pre-programmed release properties. Keywords: Triblock copolymer; Microparticle; Lysozyme; PLGA–PEG–PLGA; Controlled release; Glass transition temperature Highlights: Two triblock copolymers (PLGA–PEG1500–PLGA and PLGA–PEG1000–PLGA) were synthesized. Triblock copolymers have similar effects on the lysozyme release from PLGA microparticles. Triblock copolymers increased the total lysozyme release and shortened the release period. Increase in triblock copolymer mass was associated with higher release rate. Increase in triblock copolymer mass was associated with shorter release period.”

Ocular peptide delivery by PLGA and PLGA-PEG-PLGA thermogel for herpes treatment

PolySciTech (www.polyscitech.com) provides a wide array of PLGA polymers as well as thermogelling PLGA-PEG-PLGA triblock copolymers. Recently these types of polymers were utilized to develop a drug delivery system for ocular deliver of ganciclovir to treat herpes induced keratitis. Read more: Yang, Xiaoyan, Sujay J. Shah, Zhiying Wang, Vibhuti Agrahari, Dhananjay Pal, and Ashim K. Mitra. “Nanoparticle-based topical ophthalmic formulation for sustained release of stereoisomeric dipeptide prodrugs of ganciclovir.” Drug delivery 0 (2015): 1-11. http://informahealthcare.com/doi/abs/10.3109/10717544.2014.996833

Abstract: Poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles (NP) of Val-Val dipeptide monoester prodrugs of ganciclovir (GCV) including L-Val-L-Val-GCV (LLGCV), L-Val-D-Val-GCV (LDGCV) and D-Val-L-Val-GCV (DLGCV) were formulated and dispersed in thermosensitive PLGA-PEG-PLGA polymer gel for the treatment of herpes simplex virus type 1 (HSV-1)-induced viral corneal keratitis. Nanoparticles containing prodrugs of GCV were prepared by a double-emulsion solvent evaporation technique using various PLGA polymers with different drug/polymer ratios. Nanoparticles were characterized with respect to particle size, entrapment efficiency, polydispersity, drug loading, surface morphology, zeta potential and crystallinity. Prodrugs-loaded NP were incorporated into in situ gelling system. These formulations were examined for in vitro release and cytotoxicity. The results of optimized entrapment efficiencies of LLGCV-, LDGCV- and DLGCV-loaded NP are of 38.7 ± 2.0%, 41.8 ± 1.9%, and 45.3 ± 2.2%; drug loadings 3.87 ± 0.20%, 2.79 ± 0.13% and 3.02 ± 0.15%; yield 85.2 ± 3.0%, 86.9 ± 4.6% and 76.9 ± 2.1%; particle sizes 116.6 ± 4.5, 143.0 ± 3.8 and 134.1 ± 5.2 nm; and zeta potential −15.0 ± 4.96, −13.8 ± 5.26 and −13.9 ± 5.14 mV, respectively. Cytotoxicity studies suggested that all the formulations are non-toxic. In vitro release of prodrugs from NP showed a biphasic release pattern with an initial burst phase followed by a sustained phase. Such burst effect was completely eliminated when NP were suspended in thermosensitive gels with near zero-order release kinetics. Prodrugs-loaded PLGA NP dispersed in thermosensitive gels can thus serve as a promising drug delivery system for the treatment of anterior eye diseases. Keywords: Ganciclovir prodrugs, HSV-1 keratitis, PLGA nanoparticles, thermosensitive gel, topical administration”

PolySciTech PLGA used for microsphere delivery of mesenchymal stem cells in treatment of heart attack

PolySciTech (www.polyscitech.com) provides a wide array of PLGA products. Recently PLGA purchased from PolySciTech was utilized to develop PLGA-PEG microparticles which were subsequently loaded with stem cells and investigated for use in treatment of tissue damage resultant from animal model induced heart attack. Read more: Lee, Young Sook, Kwang Suk Lim, Jung-Eun Oh, Arum Yun, Wan Seok Joo, Hyun Soo Kim, Chae-Ok Yun, and Sung Wan Kim. “Development of porous PLGA/PEI< sub> 1.8 k</sub> biodegradable microspheres for the delivery of mesenchymal stem cells (MSCs).” Journal of Controlled Release (2015). http://www.sciencedirect.com/science/article/pii/S016836591500005X

“Abstract: Multipotent mesenchymal stem cells (MSCs) promise a therapeutic alternative for many debilitating and incurable diseases. However, one of the major limitations for the therapeutic application of human MSC (hMSC) is the lengthy ex vivo expansion time for preparing a sufficient amount of cells due to the low engraftment rate after transplantation. To solve this conundrum, a porous biodegradable polymeric microsphere was investigated as a potential scaffold for the delivery of MSCs. The modified water/oil/water (W1/O/W2) double emulsion solvent evaporation method was used for the construction of porous microspheres. PEI1.8k was blended with poly(lactic-co-glycolic acid) (PLGA) to enhance electrostatic cellular attachment to the microspheres. The porous PLGA/PEI1.8k (PPP) particles demonstrated an average particle size of 290 μm and an average pore size of 14.3 μm, providing a micro-carrier for the MSC delivery. PPP particles allowed for better attachment of rMSCs than non-porous PLGA/PEI1.8k (NPP) particles and non-porous (NP) and porous PLGA (PP) microspheres. rMSC successfully grew on the PPP particles for 2 weeks in vitro. Next, PPP particles loaded with 3 different amounts of hMSC showed increased in vivo engraftment rates and maintained the stemness characteristics of hMSC compared with hMSCs-alone group in rats 2 weeks after intramyocardial administration. These customized PPP particles for MSC delivery are a biodegradable and injectable scaffold that can be used for clinical applications. Keywords: PLGA; Porous microparticle; Mesenchymal stem cell; Human stem cell; Cell therapy; PEI1.8k”

polyscitech PLGA heart attack treatement

PEG-PLA used to enhance anti-HIV treatment by delivery of DAAN15h

PolySciTech (www.polyscitech.com) provides a wide array of PEG-PLA polymers. Recently this type of polymer was utilized to generate nanoparticles encapsulating DAAN15h. a potent reverse transcriptase inhibitor, to improve blood circulation time and reduce elimination. Read more: Li, Wen, Qian Wang, Yuan Li, Fei Yu, Qi Liu, Bingjie Qin, Lan Xie, Lu Lu, and Shibo Jiang. “A Nanoparticle-Encapsulated Non-Nucleoside Reverse-Transcriptase Inhibitor with Enhanced Anti-HIV-1 Activity and Prolonged Circulation Time in Plasma.” Current pharmaceutical design 21, no. 7 (2015): 925-935. http://www.ingentaconnect.com/content/ben/cpd/2015/00000021/00000007/art00011

“Abstract: Non-nucleoside reverse-transcriptase inhibitors (NNRTIs), major components of highly active antiretroviral therapy (HAART), are effective in suppressing viral replication and preventing the progress of HIV-1 infection to AIDS. However, rapid blood clearance in vivo could significantly impair the efficiency of the anti-HIV-1 activity and result in multiple daily doses which might lead to poor patient compliance. Here we attempted to employ biodegradable organic nanoparticles (NPs) to encapsulate DAAN15h, a derivative of 4-substituted 1, 5-diarylaniline with potent anti-HIV activities. Nanoparticles encapsulating DAAN15h (NP-DAAN15h) displayed a spherical shape with a size of 97.01 ± 3.64 nm and zeta potential of -19.1 ± 3.78 mV, and they exhibited a sustained controlled release behavior in vitro. The cellular uptake of NPs on TZM-b1 cells, MT-2 cells and M7 cells, possibly through lipid raft-mediated and energy dependent active transport processes, was significantly enhanced. NP-DAAN15h, which possessed no significant in vitro cytotoxicity, showed improved antiviral activity against laboratory-adapted and primary HIV-1 isolates with different subtypes and tropisms, including RT-resistant variants. NP-DAAN15h exhibited a significantly prolonged blood circulation time, decreased plasma elimination rate, and enhanced AUC(0-t). NP-DAAN15h, a nanoparticle-encapsulated NNRTI, exhibits enhanced cellular uptake, improved anti-HIV-1 efficacy and prolonged in vivo circulation time, suggesting good potential for further development as a new NNRTI formulation for clinical use. Keywords: HIV-1; antiretroviral therapy; drug resistance; nanoparticles; non-nucleoside reverse-transcriptase inhibitor; pharmacokinetics”

PolyVivo AV08 used for SiRNA delivery nanoparticle tracking

PolySciTech (www.polyscitech.com) provides a wide array of polymer products including fluorescently labelled PLGA such as PLGA-FR648 (AV08). Recently this product was utilized in a publication as a means of tracking SiRNA loaded nanoparticles. Read more: Colombo, Stefano, Dongmei Cun, Katrien Remaut, Matt Bunker, Jianxin Zhang, Birte Martin-Bertelsen, Anan Yaghmur, Kevin Braeckmans, Hanne M. Nielsen, and Camilla Foged. “Mechanistic profiling of the siRNA delivery dynamics of lipid–polymer hybrid nanoparticles.” Journal of Controlled Release (2014). http://www.sciencedirect.com/science/article/pii/S0168365914008232

“Abstract: Understanding the delivery dynamics of nucleic acid nanocarriers is fundamental to improve their design for therapeutic applications. We investigated the carrier structure–function relationship of lipid–polymer hybrid nanoparticles (LPNs) consisting of poly(dl-lactic-co-glycolic acid) (PLGA) nanocarriers modified with the cationic lipid dioleoyltrimethyl-ammoniumpropane (DOTAP). A library of siRNA-loaded LPNs was prepared by systematically varying the nitrogen-to-phosphate (N/P) ratio. Atomic force microscopy (AFM) and cryo-transmission electron microscopy (cryo-TEM) combined with small angle X-ray scattering (SAXS) and confocal laser scanning microscopy (CLSM) studies suggested that the siRNA-loaded LPNs are characterized by a core–shell structure consisting of a PLGA matrix core coated with lamellar DOTAP structures with siRNA localized both in the core and in the shell. Release studies in buffer and serum-containing medium combined with in vitro gene silencing and quantification of intracellular siRNA suggested that this self-assembling core–shell structure influences the siRNA release kinetics and the delivery dynamics. A main delivery mechanism appears to be mediated via the release of transfection-competent siRNA–DOTAP lipoplexes from the LPNs. Based on these results, we suggest a model for the nanostructural characteristics of the LPNs, in which the siRNA is organized in lamellar superficial assemblies and/or as complexes entrapped in the polymeric matrix. Keywords: siRNA; Drug delivery; Nanomedicine; PLGA; DOTAP; Sustained release”

 

Colombo 2014 SiRNA nanoparticles polyvivo polyscitech AV08

PLGA microspheres for SiRNA delivery

PolySciTech (www.polyscitech.com) provides a wide array of PLGA polymers for research applications. Recently a very useful chapter has been published which details a protocol for loading small interfering RNA (siRNA) into PLGA microspheres by double emulsion technique. Read more: De Rosa, Giuseppe, and Giuseppina Salzano. “PLGA Microspheres Encapsulating siRNA.” In RNA Interference, pp. 43-51. Springer New York, 2015. http://link.springer.com/protocol/10.1007/978-1-4939-1538-5_4

“Abstract: The therapeutic use of small interfering RNA (siRNA) represents a new and powerful approach to suppress the expression of pathologically genes. However, biopharmaceutical drawbacks, such as short half-life, poor cellular uptake, and unspecific distribution into the body, hamper the development of siRNA-based therapeutics. Poly(lactide-co-glycolide), (PLGA) microspheres can be a useful tool to overcome these issues. siRNA can be encapsulated into the PLGA microspheres, which protects the loaded nucleic acid against the enzymatic degradation. Moreover, PLGA microspheres can be injected directly into the action site, where the siRNA can be released in controlled manner, thus avoiding the need of frequent invasive administrations. The complete biodegradability of PLGA to monomers easily metabolized by the body, and its approval by FDA and EMA for parenteral administration, assure the safety of this copolymer and do not require the removal of the device after the complete drug release. In chapter, a basic protocol for the preparation of PLGA microspheres encapsulating siRNA is described. This protocol is based on a double emulsion/solvent evaporation technique, a well known and easy to reproduce method. This specific protocol has been developed to encapsulate a siRNA anti-TNFα in PLGA microspheres, and it has been designed and optimized to achieve high siRNA encapsulation efficiency and slow siRNA release in vitro. However, it can be extended also to other siRNA as well as other RNA or DNA-based oligonucleotides (miRNA, antisense, decoy, etc.). Depending on the applications, chemical modifications of the backbone and site-specific modification within the siRNA sequences could be required.”