Category Archives: Nanoparticles/Micelles/Liposomes

category for nanoparticles or micelles or liposomes. Generally defined as drug delivery systems that for stable dispersions or solutions with a hydrophobic interior and are <1um in size.

PLGA from PolySciTech used for development of nanoparticle stability model to prevent lethal clogs in blood-stream

PolySciTech division of Akina, Inc (www.polyscitech.com) provides a wide array of biodegradable polymers including PLGA. Recently, PLGA from PolySciTech (PolyVivo AP082) was used to generate model nanoparticles for validating a system developed to determine nanoparticle colloidal stability. This research allows for a tool which ensures nanoparticles will not collect up and clog in a biological system thus improving the safety of using nanoparticles to deliver medicines. Read more: Shaikh, Muhammad Vaseem, Manika Kala, and Manish Nivsarkar. “Development and Optimization of an Ex Vivo Colloidal Stability Model for Nanoformulations.” AAPS PharmSciTech: 1-5. http://link.springer.com/article/10.1208/s12249-016-0597-9

“Abstract: Nanotechnology is having a significant impact in the drug delivery systems and diagnostic devices. As most of the nanosystems are intended to be administered in vivo, there is a need for stability models, which could simulate the biological environment. Instability issues could lead to particle aggregation and in turn could affect the release of the drug from the nanosystems and even lead to clogging of the systemic blood circulation leading to life-threatening situation. We have developed an ex vivo colloidal stability model for testing the stability of nanosystems over a period of 48 h, which is the typical residence time of the nanoparticles in vivo. Tissue homogenates of rat spleen, brain, kidney, and liver were stabilized and optimized for the study; additionally, plasma and serum were used for the same. Poly (lactide-co-glycolic acid) nanoparticles were used as model nanosystem, and no significant change was found in the size and polydispersity index of the nanoparticles in the biological solutions. Moreover, no change in morphology was observed after 48 h as observed by TEM microscopy. Hence, the developed model could prevent the failure of the developed nanosystem during clinical and preclinical application by serving as an initial checkpoint to study their interaction with the complex milieu. Keywords:ex vivo colloidal stability PLGA nanoparticle nanosystem”

PLGA-PEG-PLGA from PolySciTech used for assaying nanoparticle interactions with proteins

PolySciTech division of Akina, Inc. (www.polyscitech.com) provides a wide variety of block copolymers including PLGA-PEG-PLGA. Recently, PLGA-PEG-PLGA from Akina, Inc. was purchased (PolyVivo Catalog#: AK032 and Catalog#: AK017) and used for testing Albumin interaction with these nanoparticles. They confirmed the importance of PEG’s steric hinderance for preventing protein adsorption to nanoparticle. Read more: Geskovski, Nikola, Simona Dimchevska, Rozafa Koliqi, Gjorgji Petruševski, Marina Chacorovska, Sonja Ugarkovic, and Katerina Goracinova. “A spectroscopic insight into the albumin structure on the nano-bio interface.” Your hosts Macedonian Pharmaceutical Association and Faculty of Pharmacy, Ss Cyril and Methodius University in Skopje: 367. https://www.researchgate.net/profile/Irina_Mladenoska/publication/304577752_Effect_of_glucose_concentration_on_glucose_oxidase_activity_in_a_minimal_model_must/links/5773d3e908aeb9427e241721.pdf#page=367

“Synopsis (* quotes compiled from paper sections): It is becoming clear that, when placed into a biological environment, nanoparticles initiate a cascade of interactions with the biomacromolecules resulting in the formation of the ‘protein corona’ (a layer(s) of proteins adsorbed on the nanoparticles surface) (Monopoli et al., 2011). These interactions can alter the secondary structure of the adsorbed proteins promoting instability and/or exposure of new epitopes at the protein surface, thus giving rise to unexpected biological responses (Calzolai et al., 2010). PLGA-PEO-PLGA (Mw 148KDa and Mw 22KDa) was purchased from Akina Inc (USA). Nanoparticle formulations were prepared from PLGAPEO-PLGA (Mw 70,000:8,000:70,000Da) – NP1 and PLGA-PEO-PLGA (Mw 6,000:10,000:6,000Da) – NP2, using the nanoprecipitation method, as described previously All samples were diluted to concentration of 2mg/ml and subsequently 1ml from each formulation was mixed with 1ml of 2mg/mL BSA solution in phosphate buffer (pH 7.4). The NP dispersions with BSA were incubated for 1h at 37°C in a water bath with horizontal shaking at 100 min- 1. After the incubation, the samples were concentrated to 1mL using ultrafiltration tubes with pore size of 1000 kDa, and washed with phosphate buffer pH 7.4. Blank (BSA free) and control sample (without nanoparticles) were also used in the experiment. The amount of adsorbed BSA was indirectly quantified using the Bradford protein assay. The results from the quantitative BSA adsorption studies revealed that 24.6±1.9 and 13.1±0.9% of BSA were adsorbed on the surface of NP1 and NP2, respectively. The results unambiguously point to the effect of the hydrophilic outer nanoparticle layer as a steric barrier for nanoparticle-BSA interactions.”

PEG-PLGA and PLGA from PolySciTech used for mechanistic study of nanoparticle binding to tumor tissue

PolySciTech division of Akina, Inc. (www.polyscitech.com) provides a wide array of biodegradable polymers and biodegradable block copolymers for research applications. Recently, researchers at the University of Maryland utilized mPEG-PLGA 5K-10K (PolyVivo Cat# AK010) and PLGA (PolyVivo AP081) to generate nanoparticles and then tracked these nanoparticles in regards to their uptake into tumor cells as compared to their non-specific binding towards extracellular matrix and other biological components. They found that PEG plays an important role in preventing non-specific binding. This research holds promise for improved therapeutic delivery strategies. Read more: Dancy, Jimena G., Aniket S. Wadajkar, Craig S. Schneider, Joseph RH Mauban, Olga G. Goloubeva, Graeme F. Woodworth, Jeffrey A. Winkles, and Anthony J. Kim. “Non-specific binding and steric hindrance thresholds for penetration of particulate drug carriers within tumor tissue.” Journal of Controlled Release (2016). http://www.sciencedirect.com/science/article/pii/S0168365916304692

“Abstract: Therapeutic nanoparticles (NPs) approved for clinical use in solid tumor therapy provide only modest improvements in patient survival, in part due to physiological barriers that limit delivery of the particles throughout the entire tumor. Here, we explore the thresholds for NP size and surface poly(ethylene glycol) (PEG) density for penetration within tumor tissue extracellular matrix (ECM). We found that NPs as large as 62 nm, but less than  110 nm in diameter, diffused rapidly within a tumor ECM preparation (Matrigel) and breast tumor xenograft slices ex vivo. Studies of PEG-density revealed that increasing PEG density enhanced NP diffusion and that PEG density below a critical value led to adhesion of NP to ECM. Non-specific binding of NPs to tumor ECM components was assessed by surface plasmon resonance (SPR), which revealed excellent correlation with the particle diffusion results. Intravital microscopy of NP spread in breast tumor tissue confirmed a significant difference in tumor tissue penetration between the 62 and 110 nm PEG-coated NPs, as well as between PEG-coated and uncoated NPs. SPR assays also revealed that Abraxane, an FDA-approved non-PEGylated NP formulation used for cancer therapy, binds to tumor ECM. Our results establish limitations on the size and surface PEG density parameters required to achieve uniform and broad dispersion within tumor tissue and highlight the utility of SPR as a high throughput method to screen NPs for tumor penetration. Graphical abstract: Nanoparticle (NP) penetration was visualized via intravital microscopy after direct injection into flank tumors. Uncoated NPs were immobilized at the tumor injection site and densely PEG-coated NPs as large as 63 nm penetrated into the tumor. Keywords: Nanoparticles; PEG density; Tumor tissue penetration; Surface plasmon resonance (SPR); Multiple particle tracking (MPT); Intravital microscopy”

PEG-PLA and oligomeric PLA used for paclitaxel delivery

PolySciTech division of Akina, Inc. (www.polyscitech.com) provides a wide array of biodegradable research products including short-chain PLA and PEG-PLA copolymers. Recently, researchers at the University of Wisconsin-Madison conjugated short-chain PLA to paclitaxel in order to form a prodrug (e.g. a molecule which degrades in the human body to generate a medicinal molecule). Subsequently, they loaded this prodrug into PEG-PLA nanocarriers. This system was tested in mice and it was found that the tumors (A549 human lung cancer) actually shrunk and regressed wheras loose PTX only served to only delay tumor growth. This research holds promise for improved chemotherapeutic outcomes. Read more: Tam, Yu Tong, Jieming Gao, and Glen S. Kwon. “Oligo (lactic acid) n-paclitaxel prodrugs for poly (ethylene glycol)-block-poly (lactic acid) micelles: Loading, release and backbiting conversion for anticancer activity.” Journal of the American Chemical Society (2016). http://pubs.acs.org/doi/abs/10.1021/jacs.6b03995

“Poly(ethylene glycol)-block-poly(d,l-lactic acid) (PEG-b-PLA) micelles are nanocarriers for poorly water-soluble anticancer agents and have advanced paclitaxel (PTX) to humans due to drug solubilization, biocompatibility, and dose escalation. However, PEG-b-PLA micelles rapidly release PTX, resulting in widespread biodistribution and low tumor exposure. To improve delivery of PTX by PEG-b-PLA micelles, monodisperse oligo(l-lactic acid), o(LA)8 or o(LA)16, has been coupled onto PTX at the 7-OH position, forming ester prodrugs: o(LA)8-PTX and o(LA)16-PTX, respectively. As expected, o(LA)n-PTX was more compatible with PEG-b-PLA micelles than PTX, increasing drug loading from 11 to 54%. While in vitro release of PTX was rapid, resulting in precipitation, o(LA)n-PTX release was more gradual: t1/2 = 14 and 26 h for o(LA)8-PTX and o(LA)16-PTX, respectively. Notably, o(LA)8-PTX and o(LA)16-PTX in PEG-b-PLA micelles resisted backbiting chain end scission, based on reverse-phase HPLC analysis. By contrast, o(LA)8-PTX and o(LA)16-PTX degraded substantially in 1:1 acetonitrile:10 mM PBS, pH 7.4, at 37 °C, generating primarily o(LA)2-PTX. The IC50 value of o(LA)2-PTX was ∼2.3 nM for A549 human lung cancer cells, equipotent with PTX in vitro. After weekly IV injections at 20 mg/kg as PEG-b-PLA micelles, o(LA)8-PTX induced tumor regression in A549 tumor-bearing mice, whereas PTX delayed tumor growth. Surprisingly, o(LA)8-PTX caused less toxicity than PTX in terms of change in body weight. In conclusion, o(LA)n acts as a novel promoiety, undergoing backbiting conversion without a reliance on metabolizing enzymes, and o(LA)n-PTX improves PTX delivery by PEG-b-PLA micelles, providing a strong justification for clinical evaluation.”

PLGA-Rhodamine from PolySciTech used for development of drug-delivery system as potential treatment of Peritoneal Mesothelioma

PolySciTech Division of Akina, Inc. (www.polyscitech.com) provides a wide array of biodegradable polymers including fluorescently conjugated PLGA’s used for nanoparticle tracking. Recently, researchers used Poly(lactide-co-glycolide)-Rhodamine B (PolyVivo# AV011) from PolySciTech as part of a nanoparticle tracking system in the development of paclitaxel loaded nanoparticles for targeted drug delivery to mesothelioma. This research has the potential to treat a deadly disease. Read more here: Liu, Rong, Aaron H. Colby, Denis Gilmore, Morgan Schulz, Jialiu Zeng, Robert F. Padera, Orian Shirihai, Mark W. Grinstaff, and Yolonda L. Colson. “Nanoparticle tumor localization, disruption of autophagosomal trafficking, and prolonged drug delivery improve survival in peritoneal mesothelioma.” Biomaterials 102 (2016): 175-186. http://www.sciencedirect.com/science/article/pii/S014296121630285X

“Abstract: The treatment outcomes for malignant peritoneal mesothelioma are poor and associated with high co-morbidities due to suboptimal drug delivery. Thus, there is an unmet need for new approaches that concentrate drug at the tumor for a prolonged period of time yielding enhanced antitumor efficacy and improved metrics of treatment success. A paclitaxel-loaded pH-responsive expansile nanoparticle (PTX-eNP) system is described that addresses two unique challenges to improve the outcomes for peritoneal mesothelioma. First, following intraperitoneal administration, eNPs rapidly and specifically localize to tumors. The rate of eNP uptake by tumors is an order of magnitude faster than the rate of uptake in non-malignant cells; and, subsequent accumulation in autophagosomes and disruption of autophagosomal trafficking leads to prolonged intracellular retention of eNPs. The net effect of these combined mechanisms manifests as rapid localization to intraperitoneal tumors within 4 h of injection and persistent intratumoral retention for >14 days. Second, the high tumor-specificity of PTX-eNPs leads to delivery of greater than 100 times higher concentrations of drug in tumors compared to PTX alone and this is maintained for at least seven days following administration. As a result, overall survival of animals with established mesothelioma more than doubled when animals were treated with multiple doses of PTX-eNPs compared to equivalent dosing with PTX or non-responsive PTX-loaded nanoparticles. Keywords: Mesothelioma; Nanoparticle; Drug delivery; Paclitaxel; Autophagosome; Tumor localization”

PLCL from PolySciTech used as part of nanoparticle carrier for SN-38 and investigated for chemotherapy

PolySciTech division of Akina, Inc. (www.polyscitech.com) provides a wide array of biodegradable polymers including poly(lactide-co-caprolactone) PLCL. Recently, PLCL from Akina, Inc. (PolyVivo AP103) was used to generate a poloxamer-PLCL nanoparticle which was loaded with the novel antineoplastic drug SN-38 which acts to prevent cancer from growing new cells. These nanoparticles were then investigated to determine their applicability to biological systems. This research holds promise for development of novel chemotherapeutic strategies to treat cancer. Read more: Koliqi, Rozafa, Simona Dimchevska, Nikola Geskovski, Gjorgji Petruševski, Marina Chacorovska, Biljana Pejova, Delyan R Hristov, Sonja Ugarkovic, and Katerina Goracinova. “PEO-PPO-PEO/Poly (DL-lactide-co-caprolactone) Nanoparticles as Carriers for SN-38: Design, Optimization and Nano-Bio Interface Interactions.” Current drug delivery 13, no. 3 (2016): 339-352. http://www.ingentaconnect.com/contentone/ben/cdd/2016/00000013/00000003/art00008

“Abstract: Encapsulation of extremely hydrophobic substances such as SN-38 into nanoparticles, is a promising approach to solve the solubility issue and enable drug administration. Moreover, nanocarriers’ tumor homing behavior, targeted and controlled release at the site of action will optimize therapeutic potency and decrease toxicity of the incorporated drug substance. However, the enormous drug hydrophobicity might limit the capacity for encapsulation as the premature drug precipitation will contribute to fast free drug crystal growth, low drug incorporation and huge waste of the active material. In this article we defined the optimal region for manufacturing of SN-38 loaded PEO-PPO-PEO/P(DL)LCL nanoparticles (NPs) with high efficacy of encapsulation, suitable particle size and different surface properties, using D-optimal design and nanoprecipitation as production method. Further we made an approach to investigate the interactions with macromolecules at the nano-bio interface which are predetermined by the physico-chemical and surface properties of the NPs, and are important determinants for the biological identity of the nanoparticles, the potential for evasion of the physiological barriers and the efficacy of localization at the site of action. Here we present in depth analysis of the behavior of two types of nanoparticles with different surface properties through structured protein interaction and bioreactivity experiments in order to presuppose NP performance and toxicological profile in biological environment. Keywords: D-optimal design; P(DL)LCL; PEO-PPO-PEO; Polymeric nanoparticles; SN-38; nano-bio interface; protein corona”

PEG-PLA from PolySciTech used as part of development of hypoxia targeted pancreatic cancer drug delivery system

PolySciTech division of Akina, Inc (www.polyscitech.com) provides a wide array of biodegradable block copolymers. Recently, researchers at North Dakota State University purchased mPEG-PLLA (2000-5000Da) (PolyVivo AK004). They used this well characterized polymer as a control to generate ‘typical’ polymersomes loaded with gemcitabine (a nucleoside analog) and erlotinib (a tyrosine kinase) for pancreatic cancer treatment. They compared this against ‘responsive’ polymersomes made with their developed hypoxia-targeted system. Read more: Kulkarni, Prajakta, Manas K. Haldar, Seungyong You, Yongki Choi, and Sanku Mallik. “Hypoxia-responsive polymersomes for drug delivery to hypoxic pancreatic cancer cells.” Biomacromolecules (2016). http://pubs.acs.org/doi/abs/10.1021/acs.biomac.6b00350

“Abstract: Hypoxia in the tumors contributes to overall tumor progression by assisting in epithelial-to-mesenchymal transition, angiogenesis, and metastasis of cancer. In this study, we have synthesized a hypoxia-responsive, di-block copolymer polylactic acid-azobenzene-polyethylene glycol, which self-assembles to form polymersomes in an aqueous medium. The polymersomes were stable under normoxic conditions. However, under hypoxia, 90% of the encapsulated dye was released in 50 minutes. The polymersomes encapsulated the combination of anticancer drugs gemcitabine and erlotinib with entrapment efficiency of 40% and 28% respectively. We used the three-dimensional spheroid cultures of the pancreatic cancer cells BxPC-3 to demonstrate hypoxia-mediated release of the drugs from the polymersomes. The vesicles were non-toxic. However, a significant decrease in cell viability was observed in hypoxic spheroidal cultures of BxPC-3 cells in the presence of drug encapsulated polymersomes. These polymersomes have the potential for further applications in imaging and treatment of hypoxic tumors.”

PolySciTech Poly(aspartic acid) used in development of SiRNA delivery

PolySciTech division of Akina, Inc. (www.polyscitech.com) provides a wide array of biodegradable polymers including poly(aspartic acid). Recently, this material was used in part of development of SiRNA delivery system. Read more: Hattori, Yoshiyuki, Yuki Yoshiike, Takuto Kikuchi, Natsumi Yamamoto, Kei-ichi Ozaki, and Hiraku Onishi. “Evaluation of the injection route of an anionic polymer for small interfering RNA delivery into the liver by sequential injection of anionic polymer and cationic lipoplex of small interfering RNA.” Journal of Drug Delivery Science and Technology (2016). http://www.sciencedirect.com/science/article/pii/S1773224716301812

“Abstract: Previously, we developed a novel small interfering RNA (siRNA) transfer method for the liver by sequential intravenous injection of an anionic polymer and cationic liposome/siRNA complex (cationic lipoplex). In this study, we examined the effects of the type of anionic polymer and injection route of the anionic polymer on the biodistribution of siRNA after sequential injection of anionic polymer and cationic lipoplexes. When cationic lipoplexes were injected intravenously into mice, siRNA largely accumulated in the lungs. In contrast, sequential injection of cationic lipoplex after intravenous injection of 1 mg chondroitin sulfate C and A (CS-C and CS-A) or polyaspartic acid decreased the accumulation of siRNA in the lungs and increased it in the liver, compared with injection of cationic lipoplex. Regarding the injection route of the anionic polymer, intramuscular, intraperitoneal, or subcutaneous injection of 10 mg CS-C before intravenous injection of cationic lipoplex resulted in siRNA accumulation mainly in the liver. Furthermore, the injection of cationic lipoplex of apolipoprotein B (ApoB) siRNA after intravenous or intramuscular injection of CS-C could suppress ApoB mRNA levels in the liver. Sequential injection of CS-C plus cationic lipoplex could deliver siRNA efficiently into the liver regardless of the injection route of CS-C. Keywords: siRNA delivery; liposome; chondroitin sulfate; liver; gene silencing”

PLGA purchased from PolySciTech used for development of composite polymer-iron nanoparticles for EPR-independent delivery system as a cancer treatment

PolySciTech Division of Akina, inc. (www.polyscitech.com) provides a wide array of biodegradable polymers including PLGA. Recently, PLGA (85:15) 150kDa (PolyVivo AP020) purchased from PolySciTech was utilized by researchers to generate a composite nanoparticle containing iron oxide. They found that the flow of these particles could be controlled in-vivo by using magnetic fields to focus their concentration at the tumor site. Under certain conditions, leaky tumor vasculature and greater vascularization can lead to an effect referred to as Enhanced Permeation and Retention (EPR). However, this does not work for all tumors. This method of nanoparticle delivery relies on magnetism rather than EPR and holds promise for cancers where the tumor is poorly vascularized and EPR effect is little. Read more about this exciting research here: Park, Jinho, Naveen R. Kadasala, Sara A. Abouelmagd, Mark A. Castanares, David S. Collins, Alexander Wei, and Yoon Yeo. “Polymer–iron oxide composite nanoparticles for EPR-independent drug delivery.” Biomaterials (2016). http://www.sciencedirect.com/science/article/pii/S0142961216302617

“Abstract: Nanoparticle (NP)-based approaches to cancer drug delivery are challenged by the heterogeneity of the enhanced permeability and retention (EPR) effect in tumors and the premature attrition of payload from drug carriers during circulation. Here we show that such challenges can be overcome by a magnetophoretic approach to accelerate NP delivery to tumors. Payload-bearing poly(lactic-co-glycolic acid) NPs were converted into polymer–iron-oxide nanocomposites (PINCs) by attaching colloidal Fe3O4 onto the surface, via a simple surface modification method using dopamine polymerization. PINCs formed stable dispersions in serum-supplemented medium and responded quickly to magnetic field gradients above 1 kG/cm. Under the field gradients, PINCs were rapidly transported across physical barriers and into cells and captured under flow conditions similar to those encountered in postcapillary venules, increasing the local concentration by nearly three orders of magnitude. In vivo magnetophoretic delivery enabled PINCs to accumulate in poorly vascularized subcutaneous SKOV3 xenografts that did not support the EPR effect. In vivo magnetic resonance imaging, ex vivo fluorescence imaging, and tissue histology all confirmed that the uptake of PINCs was higher in tumors exposed to magnetic field gradients, relative to negative controls. Keywords: Polymer–iron oxide nanocomposite; Magnetic drug delivery; Polymeric nanoparticles; Polydopamine; In vivo delivery”

PEG precursor from PolySciTech used as part of folate-mediated delivery system development for brain cancer treatment

PolySciTech Division of Akina, Inc. (www.polyscitech.com) provides a wide array of polymers including heterobifunctional PEG precursors. Recently PolyVivo AE003 (Folate-PEG-COOH (3000Da)) was used by researchers at University of Puerto Rico to develop a folate-mediated delivery system for targeted application of cytochrome c, a protein that initiates apoptosis (cell-death). This research holds promise for enhanced chemotherapy techniques to kill off tumor cells while minimalizing toxic side-effects against normal cells. Read more: Morales-Cruz, Moraima, Alejandra Cruz-Montañez, Cindy M. Figueroa, Tania Gonzalez-Robles, Josue Davila, Mikhail Inyushin, Sergio A. Loza-Rosas et al. “Combining stimulus-triggered release and active targeting strategies improves cytotoxicity of cytochrome c nanoparticles in tumor cells.” Molecular Pharmaceutics (2016). http://pubs.acs.org/doi/abs/10.1021/acs.molpharmaceut.6b00461

“Proteins often possess highly specific biological activities that make them potential therapeutics, but their physical and chemical instabilities during formulation, storage, and delivery have limited their medical use. Therefore, engineering of nano-sized vehicles to stabilize protein therapeutics and to allow for targeted treatment of complex diseases, such as cancer, is of considerable interest. A micelle-like nanoparticle (NP) was designed for both, tumor targeting and stimulus-triggered release of the apoptotic protein cytochrome c (Cyt c). This system is composed of a Cyt c NP stabilized by a folate-receptor targeting amphiphilic copolymer (FA-PEG-PLGA) attached to Cyt c through a redox-sensitive bond. FA-PEG-PLGA-S-S-Cyt c NPs exhibited excellent stability under extracellular physiological conditions, whereas once in the intracellular reducing environment, Cyt c was released from the conjugate. Under the same conditions, the folate-decorated NP reduced folate receptor positive HeLa cell viability to 20% while the same complex without FA only reduced it to 80%.  Confocal microscopy showed that the FA-PEG-PLGA-S-S-Cyt c NPs were internalized by HeLa cells and were capable of endosomal escape.  The specificity of the folate receptor-mediated internalization was confirmed by the lack of uptake by two folate receptor deficient cell lines: A549 and NIH-3T3. Finally, the potential as anti-tumor therapy of our folate-decorated Cyt c-based NPs was confirmed with an in vivo brain tumor model. In conclusion, we were able to create a stable, selective, and smart nanosized Cyt c delivery system.”