Impact of Silicone Oil on Free Fatty Acid Particle Formation due to Polysorbate 20 DegradationFish, Raphael; Lin, Jasper; Doshi, Nidhi
doi: 10.1007/s11095-020-02936-3pmid: 33029664
PurposePolysorbate 20 (PS20), a commonly used surfactant in biopharmaceutical formulations, can undergo hydrolytic degradation resulting in free fatty acids (FFAs) that precipitate to form particles. This work investigates the ability for silicone oil (si-oil) coated on the interior walls of prefilled syringes (PFSs) to act as a sink for FFAs and potentially delay FFA particle formation.MethodsMyristic acid distribution coefficient was measured in a two-phase system containing si-oil and formulation buffer at a range of aqueous conditions. An empirical model was built from these data to predict distribution coefficient based on aqueous conditions. To verify the model, PS20 was degraded using model lipases side-by-side in glass vials and PFSs while monitoring sub-visible particles.ResultsThe empirical model demonstrates that the partitioning of myristic acid into si-oil is maximized at low pH and low PS20 concentration. The model predicts that the presence of si-oil at levels typical in PFSs provides at most an 8.5% increase in the total carrying capacity for myristic acid compared to a non-coated glass vial. The time to onset of FFA particles was equivalent between degradations performed in two PFS models coated with differing levels of silicone oil and in non-coated glass vials.ConclusionHerein, we demonstrate that FFAs partition from aqueous solution into si-oil. However, the extent of the partitioning effect is not large enough to delay PS20-related FFA particle formation at typical formulation conditions (pH 5.0–7.5, 0.01% - 0.1% w/v PS20) filled in typical PFSs (<1.0 mg si-oil/mL aqueous fill).
A Systems Biology Workflow for Drug and Vaccine Repurposing: Identifying Small-Molecule BCG Mimics to Reduce or Prevent COVID-19 MortalityHajjo, Rima; Tropsha, Alexander
doi: 10.1007/s11095-020-02930-9pmid: 33025261
PurposeCoronavirus disease 2019 (COVID-19) is expected to continue to cause worldwide fatalities until the World population develops ‘herd immunity’, or until a vaccine is developed and used as a prevention. Meanwhile, there is an urgent need to identify alternative means of antiviral defense. Bacillus Calmette–Guérin (BCG) vaccine that has been recognized for its off-target beneficial effects on the immune system can be exploited to boast immunity and protect from emerging novel viruses.MethodsWe developed and employed a systems biology workflow capable of identifying small-molecule antiviral drugs and vaccines that can boast immunity and affect a wide variety of viral disease pathways to protect from the fatal consequences of emerging viruses.ResultsOur analysis demonstrates that BCG vaccine affects the production and maturation of naïve T cells resulting in enhanced, long-lasting trained innate immune responses that can provide protection against novel viruses. We have identified small-molecule BCG mimics, including antiviral drugs such as raltegravir and lopinavir as high confidence hits. Strikingly, our top hits emetine and lopinavir were independently validated by recent experimental findings that these compounds inhibit the growth of SARS-CoV-2 in vitro.ConclusionsOur results provide systems biology support for using BCG and small-molecule BCG mimics as putative vaccine and drug candidates against emergent viruses including SARS-CoV-2.
Exosomal Secretion of Adipose Tissue during Various Physiological StatesQuan, Menchus; Kuang, Shihuan
doi: 10.1007/s11095-020-02941-6pmid: 33063193
Exosomes are secreted extracellular vesicles containing a wide array of biologically active components. Recent studies have demonstrated that exosomes serve as an important vehicle for extracellular communication and exert systemic effects on the physiology of organisms. Adipose tissues (ATs) play a key role in balancing systemic energy homeostasis as a central hub for fatty acid metabolism. At the same time, proper endocrine function of ATs has also been shown to be crucial for regulating physiological and metabolic health. The endocrine function of ATs is partially mediated by AT-derived exosomes that regulate metabolic homeostasis, such as insulin signaling, lipolysis, and inflammation. During the pathogenesis of obesity, metabolic syndrome, and cancer, exosomes shed by the resident cells in ATs may also have a role in regulating the progression of these diseases along with associated pathologies. In this review, we summarize the contents of AT-derived exosomes and their effects on various cell populations along with possible underlying molecular mechanisms. We further discuss the potential applications of exosomes as a drug delivery tool and therapeutic target.
Correction to: Optimizing Predictive Performance of Bayesian Forecasting for Vancomycin Concentration in Intensive Care PatientsGuo, Tingjie; van Hest, Reinier M.; Zwep, Laura B.; Roggeveen, Luca F.; Fleuren, Lucas M.; Bosman, Rob J.; van der Voort, Peter H. J.; Girbes, Armand R. J.; Mathot, Ron A. A.; Elbers, Paul W. G.; van Hasselt, Johan G. C.
doi: 10.1007/s11095-020-02934-5pmid: 37452467
This article was updated to correct Figs. 1 and 4 as author corrections were overlooked during the production process.
Fluorescent Nanoparticles Coated with a Somatostatin Analogue Target Blood Monocyte for Efficient Leukaemia TreatmentAbdellatif, Ahmed A. H.; Hennig, Robert; Pollinger, Klaus; Tawfeek, Hesham M.; Bouazzaoui, Abdellatif; Goepferich, Achim
doi: 10.1007/s11095-020-02938-1pmid: 33037505
BackgroundLeukaemia is the most prevalent form of cancer-causing death in a large number of populations and needs prompt and effective treatment. Chemotherapeutics can be used to treat leukaemia, but their pronounced killing effects to other living cells is still an issue. Active targeting to certain specific receptors in leukaemic cells is the best way to avoid damage to other living cells. Leukaemic cells can be targeted using novel nanoparticles (NPs) coated with a specific ligand, such as octreotide (OCD), to target somatostatin receptor type 2 (SSTR2), which is expressed in leukaemic cells.MethodsAmino-PEGylated quantum dots (QDs) were chosen as model NPs. The QDs were first succinylated using succinic anhydride and then coated with OCD. The reactivity and selectivity of the formulated QDs-OCD were studied in cell lines with well-expressed SSTR2, while fluorescence was detected using confocal laser scanning microscopy (CLSM) and flow cytometry (FACS). Conclusively, QD-OCD targeting to blood cells was studied in vivo in mice and detected using inductively coupled plasma mass spectrometry and CLSM in tissues.ResultsHighly stable QDs coated with OCD were prepared. FACS and CLSM showed highly definite interactions with overexpressed SSTR2 in the investigated cell lines. Moreover, the in vivo results revealed a higher concentration of QDs-OCD in blood cells. The fluorescence intensity of the QDs-OCD was highly accumulated in blood cells, while the unmodified QDs did not accumulate significantly in blood cells. Conclusion: The formulated novel QDs-OCD can target SSTR2 overexpressed in blood cells with great potential for treating blood cancer.
Multifunctional Microparticles Incorporating Gold Compound Inhibit Human Lung Cancer XenograftLee, Pui -Yan; Lok, Chun-Nam; Che, Chi-Ming; Kao, Weiyuan John
doi: 10.1007/s11095-020-02931-8pmid: 33051728
PurposeGold porphyrin (AuP) is a complex that has been shown to be potent against various tumors. A biocompatible interpenetrating network (IPN) system comprised of polyethyleneglycol diacrylate (PEGdA) and chemically-modified gelatin has been shown to be an effective implantable drug depot to deliver AuP locally. Here we designed IPN microparticles complexed with AuP to facilitate intravenous administration and to diminish systemic toxicity.MethodsWe have synthesized and optimized an IPN microparticle formulation complexed with AuP. Tumor cell cytotoxicity, antitumor activity, and survival rate in lung cancer bearing nude mice were analyzed.ResultsIPN microparticles maintained AuP bioactivity against lung cancer cells (NCI-H460). In vivo study showed no observable systemic toxicity in nude mice bearing NCI-H460 xenografts after intravenous injection of 6 mg/kg AuP formulated with IPN microparticles. An anti-tumor activity level comparable to free AuP was maintained. Mice treated with 6 mg/kg AuP in IPN microparticles showed 100% survival rate while the survival rate of mice treated with free AuP was much less. Furthermore, microparticle-formulated AuP significantly reduced the intratumoral microvasculature when compared with the control.ConclusionAuP in IPN microparticles can reduce the systemic toxicity of AuP without compromising its antitumor activity. This work highlighted the potential application of AuP in IPN microparticles for anticancer chemotherapy.
Extended Pharmacokinetic Model of the Intravitreal Injections of Macromolecules in Rabbits. Part 2: Parameter Estimation Based on Concentration Dynamics in the Vitreous, Retina, and Aqueous HumorLamminsalo, Marko; Karvinen, Timo; Subrizi, Astrid; Urtti, Arto; Ranta, Veli-Pekka
doi: 10.1007/s11095-020-02946-1pmid: 33094404
PurposeTo estimate the diffusion coefficients of an IgG antibody (150 kDa) and its antigen-binding fragment (Fab; 50 kDa) in the neural retina (Dret) and the combined retinal pigment epithelium-choroid (DRPE-cho) with a 3-dimensional (3D) ocular pharmacokinetic (PK) model of the rabbit eye.MethodsVitreous, retina, and aqueous humor concentrations of IgG and Fab after intravitreal injection in rabbits were taken from Gadkar et al. (2015). A least-squares method was used to estimate Dret and DRPE-cho with the 3D finite element model where mass transport was defined with diffusion and convection. Different intraocular pressures (IOP), initial distribution volumes (Vinit), and neural retina/vitreous partition coefficients (Kret/vit) were tested. Sensitivity analysis was performed for the final model.ResultsWith the final IgG model (IOP 10.1 Torr, Vinit 400 μl, Kret/vit 0.5), the estimated Dret and DRPE-cho were 36.8 × 10−9 cm2s−1 and 4.11 × 10−9 cm2s−1, respectively, and 76% of the dose was eliminated via the anterior chamber. Modeling of Fab revealed that a physiological model parameter “aqueous humor formation rate” sets constraints that need to be considered in the parameter estimation.ConclusionsThis study extends the use of 3D ocular PK models for parameter estimation using simultaneously macromolecule concentrations in three ocular tissues.