Hydrophobic Counterions Research Articles

Influence of alkyl spacer length on ion transport, polarization and electro-responsive electrorheological effect of self-crosslinked poly(ionic liquid)s

Different from classic polyelectrolytes, poly(ionic liquid)s (PILs) bearing hydrophobic counterions show high electrorheological (ER) effect in dry state. This opens a way to develop new generation of anhydrous polyelectrolyte ER fluids. However, PILs with linear backbone are limited in practical applications due to low glass transition temperature. Crosslinking is an effective method to overcome this problem but the structure-property relationship in crosslinked PIL ER system is not fully understood. Herein, a family of self-crosslinked poly(bis-vinylimidazolium bis(trifluoromethane sulfonylimide))-based PILs with different length of alkyl spacer (P[CnDVIM][TFSI]) were synthesized. The influence of alkyl spacer length on ER effect was studied and the influence mechanism was analyzed by combination of rheology, dielectric spectroscopy and X-ray scattering measurements. It shows that as alkyl spacer length increases, the ER effect increases but the working temperature range becomes narrow. This is related to the fact that the length variation of alkyl spacer alters the mesh size of crosslinking network of P[CnDVIM][TFSI], which further influences the transport dynamic of mobile counterions and ion motion-induced interfacial polarization.

Interactions of star-like polyelectrolyte micelles with hydrophobic counterions

Hydrophobicity of a counterion has a profound effect on the interaction with polyelectrolytes similar to that of multivalency. Specifically, understanding this interaction in weak polyelectrolyte micelles might assist in developing nanocarriers for pH-controlled encapsulation and release.We used star-like weak polyelectrolyte micelles of polystyrene-block-poly(2-vinyl pyridine) (PS-P2VP) with fixed aggregation number as a model polyelectrolyte, and cobalt bis(1,2-dicarbollide) (COSAN) as a model hydrophobic anion. We used NMR to assess the mobility of the polymer segments in the presence of varying amounts of COSAN, and at varying protonation degrees of the polyelectrolyte. Same experiments with indifferent electrolyte (NaCl) were used as a control. Furthermore, we used coarse-grained simulations to obtain a detailed picture of the effect of hydrophobic counterions on the conformation of the micelles.A small amount of hydrophobic counterions causes morphological changes within the micelles, whereas a bigger amount causes precipitation. This was confirmed both in simulations and in experiments. Furthermore, adsorption of the counterions induces ionization of the collapsed segments of the polyelectrolyte. Although the COSAN/P2VP system is rather specific, the generic model used in the coarse-grained simulations shows that the observed behavior is a consequence of synergy of hydrophobic and electrostatic attraction between polyelectrolytes and hydrophobic counterions. Our study provides general insights into the molecular mechanisms of these interactions.

Fighting Aggregation-Caused Quenching and Leakage of Dyes in Fluorescent Polymer Nanoparticles: Universal Role of Counterion.

Dye-loaded polymer nanoparticles (NPs) emerge as a powerful tool for bioimaging applications, owing to their exceptional brightness and controlled small size. However, aggregation-caused quenching (ACQ) and leakage of dyes at high loading remain important challenges of these nanomaterials. The use of bulky hydrophobic counterions has been recently proposed as an effective approach to minimize ACQ and dye leakage, but the role of counterion structure is still poorly understood. Here, a systematic study based on ten counterions, ranging from small hydrophilic perchlorate up to large hydrophobic tetraphenylborate derivatives, reveals how counterion nature can control encapsulation and emission of a cationic dye (rhodamine B octadecyl ester) in NPs prepared by nanoprecipitation of a biodegradable polymer, poly-lactide-co-glycolide (PLGA). We found that increase in counterion hydrophobicity enhances dye encapsulation efficiency and prevents dye adsorption at the particle surface. Cellular imaging studies revealed that ≥95 % encapsulation efficiency, achieved with most hydrophobic counterions (fluorinated tetraphenylborates), is absolutely required because non-encapsulated dye species at the surface of NPs are the origin of dye leakage and strong fluorescence background in cells. The size of counterions is found to be essential to prevent ACQ, where the largest species, serving as effective spacer between dyes, provide the highest fluorescence quantum yield. Moreover, we found that the most hydrophobic counterions favor dye-dye coupling inside NPs, leading to ON/OFF fluorescence switching of single particles. By contrast, less hydrophobic counterions tend to disperse dyes in the polymer matrix favoring stable emission of NPs. The obtained structure-property relationships validate the counterion-based approach as a mature concept to fight ACQ and dye leakage in the development of advanced polymeric nanomaterials with controlled optical properties.

Ionic aggregation-induced emission dye with bulky counterions for preparation of bright near-infrared polymeric nanoparticles.

Dyes exhibiting aggregation-induced emission (AIE) are attractive building blocks for the preparation of bright fluorescent nanomaterials. AIEgens are especially efficient in pure dye aggregates, whereas they are much less explored as dopants in NPs built of hydrophobic polymers. Here, we describe an approach that combines cationic AIEgens with bulky hydrophobic counterions (fluorinated tetraphenylborates) that enables preparation of small and bright AIEgen-loaded polymeric NPs. To this end, we synthesised a cationic tetraphenylethylene (TPE) derivative and studied its salts with counterions of different sizes and hydrophobicities. In organic solvent/water mixtures, all these salts exhibited typical AIE behaviour, whereas only salts with bulky hydrophobic counterions exhibited strongly red-shifted emission in the near-infrared (NIR) region. Encapsulation of these salts into poly(methyl methacrylate-co-methacrylic acid) (PMMA-MA) NPs revealed that bulky counterions ensure (i) formation of small (∼50 nm) AIEgen-loaded polymeric NPs; (ii) good fluorescence quantum yield (up to 30%); and (iii) NIR emission reaching 700 nm. By contrast, AIEgens with small inorganic anions (perchlorate and hexafluorophosphate) blended with PMMA-MA produced large aggregates with emission in the far-red region. Single-particle microscopy revealed that our 50 nm AIEgen-loaded PMMA-MA NPs were 6-fold brighter than the NIR emitting quantum dots (QD705). These NPs feature low cytotoxicity and compatibility with live cell imaging, in contrast to large aggregates of AIEgens with small inorganic counterions that failed to internalize into the cells. The present work shows that combination of cationic AIEgens with bulky counterions opens new routes for the preparation of bright polymer-based nanomaterials.

Synchronized Ratiometric Codelivery of Metformin and Topotecan through Engineered Nanocarrier Facilitates In Vivo Synergistic Precision Levels at Tumor Site.

The combination of metabolic modulators with chemotherapy holds vast promise for effective inhibition of tumor progression and invasion. Herein, a ratiometric codelivery platform is developed for metformin (MET), a known metabolic modulator and topotecan (TPT), a chemotherapeutic drug, by engineering lipid bilayer-camouflaged mesoporous silica nanoparticles (LB-MSNs). In an attempt to deliver and maintain high tumor site concentrations of MET and TPT, a novel ion pairing-assisted loading procedure is developed using pamoic acid (PA) as an in situ trapping agent. PA, a hydrophobic counterion, increases the hydrophobicity of MET and TPT and facilitates MSNs with exceptionally high payload capacity (>40 and 32 wt%, respectively) and controlled release profile. Further, the synergy between MET and TPT determined by a modeling approach helps to afford synchronized delivery of both the drugs. Coloaded MET and TPT LB-MSNs present synergistic cytotoxicity against MDA-MB-231/4T1 cells and effectively promote apoptosis via mitochondrial membrane depolarization and cell cycle arrest. Extended pharmacokinetic profiles in preclinical models with fourfold to sevenfold longer circulation half-life and 7.5-100 times higher tumor site concentrations correspond to a significant increase in pharmacodynamic efficacy. Taken together, the developed codelivery approach effectively addresses the challenges in the chemotherapeutic efficacy of MET and TPT collectively.

Behavior of Weak Polyelectrolyte Brushes in Mixed Salt Solutions.

Hydrophilic and hydrophobic weak polybasic brushes immersed in aqueous solutions of mixed salt counterions are considered using a mean-field numerical self-consistent field approach. On top of the solvent quality of the polymer, the counterion–solvent interactions are accounted for by implementing Flory–Huggins interaction parameters. We show that ion specificity within the brush can bring about large changes in conformation. It is found that the collapse transition of hydrophobic, weak polyelectrolyte brushes features an intermediate two-phase state wherein a subset of chains are collapsed in a dense layer at the substrate, while the remainder of chains are well-solvated and strongly stretched away from the it. Besides pH and ionic strength, solvent quality of counterions and the composition of ions in the solvent are important control parameters for the behavior of polyelectrolyte brushes. Increasingly hydrophobic counterions penetrate deeper within the brush and stabilize the collapsed region, while hydrophilic counterions do the opposite.

Hierarchical self-assembly of amphiphilic building blocks into various supramolecular architectures

Molecular self-assembly is a process to obtain a well defined structure from suitable starting materials. The study of self-assembly provides a fundamental understanding of the driving forces and co-operative interaction behind these processes. Among the plenty of molecules, an amphiphilic molecule, containing both hydrophilic and hydrophobic counter parts is one of the interesting building blocks to study the self-assembly processes. In this short review, the hierarchical self-assembly of amphiphilic molecules into various supramolecular architectures such as vesicles, spheres, flowers, tubes and fibrillar networks of nano- to micrometer dimensions and gels have been discussed.

Aggregation and charge reversal of humic substances in the presence of hydrophobic monovalent counter-ions: Effect of hydrophobicity of humic substances

To investigate the effect of hydrophobicity of humic substances (HSs) on their charging and aggregation, we studied the electrophoretic mobility and aggregation-dispersion of HSs in the presence of hydrophobic monovalent cations, namely, tetraphenylphosponium TPP+. The used HSs were standard Suwannee river fulvic acid (SRFA), Suwannee river humic acid (SRHA), and Leonardite humic acid (LHA) with different contents of aromatic carbons. All of the HSs in the presence of TPP+ showed charger reversal. The charge reversal pH or iso-electric point (IEP) of LHA was higher than that of SRFA and SRHA in every concentrations of TPPCl, demonstrating the strong hydrophobic interaction between HSs, especially LHA, and TPP+. We also found that the formation of large visible aggregates of all the HSs at lower pH in the presence of TPP+. Large HS aggregates were markedly formed for LHA, manifesting the existence of stronger hydrophobic attraction among LHAs with TPP+. The appearance of aggregates of all the HSs with TPP+ was confirmed by microscopic observation and the size determination by dynamic light scattering. The HS aggregates showed fractal structure. The values of fractal dimension Df of HS aggregates were 2–2.2 in quiescent conditions, indicating that the HS aggregates with TPP+ were formed via cluster-cluster aggregation with restructuring. The Df increased to 2.8–2.9 in stirring conditions, implying that the compact aggregates were formed through the continuous aggregate breakage and the regrowth between smaller aggregates and larger aggregates.

Hydrophobic Ion Pairing of Peptide Antibiotics for Processing into Controlled Release Nanocarrier Formulations.

Nanoprecipitation of active pharmaceutical ingredients (APIs) to form nanocarriers (NCs) is an attractive method of producing formulations with improved stability and biological efficacies. However, nanoprecipitation techniques have not been demonstrated for highly soluble peptide therapeutics. We here present a model and technique to encapsulate highly water-soluble biologic APIs by manipulating API salt forms. APIs are ion paired with hydrophobic counterions to produce new API salts that exhibit altered solubilities suitable for nanoprecipitation processing. The governing rules of ion pair identity and processing conditions required for successful encapsulation are experimentally determined and assessed with theoretical models. Successful NC formation for the antibiotic polymyxin B requires hydrophobicity of the ion pair acid to be greater than logP = 2 for strong acids and greater than logP = 8 for weak acids. Oleic acid with a logP = 8, and pKa = 5, appears to be a prime candidate as an ion pair agent since it is biocompatible and forms excellent ion pair complexes. NC formation from preformed, organic soluble ion pairs is compared to in situ ion pairs where NCs are made in a single precipitation step. NC properties, such as stability and release rates, can be tuned by varying ion pair molecular structure and ion pair-to-API molar ratios. For polymyxin B, NCs ≈ 100-200 nm in size, displaying API release rates over 3 days, were produced. This work demonstrates a new approach that enables the formation of nanoparticles from previously intractable compounds.

Tailoring Fluorescence Brightness and Switching of Nanoparticles through Dye Organization in the Polymer Matrix.

Fluorescent nanoparticles (NPs) help to increase spatial and temporal resolution in bioimaging. Advanced microscopy techniques require very bright NPs that exhibit either stable emission for single-particle tracking or complete on/off switching (blinking) for super-resolution imaging. Here, ultrabright dye-loaded polymer NPs with controlled switching properties are developed. To this aim, the salt of a dye (rhodamine B octadecyl ester) with a hydrophobic counterion (fluorinated tetraphenylborate) is encapsulated at very high concentrations up to 30 wt % in NPs made of poly(lactic-co-glycolic acid) (PLGA), poly(methyl methacrylate) (PMMA), and polycaprolactone (PCL) through nanoprecipitation. The obtained 35 nm NPs are nearly 100 times brighter than quantum dots. The nature of the polymer is found to define the collective behavior of the encapsulated dyes so that NPs containing thousands of dyes exhibit either whole particle blinking, for PLGA, or stable emission, for PMMA and PCL. Fluorescence anisotropy measurements together with small-angle X-ray scattering experiments suggest that in less hydrophobic PLGA, dyes tend to cluster, whereas in more hydrophobic PMMA and PCL, dyes are dispersed within the matrix, thus altering the switching behavior of NPs. Experiments using a perylene diimide derivative show a similar effect of the polymer nature. The resulting fluorescent NPs are suitable for a wide range of imaging applications from tracking to super-resolution imaging. The findings on the organization of the load innside NPs will have impact on the development of materials for applications ranging from photovoltaics to drug delivery.

Influence of counterion type on dielectric and electrorheological responses of poly(ionic liquid)s

Different from classic water activated polyelectrolytes, poly(ionic liquid)s (PILs) bearing hydrophobic counterions show high electrorheological (ER) response in dry state. This offers opportunity for practical applications of polyelectrolyte-based ER materials in wide temperature region. For guiding the design of PIL-based ER materials with improved performance, understanding the structure-property relationship is very important. In this paper, a series of poly(p-vinylbenzyl trimethylammonium)-based PIL particles with different counteranions ([PVBTMA][X]) were synthesized with the goal of understanding the role of mobile counterions on ER response of PILs. To exclude particle shape effect, the PIL series were controlled to be monodisperse spheres with a similar diameter via microwave-assisted dispersion polymerization. Under electric fields, the ER response of PIL particles when dispersed in insulating oil was investigated by temperature-modulated rheological test. It showed that the ER response of PILs depends on the type of counteranions. The order of magnitude of ER response of PILs with different counteranion is trifluoromethanesulfonate (TfO−) > tetrafluoroborates (BF4−) > bis-(trifluoromethanesulfonylimide) (TFSI−) > hexafluorophosphates (PF6−). The mechanism behind the influence of counterion type on ER response was analysed by dielectric relaxation spectroscopy. It demonstrated that the influence of counteranion type on ER response may be related to the variation of size and plasticization effect of counteranions that has altered the transport dynamic of mobile counterions and ion motion-induced interfacial polarization.

Electrophoretic mobility of carboxyl latex particles: effects of hydrophobic monovalent counter-ions

To investigate the effect of hydrophobicity on the charge reversal of colloidal particles, we measured and analyzed the electrophoretic mobility (EPM) of carboxyl latex particles in mixed electrolytes solutions containing potassium chloride KCl and tetraphenylphosphonium chloride TPPCl. Tetraphenylphosphonium (TPP+) ion strongly adsorbs on the particle surface due to its hydrophobicity and thus causes the charge reversal/overcharging. Measurements of EPM were carried out as functions of pH, ionic strength, and the mixed molar ratio of X = [TPP+]/[K+] to unveil the influence of surface charge on hydrophobic interaction. Experimental EPM was analyzed by using 1-pK H Stern Gouy Chapmann model with the Ohshima equation including the relaxation effect or the Smoluchowski equation neglecting the relaxation effect for calculating theoretical EPM values. Our results demonstrate that carboxyl latex particles show charge reversal indicated by positive EPMs at low pH due to the accumulation of TPP+ ions on the surface and the reversed EPM values at low pH are augmented with increasing the mixed molar ratio of X = [TPP+]/[K+]. Also, we observed that charge re-reversal at higher pH as the deprotonation of surface carboxyl groups proceeded. The pH at which the charge re-reversal occurred increased with increasing the mixed molar ratio. From the comparison between our experiments and theoretical analysis, we found that the intrinsic energy of adsorption decreases with increasing the surface charge density to describe the observed charge re-reversal. These results indicate that the intrinsic adsorption energy of TPP+, which is probably due to hydrophobic interaction, decreases with increasing the surface charge density.

Impact of the molar ratio and the nature of the counter-ion on the self-assembly of myristic acid

HypothesisIn fatty acid systems, the role of the nature of the counter-ion on their solubility is well described. However, the effect of the molar ratio (R) between the fatty acid and its counter-ion is less explored. We investigated the effect of R as a function of the temperature in aqueous solution between myristic acid and two organic amines under hydroxide form: tetramethylammonium (TMAOH) and benzyltrimethylammonium hydroxide (BTAOH). We compare with the results previously obtained for choline hydroxide as counter-ion (Arnould et al., 2015). ExperimentsWe characterized the phase behavior by coupling phase-contrast microscopy, SANS, DSC and WAXS experiments. The myristic acid ionization state was determined by pH, conductivity and infra-red spectroscopy measurements. FindingsOur results highlight that R tunes the phase behavior. The amount of hydroxide groups in solution fixes the ionization state of the fatty acids, which governs the headgroup interactions. At low R, the counter-ion hydrophobicity plays a role on the phase behavior: TMAOH and choline hydroxide shows a broad polymorphism (facetted and unilamellar vesicles, lamellar phases) due to their hydrophilicity while the more hydrophobic BTAOH gives fatty acid crystals at low temperatures and vesicles at high temperatures. At high R, spherical micelles are observed for all counter-ions.

Spontaneous wormlike micelles formed in a single-tailed zwitterionic surface-active ionic liquid aqueous solution.

Wormlike micelles were successfully fabricated by the self-assembly of a single-tailed zwitterionic surface-active ionic liquid (SAIL), 3-(1-hexadecyl-3-imidazolio) propanesulfonate β-naphthalene sulfonate (C16IPS-Nsa), in aqueous solutions without any additives. With increasing zwitterionic SAIL concentration, spontaneous transition from micelles to wormlike micelles and then a hexagonal phase occurs. Interestingly, the wormlike micelles are closed, stretched and directionally arranged, which was rarely found in previous research studies. This kind of wormlike micelle is useful to serve as novel soft template in the synthesis of functional materials. 1H NMR illustrated that the introduced π-π stacking and hydrophobic interactions originated from the hydrophobic aromatic counterions are responsible for the structural transformation. Density functional theory (DFT) simulated the optimum configuration of C16IPS-Nsa and calculated the interaction energy of C16IPS-Nsa-H2O is 39.6 kJ mol-1. This work paves the way for regulating the self-assembly structures of amphiphiles through changing specific weak interactions.

Interpenetrating photopolymers for intraocular lens application

ABSTRACTInterpenetrating photopolymer network materials suitable for intraocular lens application are presented. A rapidly curable, transparent, hydrophobic material with appropriate optical and thermomechanical properties has been prepared from Benzyl acrylate and Benzyl methacrylate. To improve its biocompatibility and optimize surface—cell interactions, this material was modified with respect to its hydrophobicity. Materials which are more hydrophobic, and more hydrophilic, than the base resin were prepared by copolymerization with either a fluoroacrylate or a PEG acrylate respectively. All materials were characterized for their optical and thermomechanical properties. Their in‐vitro cytotoxicity and interaction with mouse fibroblast cells were also studied. It was shown that all materials of the study were biocompatible and more hydrophilic materials resisted cell attachment and may be more suitable for IOL application than their more hydrophobic counter parts of the study. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017, 134, 44496.

Self-Assembly of Magnetic Bacillus-Shaped Bilayer Vesicles in Catanionic Surfactant Solutions.

Bacillus-shaped bilayer vesicles of nanoscale size are very rare structures of stable surfactant self-assembly, because they are both thermodynamically and electrostatically unfavorable in solution. It is evidently demonstrated that appropriately aqueous mixtures of single-tailed cationic and anionic (catanionic) surfactants can produce rigidly bacillus-shaped bilayer vesicles with both flat parts and bent edges. The crucial requirement for forming bacillus-shaped bilayer vesicles is the use of cationic surfactants with relatively hydrophobic [FeCl3Br]- as counterions. [FeCl3Br]- can strongly associate with cationic surfactants to partition into the hydrophobic bilayer of bacillus-shaped bilayer vesicles, significantly increasing the edge energy of cationic surfactants to make them distribute in the low curvature part of bilayers. This causes the formation of bacillus-shaped bilayer vesicles, but not completely bent spherical vesicles, in the case of cationic surfactant excess. The specificity of hydrophobic counterions, [FeCl3Br]-, could also make the catanionic mixtures do not precipitate at the stoichiometric point. This new self-assembly on catanionic systems is culminated in the discovery of beautifully structured colloidal objects which are of practical use for molecular templating and controlled drug or DNA release.

Charge reversal of sulfate latex induced by hydrophobic counterion: effects of surface charge density

We studied experimentally and theoretically the charge reversal of sulfate latex colloid in the presence of monovalent hydrophobic counterion TPP+ (tetraphenylphosphonium). The intrinsic or chemical energy of adsorption of TPP+ on the latex was evaluated from the concentration at charge reversal. The isoelectric point (IEP) increases with increasing the surface or electrokinetic charge density of sulfate latex spheres. That is, at low surface or electrokinetic charge density, the charge inversion concentration is low, and IEP shifts to higher values with the increase of surface or electrokinetic charge density. The intrinsic energy of adsorption decreases with increasing the surface or electrokinetic charge density. Finally, our experimental and theoretical results suggest that the hydrophobicity is a determining factor for the charge inversion of hydrophobic colloids, and the intrinsic energy of adsorption also varies with the variations of surface or electrokinetic charge density.

Micellization of Lactosylammonium Surfactants with Different Counter Ions and Their Interaction with DNA

So far, the studies about the physical chemical properties of sugar-based surfactants have been still unsystematic; most of the studies have been focused on nonionic sugar-based surfactants. In the present work, we studied the micellization of four lactose-based surfactants, with the same headgroup (lactosylammonium) and the same hydrophobic alkyl chain (dodecyl) but different counterions (malonate, adipate, propionate, and hexanoate), at 25.0 and/or 50.0 °C. We found that these four surfactants could decrease the surface tension of water to ca. 30 mN/m. When the number of carboxylate groups in the counterion was the same, the counterion having a shorter alkyl chain could lead to a smaller minimum area per surfactant molecule. Moreover, the surfactants with monocarboxylates as counterions had much lower critical micelle concentrations than those with dicarboxylates as counterions, and the micelles from the former surfactants had a lower counterion binding degree. The lactosylammonium surfactants could bin...

Integrity of lipid nanocarriers in bloodstream and tumor quantified by near-infrared ratiometric FRET imaging in living mice

Lipid nanocarriers are considered as promising candidates for drug delivery and cancer targeting because of their low toxicity, biodegradability and capacity to encapsulate drugs and/or contrasting agents. However, their biomedical applications are currently limited because of a poor understanding of their integrity in vivo. To address this problem, we report on fluorescent nano-emulsion droplets of 100nm size encapsulating lipophilic near-infrared cyanine 5.5 and 7.5 dyes with a help of bulky hydrophobic counterion tetraphenylborate. Excellent brightness and efficient Förster Resonance Energy Transfer (FRET) inside lipid NCs enabled for the first time quantitative fluorescence ratiometric imaging of NCs integrity directly in the blood circulation, liver and tumor xenografts of living mice using a whole-animal imaging set-up. This unique methodology revealed that the integrity of our FRET NCs in the blood circulation of healthy mice is preserved at 93% at 6h of post-administration, while it drops to 66% in the liver (half-life is 8.2h). Moreover, these NCs show fast and efficient accumulation in tumors, where they enter in nearly intact form (77% integrity at 2h) before losing their integrity to 40% at 6h (half-life is 4.4h). Thus, we propose a simple and robust methodology based on ratiometric FRET imaging in vivo to evaluate quantitatively nanocarrier integrity in small animals. We also demonstrate that nano-emulsion droplets are remarkably stable nano-objects that remain nearly intact in the blood circulation and release their content mainly after entering tumors.

A novel in situ hydrophobic ion pairing (HIP) formulation strategy for clinical product selection of a nanoparticle drug delivery system

The present studies were aimed at formulating AZD2811-loaded polylactic acid–polyethylene glycol (PLA–PEG) nanoparticles with adjustable release rates without altering the chemical structures of the polymer or active pharmaceutical ingredient (API). This was accomplished through the use of a hydrophobic ion pairing approach. A series of AZD2811-containing nanoparticles with a variety of hydrophobic counterions including oleic acid, 1-hydroxy-2-naphthoic acid, cholic acid, deoxycholic acid, dioctylsulfosuccinic acid, and pamoic acid is described. The hydrophobicity of AZD2811 was increased through formation of ion pairs with these hydrophobic counterions, producing nanoparticles with exceptionally high drug loading—up to five fold higher encapsulation efficiency and drug loading compared to nanoparticles made without hydrophobic ion pairs. Furthermore, the rate at which the drug was released from the nanoparticles could be controlled by employing counterions with various hydrophobicities and structures, resulting in release half-lives ranging from about 2 to 120h using the same polymer, nanoparticle size, and nanoemulsion process. Process recipe variables affecting drug load and release rate were identified, including pH and molarity of quench buffer.Ion pair formation between AZD2811 and pamoic acid as a model counterion was investigated using solubility enhancement as well as nuclear magnetic resonance spectroscopy to demonstrate solution-state interactions. Further evidence for an ion pairing mechanism of controlled release was provided through the measurement of API and counterion release profiles using high-performance liquid chromatography, which had stoichiometric relationships. Finally, Raman spectra of an AZD2811-pamoate salt compared well with those of the formulated nanoparticles, while single components (AZD2811, pamoic acid) alone did not.A library of AZD2811 batches was created for analytical and preclinical characterization. Dramatically improved preclinical efficacy and tolerability data were generated for the pamoic acid lead formulation, which has been selected for evaluation in a Phase 1 clinical trial (ClinicalTrials.gov Identifier NCT 02579226). This work clearly demonstrates the importance of assessing a wide range of drug release rates during formulation screening as a critical step for new drug product development, and how utilizing hydrophobic ion pairing enabled this promising nanoparticle formulation to proceed into clinical development.