Boosting the sonodynamic performance of CoBiMn-layered double hydroxide nanoparticles via tumor microenvironment regulation for ultrasound imaging-guided sonodynamic therapy.

Sonodynamic therapy (SDT), a promising strategy for cancer treatment with the ability for deep tissue penetration, has received widespread attention in recent years. Sonosensitizers with intrinsic characteristics for tumor-specific curative effects, tumor microenvironment (TME) regulation and tumor diagnosis are in high demand. Herein, amorphous CoBiMn-layered double hydroxide (a-CoBiMn-LDH) nanoparticles are presented as multifunctional sonosensitizers to trigger reactive oxygen species (ROS) generation for ultrasound (US) imaging-guided SDT. Hydrothermal-synthesized CoBiMn-LDH nanoparticles are etched via a simple acid treatment to obtain a-CoBiMn-LDH nanoparticles with abundant defects. The a-CoBiMn-LDH nanoparticles give greater ROS generation upon US irradiation, reaching levels ~ 3.3 times and ~ 8.2 times those of the crystalline CoBiMn-LDH nanoparticles and commercial TiO2 sonosensitizer, respectively. This excellent US-triggered ROS generation performance can be attributed to the defect-induced narrow band gap and promoted electrons and holes (e-/h+) separation. More importantly, the presence of Mn4+ enables the a-CoBiMn-LDH nanoparticles to regulate the TME by decomposing H2O2 into O2 for hypoxia relief and US imaging, and consuming glutathione (GSH) for protection against ROS clearance. Biological mechanism analysis shows that a-CoBiMn-LDH nanoparticles modified with polyethylene glycol can serve as a multifunctional sonosensitizer to effectively kill cancer cells in vitro and eliminate tumors in vivo under US irradiation by activating p53, apoptosis, and oxidative phosphorylation-related signaling pathways.

Advanced Formulation Approaches for Proteins.

Proteins and peptides are highly desirable as therapeutic agents, being highly potent and specific. However, there are myriad challenges with processing them into patient-friendly formulations: they are often unstable and have a tendency to aggregate or degrade upon storage. As a result, the vast majority of protein actives are delivered parenterally as solutions, which has a number of disadvantages in terms of cost, accessibility, and patient experience. Much work has been undertaken to develop new delivery systems for biologics, but to date this has led to relatively few products on the market. In this chapter, we review the challenges faced when developing biologic formulations, discuss the technologies that have been explored to try to overcome these, and consider the different delivery routes that can be applied. We further present an overview of the currently marketed products and assess the likely direction of travel in the next decade.

Advanced Formulation Approaches for Emerging Therapeutic Technologies.

In addition to proteins, discussed in the Chapter "Advances in Vaccine Adjuvants: Nanomaterials and Small Molecules", there are a wide range of alternatives to small molecule active ingredients. Cells, extracellular vesicles, and nucleic acids in particular have attracted increasing research attention in recent years. There are now a number of products on the market based on these emerging technologies, the most famous of which are the mRNA-based vaccines against SARS-COV-2. These advanced therapeutic moieties are challenging to formulate however, and there remain significant challenges for their more widespread use. In this chapter, we consider the potential and bottlenecks for developing further medical products based on these systems. Cells, extracellular vesicles, and nucleic acids will be discussed in terms of their mechanism of action, the key requirements for translation, and how advanced formulation approaches can aid their future development. These points will be presented with selected examples from the literature, and with a focus on the formulations which have made the transition to clinical trials and clinical products.

Layered double hydroxide-based nanomaterials for biomedical applications.

Against the backdrop of increased public health awareness, inorganic nanomaterials have been widely explored as promising nanoagents for various kinds of biomedical applications. Layered double hydroxides (LDHs), with versatile physicochemical advantages including excellent biocompatibility, pH-sensitive biodegradability, highly tunable chemical composition and structure, and ease of composite formation with other materials, have shown great promise in biomedical applications. In this review, we comprehensively summarize the recent advances in LDH-based nanomaterials for biomedical applications. Firstly, the material categories and advantages of LDH-based nanomaterials are discussed. The preparation and surface modification of LDH-based nanomaterials, including pristine LDHs, LDH-based nanocomposites and LDH-derived nanomaterials, are then described. Thereafter, we systematically describe the great potential of LDHs in biomedical applications including drug/gene delivery, bioimaging diagnosis, cancer therapy, biosensing, tissue engineering, and anti-bacteria. Finally, on the basis of the current state of the art, we conclude with insights on the remaining challenges and future prospects in this rapidly emerging field.

Dual-Mode and Label-Free Detection of Exosomes from Plasma Using an Electrochemical Quartz Crystal Microbalance with Dissipation Monitoring.

The biomolecular contents of extracellular vesicles, such as exosomes, have been shown to be crucial in intercellular communication and disease propagation. As a result, there has been a recent surge in the exploration of novel biosensing platforms that can sensitively and specifically detect exosomal content such as proteins and nucleic acids, with a view toward application in diagnostic assays. Here, we demonstrate dual-mode and label-free detection of plasma exosomes using an electrochemical quartz crystal microbalance with dissipation monitoring (EQCM-D). The platform adopts a direct immunosensing approach to effectively capture exosomes via their surface protein expression of CD63. By combining QCM-D with a tandem in situ electrochemical impedance spectroscopy measurement, we are able to demonstrate relationships between mass, viscoelasticity and impedance inducing properties of each functional layer and analyte. In addition to lowering the limit of detection (by a factor of 2-4) to 6.71 × 107 exosome-sized particles (ESP) per mL in 25% v/v serum, the synergy between dissipation and impedance response introduces improved sensing specificity by offering further distinction between soft and rigid analytes, thereby promoting EQCM-D as an important technique for exosome analysis.

Monitoring Polymorphic Phase Transitions in Flufenamic Acid Amorphous Solid Dispersions Using Hyphenated X-ray Diffraction-Differential Scanning Calorimetry.

Flufenamic acid (FFA) is a highly polymorphic drug molecule with nine crystal structures reported in the Cambridge Structural Database. This study explores the use of synchrotron X-ray powder diffraction combined with differential scanning calorimetry to study crystallization and polymorphic phase transitions upon heating FFA-polymer amorphous solid dispersions (ASDs). Ethyl cellulose (EC, 4 cp) and hydroxypropylmethylcellulose (HPMC) grades with different viscosities and substitution patterns were used to prepare dispersions with FFA at 5:1, 2:1, 1:1, and 1:5 w/w drug/polymer ratios by quench cooling. We employed a 6 cp HPMC 2910 material and two HPMC 2208 samples at 4000 and 100 000 cp. Hyphenated X-ray diffraction (XRD)-differential scanning calorimetry (DSC) studies show that the 6 and 100 000 cp HPMCs and 4 cp EC polymers can stabilize FFA form IV by inhibiting the transition to form I during heating. It appears that the polymers stabilize FFA in both amorphous and metastable forms via a combination of intermolecular interactions and viscosity effects. Increasing the polymer content of the ASD also inhibits polymorphic transitions, with drug/polymer ratios of 1:5 w/w resulting in FFA remaining amorphous during heating. The comparison of FFA ASDs prepared with different samples of HPMCs and ECs suggests that the chemical substitution of the polymer (HPMC 2208 has 19-24% methoxy groups and 4-12% hydroxypropyl groups, while HPMC 2910 has 28-30% methoxy groups and 7-12% hydroxypropyl groups) plays a more significant role in directing polymorphic transitions than the viscosity. A previously unreported polymorph of FFA was also noted during heating but its structure could not be determined.

An investigation of alkaline phosphatase enzymatic activity after electrospinning and electrospraying.

The high target specificity and multifunctionality of proteins has led to great interest in their clinical use. To this end, the development of delivery systems capable of preserving their bioactivity and improving bioavailability is pivotal to achieve high effectiveness and satisfactory therapeutic outcomes. Electrohydrodynamic (EHD) techniques, namely electrospinning and electrospraying, have been widely explored for protein encapsulation and delivery. In this work, monoaxial and coaxial electrospinning and electrospraying were used to encapsulate alkaline phosphatase (ALP) into poly(ethylene oxide) fibres and particles, respectively, and the effects of the processing techniques on the integrity and bioactivity of the enzyme were assessed. A full morphological and physicochemical characterisation of the blend and core-shell products was performed. ALP was successfully encapsulated within monolithic and core-shell electrospun fibres and electrosprayed particles, with drug loadings and encapsulation efficiencies of up to 21% and 99%, respectively. Monoaxial and coaxial electrospinning were equally effective in preserving ALP function, leading to no activity loss compared to fresh aqueous solutions of the enzyme. While the same result was observed for monoaxial electrospraying, coaxial electrospraying of ALP caused a 40% reduction in its bioactivity, which was attributed to the high voltage (22.5 kV) used during processing. This demonstrates that choosing between blend and coaxial EHD processing for protein encapsulation is not always straightforward, being highly dependent on the chosen therapeutic agent and the effects of the processing conditions on its bioactivity.

Acoustic Immunosensing of Exosomes Using a Quartz Crystal Microbalance with Dissipation Monitoring.

Exosomes are endocytic lipid-membrane bound bodies with the potential to be used as biomarkers in cancer and neurodegenerative disease. The limitations and scarcity of current exosome characterization approaches have led to a growing demand for translational techniques, capable of determining their molecular composition and physical properties in physiological fluids. Here, we investigate label-free immunosensing, using a quartz crystal microbalance with dissipation monitoring (QCM-D), to detect exosomes by exploiting their surface protein profile. Exosomes expressing the transmembrane protein CD63 were isolated by size-exclusion chromatography from cell culture media. QCM-D sensors functionalized with anti-CD63 antibodies formed a direct immunoassay toward CD63-positive exosomes in 75% v/v serum, exhibiting a limit-of-detection of 2.9 × 108 and 1.4 × 108 exosome sized particles (ESPs)/mL for frequency and dissipation response, respectively, i.e., clinically relevant concentrations. Our proof-of-concept findings support the adoption of dual-mode acoustic analysis of exosomes, leveraging both frequency and dissipation monitoring for use in bioanalytical characterization.

Mechanistic In Situ and Ex Situ Studies of Phase Transformations in Molecular Co-Crystals.

Co-crystallisation is widely explored as a route to improve the physical properties of pharmaceutical active ingredients, but little is known about the fundamental mechanisms of the process. Herein, we apply a hyphenated differential scanning calorimetry-X-ray diffraction technique to mimic the commercial hot melt extrusion process, and explore the heat-induced synthesis of a series of new co-crystals containing isonicotinamide. These comprise a 1:1 co-crystal with 4-hydroxybenzoic acid, 2:1 and 1:2 systems with 4-hydroxyphenylacetic acid and a 1:1 crystal with 3,4-dihydroxyphenylactic acid. The formation of co-crystals during heating is complex mechanistically. In addition to co-crystallisation, conversions between polymorphs of the co-former starting materials and co-crystal products are also observed. A subsequent study exploring the use of inkjet printing and milling to generate co-crystals revealed that the synthetic approach has a major effect on the co-crystal species and polymorphs produced.

A Simultaneous Differential Scanning Calorimetry-X-ray Diffraction Study of Olanzapine Crystallization from Amorphous Solid Dispersions.

Amorphous solid dispersions (ASDs) of class II and IV biopharmaceutics classification system drugs in water-miscible polymers are a well-recognized means of enhancing dissolution, while such dispersions in hydrophobic polymers form the basis of micro- and nanoparticulate technologies. However, drug recrystallization presents significant problems for product development, and the mechanisms and pathways involved are poorly understood. Here, we outline the use of combined differential scanning calorimetry (DSC)-synchrotron X-ray diffraction to monitor the sequential appearance of polymorphs of olanzapine (OLZ) when dispersed in a range of polymers. In a recent study (Cryst. Growth Des.2019,19, 2751-2757), we reported a new polymorph (form IV) of OLZ which crystallized from a spray-dried dispersion of OLZ in polyvinylpyrrolidone. Here, we extend our earlier study to explore OLZ dispersions in poly(lactide-co-glycolide) (PLGA), polylactide (PLA), and hydroxypropyl methyl cellulose acetate succinate (HPMCAS), with a view to identifying the sequence of form generation on heating each dispersion. While spray-dried OLZ results in the formation of crystalline form I, the spray-dried material with HPMCAS comprises an ASD, and forms I and IV are generated upon heating. PLGA and PLA result in a product which contains both amorphous OLZ and the dichloromethane solvate; upon heating, the amorphous material converts to forms I, II, and IV and the solvate to forms I and II. Our data show that it is possible to quantitatively assess not only the polymorph generation sequence but also the relative proportions as a function of temperature. Of particular note is that the sequence of form generation is significantly more complex than may be indicated by DSC data alone, with coincident generation of different polymorphs and complex interconversions as the material is heated. We argue that this may have implications not only for the mechanistic understanding of polymorph generation but also as an aid to identifying the range of polymorphic forms that may be produced by a single-drug molecule.

A kinetic and mechanistic study into the transformation of calcium sulfate hemihydrate to dihydrate.

The conversion of CaSO4·0.5H2O to CaSO4·2H2O is of great importance industrially, being the reaction behind plasterboard production and the setting of medical plasters. A detailed kinetic and mechanistic study of this process was conducted using time-resolved synchrotron X-ray diffraction in this work. The CaSO4·2H2O product is very similar regardless of whether the α- or ß-form of CaSO4·0.5H2O is used as the starting material, but the reaction process is very different. The induction time is usually shorter for α-CaSO4·0.5H2O than ß-CaSO4·0.5H2O, and a greater conversion percentage is observed with the former (although in neither case does the reaction proceed to 100% completion). The temperature of the system, widely used in industry as an indirect measure of the extent of the hydration process, is found to be a poor proxy for this, with the maximum temperature reached well before the reaction is complete. The Avrami-Erofe'ev and Gualtieri models could both be fitted to the experimental data, with the fits being substantially closer in the case of α-CaSO4·0.5H2O. The rate of reaction in the Avrami model tends to increase with the amount of gypsum seeds added to accelerate the process, and the importance of nucleation declines. The Gualtieri analysis suggested that the rate of nucleation increases substantially with the amount of seeds added, while there are less distinct changes in the rate of crystal growth. At low seed concentrations (<0.5% w/w) the rate of crystal growth is greater than the rate of nucleation, but at concentrations above 0.5% w/w nucleation is faster. These findings represent the first synchrotron study of the conversion of CaSO4·0.5H2O to CaSO4·2H2O, and will be of importance to gypsum producers globally.

Gaseous "nanoprobes" for detecting gas-trapping environments in macroscopic films of vapor-deposited amorphous ice.

Vapor-deposited amorphous ice, traditionally called amorphous solid water (ASW), is one of the most abundant materials in the universe and a prototypical material for studying physical vapor-deposition processes. Its complex nature arises from a strong tendency to form porous structures combined with complicated glass transition, relaxation, and desorption behavior. To gain further insights into the various gas-trapping environments that exist in ASW and hence its morphology, films in the 25-100 µm thickness range were codeposited with small amounts of gaseous "nanoprobes" including argon, methane, helium, and carbon dioxide. Upon heating in the 95-185 K temperature range, three distinct desorption processes are observed which we attribute to the gas desorption out of open cracks above 100 K, from internal voids that collapse due to the glass transition at ∼125 K and finally from fully matrix-isolated gas induced by the irreversible crystallization to stacking disordered ice (ice Isd) at ∼155 K. Nanoscale films of ASW have only displayed the latter desorption process which means that the first two desorption processes arise from the macroscopic dimensions of our ASW films. Baffling the flow of water vapor toward the deposition plate greatly reduces the first desorption feature, and hence the formation of cracks, but it significantly increases the amount of matrix-isolated gas. The complex nature in which ASW can trap gaseous species is thought to be relevant for a range of cosmological processes.

A chitosan-based cascade-responsive drug delivery system for triple-negative breast cancer therapy.

BACKGROUND: It is extremely difficult to develop targeted treatments for triple-negative breast (TNB) cancer, because these cells do not express any of the key biomarkers usually exploited for this goal. RESULTS: In this work, we develop a solution in the form of a cascade responsive nanoplatform based on thermo-sensitive poly(N-vinylcaprolactam) (PNVCL)-chitosan (CS) nanoparticles (NPs). These are further modified with the cell penetrating peptide (CPP) and loaded with the chemotherapeutic drug doxorubicin (DOX). The base copolymer was optimized to undergo a phase change at the elevated temperatures of the tumor microenvironment. The acid-responsive properties of CS provide a second trigger for drug release, and the inclusion of CPP should ensure the formulations accumulate in cancerous tissue. The resultant CPP-CS-co-PNVCL NPs could self-assemble in aqueous media into spherical NPs of size < 200 nm and with low polydispersity. They are able to accommodate a high DOX loading (14.8% w/w). The NPs are found to be selectively taken up by cancerous cells both in vitro and in vivo, and result in less off-target cytotoxicity than treatment with DOX alone. In vivo experiments employing a TNB xenograft mouse model demonstrated a significant reduction in tumor volume and prolonging of life span, with no obvious systemic toxicity. CONCLUSIONS: The system developed in this work has the potential to provide new therapies for hard-to-treat cancers.

Platelet-membrane-biomimetic nanoparticles for targeted antitumor drug delivery.

BACKGROUND: Nanoscale drug-delivery systems (DDSs) have great promise in tumor diagnosis and treatment. Platelet membrane (PLTM) biomimetic DDSs are expected to enhance retention in vivo and escape uptake by macrophages, as well as minimizing immunogenicity, attributing to the CD47 protein in PLTM sends "don't eat me" signals to macrophages. In addition, P-selectin is overexpressed on the PLTM, which would allow a PLTM-biomimetic DDS to specifically bind to the CD44 receptors upregulated on the surface of cancer cells. RESULTS: In this study, porous nanoparticles loaded with the anti-cancer drug bufalin (Bu) were prepared from a chitosan oligosaccharide (CS)-poly(lactic-co-glycolic acid) (PLGA) copolymer. These were subsequently coated with platelet membrane (PLTM) to form PLTM-CS-pPLGA/Bu NPs. The PLTM-CS-pPLGA/Bu NPs bear a particle size of ~ 192 nm, and present the same surface proteins as the PLTM. Confocal microscopy and flow cytometry results revealed a greater uptake of PLTM-CS-pPLGA/Bu NPs than uncoated CS-pPLGA/Bu NPs, as a result of the targeted binding of P-selectin on the surface of the PLTM to the CD44 receptors of H22 hepatoma cells. In vivo biodistribution studies in H22-tumor carrying mice revealed that the PLTM-CS-pPLGA NPs accumulated in the tumor, because of a combination of active targeting effect and the EPR effect. The PLTM-CS-pPLGA/Bu NPs led to more effective tumor growth inhibition over other bufalin formulations. CONCLUSIONS: Platelet membrane biomimetic nanoparticles played a promising targeted treatment of cancer with low side effect.

Polymorphic Phase Transitions in Carbamazepine and 10,11-Dihydrocarbamazepine.

Temperature-induced phase transitions in carbamazepine (CBZ) and 10,11-dihydrocarbamazepine (DHC) were studied by simultaneous differential scanning calorimetry-X-ray diffraction in this work. The transitions generally involve a transitional melt phase which is quickly followed by recrystallisation. The expansions of the unit cell as a function of temperature could be quantified and allow us to determine a directional order of stability in relation to the lattice constants. Dihydrocarbamazepine form II undergoes a conversion to form I by a localised melt phase. Carbamazepine (CBZ) form IV converts to form I at 182 °C, again by a localised intermediate melt phase. CBZ form II converted to form I at 119 °C by a pathway that appears to have included some melting, and form III underwent a part melt-recrystallisation and a part sublimation-recrystallisation to form I.

Electrosprayed Janus Particles for Combined Photo-Chemotherapy.

This work is a proof of concept study establishing the potential of electrosprayed Janus particles for combined photodynamic therapy-chemotherapy. Sub-micron-sized particles of polyvinylpyrrolidone containing either an anti-cancer drug (carmofur) or a photosensitiser (rose bengal; RB), and Janus particles containing both in separate compartments were prepared. The functional components were present in the amorphous form in all the particles, and infrared spectroscopy indicated that intermolecular interactions formed between the different species. In vitro drug release studies showed that both carmofur and RB were released at approximately the same rate, with dissolution complete after around 250 min. Cytotoxicity studies were undertaken on model human dermal fibroblasts (HDF) and lung cancer (A549) cells, and the influence of light on cell death explored. Formulations containing carmofur as the sole active ingredient were highly toxic to both cell lines, with or without a light treatment. The RB formulations were non-toxic to HDF when no light was applied, and with photo-treatment caused large amounts of cell death for both A549 and HDF cells. The Janus formulation containing both RB and carmofur was non-toxic to HDF without light, and only slightly toxic with the photo-treatment. In contrast, it was hugely toxic to A549 cells when light was applied. The Janus particles are thus highly selective for cancer cells, and it is hence proposed that such electrosprayed particles containing both a chemotherapeutic agent and photosensitiser have great potential in combined chemotherapy/photodynamic therapy.

Simultaneous Differential Scanning Calorimetry-Synchrotron X-ray Powder Diffraction: A Powerful Technique for Physical Form Characterization in Pharmaceutical Materials.

We report a powerful new technique: hyphenating synchrotron X-ray powder diffraction (XRD) with differential scanning calorimetry (DSC). This is achieved with a simple modification to a standard laboratory DSC instrument, in contrast to previous reports which have involved extensive and complex modifications to a DSC to mount it in the synchrotron beam. The high-energy X-rays of the synchrotron permit the recording of powder diffraction patterns in as little as 2 s, meaning that thermally induced phase changes can be accurately quantified and additional insight on the nature of phase transitions obtained. Such detailed knowledge cannot be gained from existing laboratory XRD instruments, since much longer collection times are required. We demonstrate the power of our approach with two model systems, glutaric acid and sulfathiazole, both of which show enantiotropic polymorphism. The phase transformations between the low and high temperature polymorphs are revealed to be direct solid-solid processes, and sequential refinement against the diffraction patterns obtained permits phase fractions at each temperature to be calculated and unit cell parameters to be accurately quantified as a function of temperature. The combination of XRD and DSC has further allowed us to identify mixtures of phases which appeared phase-pure by DSC.

Theranostic Fibers for Simultaneous Imaging and Drug Delivery.

New methods for creating theranostic systems with simultaneous encapsulation of therapeutic, diagnostic, and targeting agents are much sought after. This work reports for the first time the use of coaxial electrospinning to prepare such systems in the form of core-shell fibers. Eudragit S100 was used to form the shell of the fibers, while the core comprised poly(ethylene oxide) loaded with the magnetic resonance contrast agent Gd(DTPA) (Gd(III) diethylenetriaminepentaacetate hydrate) and indomethacin as a model therapeutic agent. The fibers had linear cylindrical morphologies with clear core-shell structures, as demonstrated by electron microscopy. X-ray diffraction and differential scanning calorimetry proved that both indomethacin and Gd(DTPA) were present in the fibers in the amorphous physical form. This is thought to be a result of intermolecular interactions between the different components, the presence of which was suggested by infrared spectroscopy. In vitro dissolution tests indicated that the fibers could provide targeted release of the active ingredients through a combined mechanism of erosion and diffusion. The proton relaxivities for Gd(DTPA) released from the fibers into tris buffer increased (r1 = 4.79-9.75 s(-1) mM(-1); r2 = 7.98-14.22 s(-1) mM(-1)) compared with fresh Gd(DTPA) (r1 = 4.13 s(-1) mM(-1) and r2 = 4.40 s(-1) mM(-1)), which proved that electrospinning has not diminished the contrast properties of the complex. The new systems reported herein thus offer a new platform for delivering therapeutic and imaging agents simultaneously to the colon.

Amorphous formulations of indomethacin and griseofulvin prepared by electrospinning.

Following an array of optimization experiments, two series of electrospun polyvinylpyrrolidone (PVP) fibers were prepared. One set of fibers contained various loadings of indomethacin, known to form stable glasses, and the other griseofulvin (a poor glass former). Drug loadings of up to 33% w/w were achieved. Electron microscopy data showed the fibers largely to comprise smooth and uniform cylinders, with evidence for solvent droplets in some samples. In all cases, the drug was found to exist in the amorphous physical state in the fibers on the basis of X-ray diffraction and differential scanning calorimetry (DSC) measurements. Modulated temperature DSC showed that the relationship between a formulation's glass transition temperature (Tg) and the drug loading follows the Gordon-Taylor equation, but not the Fox equation. The results of Gordon-Taylor analysis indicated that the drug/polymer interactions were stronger with indomethacin. The interactions between drug and polymer were explored in more detail using molecular modeling simulations and again found to be stronger with indomethacin; the presence of significant intermolecular forces was further confirmed using IR spectroscopy. The amorphous form of both drugs was found to be stable after storage of the fibers for 8 months in a desiccator (relative humidity <25%). Finally, the functional performance of the fibers was studied; in all cases, the drug-loaded fibers released their drug cargo very rapidly, offering accelerated dissolution over the pure drug.