Tunable Drug Release Profiles Research Articles

Potential of multifunctional electrospun nanofibers in cancer management

Abstract A controlled and sustained release of drugs is much more desirable and beneficial when dealing with cancer, as such drugs also harm normal cells. Available anticancer drugs used in chemotherapy are associated with severe side effects due to high dosage requirements. Electrospun nanofibers have an extensive surface area, controllable pore size, and tunable drug release profiles, which make these nanofibers promising candidates in the medical field. Electrospun fibrous matrices are increasingly used in cancer research as patches for drug delivery in living organisms and as scaffolds for cancer modeling in the lab. Towards these applications, nanofibers synthesized by electrospinning have exhibited great clinical potential as a biomimetic tumor microenvironment model for drug screening, a controllable platform for localized, prolonged drug release for cancer therapy, and a human cancer diagnostic tool for capture and isolation of circulating tumor cells in the bloodstream and detection of cancer-associated biomarkers. This review briefly describes most of the materials used in electrospinning. Then, we discuss two ways that electrospinning is used to fight cancer: first, as patches with anticancer agents for therapeutic cargo delivery, and second, as three-dimensional fiber for filtering and detecting cancers.

Bioinspired Integration of Naturally Occurring Molecules towards Universal and Smart Antibacterial Coatings

AbstractSurface‐independent smart antibacterial coatings with on‐demand antibiotics release profiles have attracted increasing attention in medical instruments, antibiotics delivery platforms, and implanted devices. Although several approaches have been well documented, the facile preparation of antibacterial coatings onto universal substrates with high antibiotics loading efficiencies, tunable drug release profiles, and excellent antibacterial performances is still met with many challenges, especially related to the redundant coating material synthesis and selective substrate fabrication process. To resolve this issue, the authors report a facile and robust fabrication method towards smart antibacterial coating surfaces on various substrates via a one‐pot integration of two types of naturally occurring building blocks, aminoglycosides and protocatechualdehyde in the presence of plant enzyme horseradish peroxidase. The simultaneous dynamic imine bonds formation and enzymatic polymerization within the system during the one‐pot reaction enable the facile fabrication of diverse surface‐independent smart antibacterial coatings, which can demonstrate several promising features including high drug loading and dynamic (i.e., pH‐responsive) properties, tunable and on‐demand antibiotics release behaviors, and efficient antibacterial activities both in vitro and in vivo. This work may offer new opportunities towards the robust and universal antibacterial coating materials by the bioinspired integration of all natural building blocks.

Graphene-laden hydrogels: A strategy for thermally triggered drug delivery.

The synthesis of graphene-based materials has attracted considerable attention in drug delivery strategies. Indeed, the conductivity and mechanical stability of graphene have been investigated for controlled and tunable drug release via electric or mechanical stimuli. However, the design of a thermo-sensitive scaffold using pristine graphene (without distortions related to the oxidation processes) has not been deeply investigated yet, although it may represent a promising approach for several therapeutic treatments. Here, few-layer graphene was used as a nanofiller in a hydrogel system with a thermally tunable drug release profile. In particular, varying the temperature (25°C, 37°C and 44°C), responsive drug releases were noticed and hypothesized depending on the formation and perturbation of π-π interactions involving graphene, the polymeric matrix and the model drug (diclofenac). As a result, these hybrid hydrogels show a potential application as thermally triggered drug release systems in several healthcare scenarios.

Biodegradable β-Cyclodextrin Conjugated Gelatin Methacryloyl Microneedle for Delivery of Water-Insoluble Drug.

Transdermal delivery of water-insoluble drugs via hydrogel-based microneedle (MN) arrays is crucial for improving their therapeutic efficacies. However, direct loading of water-insoluble drug into hydrophilic matrices remains challenging. Here, a biodegradable MN array patch that is fabricated from naturally derived polymer conjugates of gelatin methacryloyl and β-cyclodextrin (GelMA-β-CD) is reported. When curcumin, an unstable and water-insoluble anticancer drug, is loaded as a model drug, its stability and solubility are improved due to the formation of an inclusion complex. The polymer-drug complex GelMA-β-CD/CUR can be formulated into MN arrays with sufficient mechanical strength for skin penetration and tunable drug release profile. Anticancer efficacy of released curcumin is observed in three-dimensional B16F10 melanoma models. The GelMA-β-CD/CUR MN exhibits relatively higher therapeutic efficacy through more localized and deeper penetrated manner compared with a control nontransdermal patch. In vivo studies also verify biocompatibility and degradability of the GelMA-β-CD MN arrays patch.

Design of 3D multi-layered electrospun membranes embedding iron-based layered double hydroxide for drug storage and control of sustained release

Nowadays polymer dressings are expected to possess multiply functions. Besides acting as physical barriers, dressings may provide for the injured tissue species able to turn wound healing process faster and painless. In this way, dressings can be designed aiming to enable the release of drugs. The possibility to modulate drug release kinetics is a desired characteristic to be achieved in order to turn drug delivery systems adequate to specific treatments. However, hydrophilic drugs and hydrophobic polymers incompatibility hinders such modulation and a long-term release cannot be achieved efficiently. Here we present the design of poly(lactic acid) (PLA) membranes containing iron-based Layered Double Hydroxide (LDH) particles able to storage a hydrophilic anionic drug (derived from the non-steroidal anti-inflammatory naproxen). LDH particles are excellent candidates to compose multifunctional composites. They may present diverse biocompatible compositions, possess an elevated encapsulation capacity and tends to promote drugs sustained release by its own, besides assisting tissues regeneration process. Nanofibrous membranes were prepared by the combination of electrospun PLA and electrosprayed LDH as alternated layers (approach A) and also by both technics performed at the same time (approach B). In approach A, by varying the thickness of the PLA fibrous layers, it was possible to easily modulate the drug release rate. Half of drug content was released after 1, 4 and 17 days for the membranes containing the thinnest, the intermediate and the thicker PLA layers, respectively, and after 56 h for the membrane prepared by the approach B. Naproxen release was kept for 18 days for the thinnest membrane, 59 days for the membrane prepared by the approach B and 66 days for the thicker membranes. We believe that this work can inspire the development of new functional membranes with tunable drug release profile thanks to the versatile electrospinning and electrospraying techniques.

A polyphenol-metal nanoparticle platform for tunable release of liraglutide to improve blood glycemic control and reduce cardiovascular complications in a mouse model of type II diabetes

Liraglutide is a GLP-1 receptor agonist recently approved for Type-II diabetes (T2D) treatment with superior hypoglycemic effect while also improving cardiovascular function for the patients. However, its application has been limited by its short half-life (~13 h), which requires daily injections to maintain effective drug concentrations in blood, thus increasing the risk of poor patient compliance and complications. In this study, we developed a ternary liraglutide/tannic acid (TA)/Al3+ nanoparticle system based on hydrogen bond formation between liraglutide and TA and stabilized by complex coordination interaction between TA and Al3+. This ternary nanoparticle formulation offers sustained release of liraglutide for >8 days by optimizing the concentration of TA during nanoparticle assembly. A flash nanocomplexation (FNC) process was adopted to confer homogeneous mixing of the three components and control the assembly kinetics, thus enabling efficient encapsulation, a tunable drug release profile, improved nanoparticle size uniformity, and a high degree of colloidal stability. Upon a single intraperitoneal (i.p.) administration, the optimized formulation effectively lowered the high blood glucose level in a T2D db/db mice model to the normal range (8–10 mmol/L) within 6 h, maintained it for 60 more hours, and kept it lower than the original level for >6 days. In a 30-day treatment study, the nanoparticle formulation with a dosage frequency of once every 5 days exhibited similar or better control of blood sugar level (20% reduction in HbA1c) and weight control than daily injection of free liraglutide at the same treatment dose. The extended glycemic control led to distinctive improvements on reducing cardiomyopathy, including inhibition in lipo-toxicity by decreasing 40% of triglyceride, 30% of diacylglycerol and 50% of PKC level in the heart, as well as ameliorating oxidative stress and cell apoptosis activities through positive regulation on superoxidase, malondialdehyde, caspase-3 and Bax. This nanoparticle system demonstrates improved therapeutic potential owing to its long-acting glycemic control with improved cardiovascular function and reduced tissue toxicity in multiple organs.

Ultramild One-Step Encapsulating Method as a Modular Strategy for Protecting Humidity-Susceptible Metal-Organic Frameworks Achieving Tunable Drug Release Profiles.

Metal-organic frameworks (MOFs), composed of metal ions or clusters and organic ligands, have emerged as a new class of porous materials. However, water instability of many MOFs has impeded their further applications. Herein, an ultramild one-step encapsulating method has been developed by incorporating γ-cyclodextrin-based MOFs (CD-MOFs) into hydrophobic ethylcellulose to fabricate composite microparticles for ideal hydrolytic stability. The whole process can be completed at ambient temperature by the novel ultrafine particle processing system in several minutes without any purification or drying steps. The composite microparticles well retained their morphology and crystal structure of CD-MOFs even after being exposed to extreme humid environment for 30 d. The composite microparticles were further exploited for drug delivery. The composite microparticles not only exhibited sustained and tunable pH-dependent drug release profiles in simulated physiological conditions but also reduced cell toxicity compared with drug-loaded CD-MOFs, which demonstrated that the composite microparticles were promising as drug carriers. In summary, this study developed a modular strategy for protecting humidity-susceptible MOFs with controlled release profiles, which is expected to open up a new avenue to expand their applications in the biomedical field.

Manipulating drug release from tridimensional porous substrates coated by initiated chemical vapor deposition

ABSTRACTIn the recent years, modern wound dressings have attracted much interest to accelerate wound healing processes with the topical delivery of drugs directly on wounds having a significant effect on wound rehabilitation. The objective of this study was to develop a model dressing that would not only provide wound protection from the environment but might also provide the possibility to keep it moist and deliver a drug for potential speeding the healing process. Poly(ethylene terephthalate), cotton fabrics, and polycaprolactone (PCL) nanofibers were used as different tridimensional porous substrates, loaded with a model drug, clotrimazole. The results show that the chemical structure and surface area to volume ratio of the pristine substrates affect the drug release profile. Coating of such substrates by hydrogels poly(2‐hydroxyethyl methacrylate) (p‐HEMA) and poly(methacrylic acid) (p‐MAA) was successfully achieved by initiated chemical vapor deposition. This method was chosen because it is gentle and solventless and most important it can coat free areas within the three‐dimensional structures. Scanning electron microscopy results revealed that p‐HEMA and p‐MAA conformally coated the fibers of the substrates. Moreover, drug release experiments showed that p‐HEMA and p‐MAA coatings provide barriers preventing sudden drug release. In conclusion, our results indicated the possibility of fabricating dressings containing a drug with tunable drug release profile depending on several parameters even though a strong porous structure exists. © 2019 The Authors. Journal of Applied Polymer Science published by Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019, 136, 47858.

Production of dry-state ketoprofen-encapsulated PMMA NPs by coupling micromixer-assisted nanoprecipitation and spray drying

We present a two-step process to produce dry-state Ketoprofen-loaded poly(methyl methacrylate) nanoparticles (NPs) with controllable size and tunable drug release profile. A colloidal suspension of drug-loaded nanoparticles was first obtained from a nanoprecipitation process and then transferred into a commercial spray dryer. Three micromixers of different designs and mixing principles (molecular diffusion and impact mixing) were tested. After the first step, highly monomodal NPs in the size range 100 to 210 nm were obtained as seen by the low polydispersity index value (ca. PDI ∼ 0.2) returned by a dynamic light scattering detector. Physicochemical properties, encapsulation efficiency/ratio and drug release kinetics of NPs before and after drying were determined. For similar operating conditions, the best micromixer tested (impact mixing) allowed concluding that the NPs size was not significantly affected by the spray drying while encapsulation parameters and drug release rate were slightly decreased compared to the non spray-dried NPs. A sustained drug release was observed over 6 h and the drug release rate (up to 70%) was found to vary with the size of the NPs which in turn was a function of the flow rate ratio between the polymer solution and the non-solvent solution.

Extrusion 3D Printing of Paracetamol Tablets from a Single Formulation with Tunable Release Profiles Through Control of Tablet Geometry

An extrusion-based 3D printer was used to fabricate paracetamol tablets with different geometries (mesh, ring and solid) from a single paste-based formulation formed from standard pharmaceutical ingredients. The tablets demonstrate that tunable drug release profiles can be achieved from this single formulation even with high drug loading (> 80% w/w). The tablets were evaluated for drug release using a USP dissolution testing type I apparatus. The tablets showed well-defined release profiles (from immediate to sustained release) controlled by their different geometries. The dissolution results showed dependency of drug release on the surface area/volume (SA/V) ratio and the SA of the different tablets. The tablets with larger SA/V ratios and SA had faster drug release. The 3D printed tablets were also evaluated for physical and mechanical properties including tablet dimension, drug content, weight variation and breaking force and were within acceptable range as defined by the international standards stated in the US Pharmacopoeia. X-ray powder diffraction, differential scanning calorimetry and attenuated total reflectance Fourier transform infrared spectroscopy were used to identify the physical form of the active and to assess possible drug-excipient interactions. These data again showed that the tablets meet USP requirement. These results clearly demonstrate the potential of 3D printing to create unique pharmaceutical manufacturing, and potentially clinical, opportunities. The ability to use a single unmodified formulation to achieve defined release profiles could allow, for example, relatively straightforward personalization of medicines for individuals with different metabolism rates for certain drugs and hence could offer significant development and clinical opportunities.

Insights into the Self assembled Lipid-Polymer hybrid Nanoparticles as Drug Delivery system

The Use of polymeric nanoparticles and lipid carrier systems, including liposomes, solid lipid nanoparticles and nanostructured lipid carriers has limitations such as drug leakage and high water content of dispersions. Thus, lipid polymer hybrid nanoparticles have been explored by the researchers to provide a better effect using biomimetic characteristics of lipids and architectural advantage of polymeric core and finally producing a system which overcomes the limitations of both polymeric nanoparticles and lipid carrier systems. The system composed of biodegradable polymeric core surrounded by layers of phospholipids, additional compounds and mixtures may also be added to the phospholipids in the amphiphilic coating as for example fatty acids, steroids (such as cholesterol), triglycerides, lipoproteins, glycolipids, vitamins, detergents, and surface active agents. They are generally prepared by mixing liposomes and Polymeric nanoparticles to form lipid–polymer complexes in which a lipid bilayer or lipid multilayers cover the surface of the polymeric core. The space between polymeric core and lipid layer is usually occupied by water or aqueous buffer. The obtained particle size of the final particles remained in the desirable range with narrow distribution. The lipid-polymer hybrid nanoparticle by design has the capacity to co-encapsulate both hydrophobic and lipophilic drugs. The metabolic pathway of lipids in the body has led to the site specific delivery of such system with the modification of the pharmacokinetics and biodistribution of active ingredients for increased efficacy. This hybrid structure provides an advantages of controllable particle size, surface functionality, high drug loading, entrapment of multiple therapeutic agents, tunable drug release profile, and good serum stability. This review focuses on current research trends on Lipid Polymer hybrid nanoparticles including methods of preparation and physicochemical characteristics.

Calcium Phosphate as a Key Material for Socially Responsible Tissue Engineering.

Socially responsible technologies are designed while taking into consideration the socioeconomic, geopolitical and environmental limitations of regions in which they will be implemented. In the medical context, this involves making therapeutic platforms more accessible and affordable to patients in poor regions of the world wherein a given disease is endemic. This often necessitates going against the reigning trend of making therapeutic nanoparticles ever more structurally complex and expensive. However, studies aimed at simplifying materials and formulations while maintaining the functionality and therapeutic response of their more complex counterparts seldom provoke a significant interest in the scientific community. In this review we demonstrate that such compositional simplifications are meaningful when it comes to the design of a solution for osteomyelitis, a disease that is in its natural, non-postoperative form particularly prevalent in the underdeveloped parts of the world wherein poverty, poor sanitary conditions, and chronically compromised defense lines of the immune system are the norm. We show that calcium phosphate nanoparticles, which are inexpensive to make, could be chemically designed to possess the same functionality as a hypothetic mixture additionally composed of: (a) a bone growth factor; (b) an antibiotic for prophylactic or anti-infective purposes; (c) a bisphosphonate as an antiresorptive compound; (d) a viral vector to enable the intracellular delivery of therapeutics; (e) a luminescent dye; (f) a radiographic component; (g) an imaging contrast agent; (h) a magnetic domain; and (i) polymers as viscous components enabling the injectability of the material and acting as carriers for the sustained release of a drug. In particular, calcium phosphates could: (a) produce tunable drug release profiles; (b) take the form of viscous and injectable, self-setting pastes; (c) be naturally osteo-inductive and inhibitory for osteoclastogenesis; (d) intracellularly deliver bioactive compounds; (e) accommodate an array of functional ions; (f) be processed into macroporous constructs for tissue engineering; and (g) be naturally antimicrobial. All in all, we see in calcium phosphates the presence of a protean nature whose therapeutic potentials have been barely tapped into.

Self-Setting Calcium Phosphate Cements with Tunable Antibiotic Release Rates for Advanced Antimicrobial Applications.

Osteomyelitis, an infectious disease predominantly tied to poor sanitary conditions in underdeveloped regions of the world, is in need of inexpensive, easily in situ synthesizable and administrable materials for its treatment. The results of this study stem from the attempt to create one such affordable and minimally invasive therapeutic platform in the form of a self-setting, injectable cement with a tunable drug release profile, composed of only nanoparticulate hydroxyapatite, the synthetic version of the bone mineral. Cements comprised two separately synthesized hydroxyapatite powders, one of which, HAP2, was precipitated abruptly, retaining the amorphous nature longer, and the other one of which, HAP1, was precipitated at a slower rate, more rapidly transitioning to the crystalline structure. Cements were made with four different weight ratios of the two hydroxyapatite components: 100/0, 85/15, 50/50, and 0/100 with respect to HAP1 and HAP2. Both the setting and the release rates measured on two different antibiotics, vancomycin and ciprofloxacin, were controlled using the weight ratio of the two hydroxyapatite components. Various inorganic powder properties were formerly used to control drug release, but here we demonstrate for the first time that the kinetics of the mechanism of formation of a solid compound can be controlled to produce tunable drug release profiles. Specifically, it was found that the longer the precursor calcium phosphate component of the cement retains the amorphous nature of the primary precipitate, the more active it was in terms of speeding up the diffusional release of the adsorbed drug. The setting rate was, in contrast, inversely proportional to the release rate and to the content of this active hydroxyapatite component, HAP2. The empirical release profiles were fitted to a set of equations that could be used to tune the release rate to the therapeutic occasion. All of the cements loaded with vancomycin or ciprofloxacin inhibited the growth of Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli and Pseudomonas aeruginosa in both agar diffusion assays and broth dilution tests with intensities either comparable to the antibiotic per se, as in the case of ciprofloxacin, or even larger than the antibiotic alone, as in the case of vancomycin. Interestingly, even the pure cements exhibited an antibacterial effect ranging from moderate to strong, while demonstrating high levels of biocompatibility with osteoclastic RAW264.7 cells and only slightly affecting the viability of the osteoblastic MC3T3-E1 cells, in direct proportion with the amount of the more active hydroxyapatite component in the cements. This antibacterial effect was especially noticeable against Gram-negative bacteria, where the growth inhibition by the cements was comparable to or even stronger than that of the pure antibiotics. The antibiofilm assay against P. aeruginosa biofilms reiterated the antibiotic effectiveness of pure, antibiotic-free cements. That the carrier per se, composed of a nontoxic, easily prepared, bone mineral composite, can exhibit a strong antibacterial effect even in the absence of an antibiotic drug is an insight highly relevant in view of the rising resistance of an array of pathogens to traditional antibiotic therapies and the demands for the timely development of suitable alternatives.

Retracted Article: Creation of ultrasound and temperature-triggered bubble liposomes from economical precursors to enhance the therapeutic efficacy of curcumin in cancer cells

An ultrasound and temperature responsive bubble liposome has been designed with high physiological stability, targeted, rapid and tunable drug release profile.

Glycoligand-targeted core–shell nanospheres with tunable drug release profiles from calixarene–cyclodextrin heterodimers

Stable core-shell nanospheres self-assemble in water from heterodimers combining a hydrophobic calix[4]arene moiety and a hydrophilic β-cyclodextrin head; their potential to encapsulate and provide sustained release of the anticancer drug docetaxel and undergo surface post-modification with glycoligands targeting the macrophage mannose receptor is discussed.

Applications of Mesoporous Materials as Excipients for Innovative Drug Delivery and Formulation

Due to uniquely ordered nanoporous structure and high surface area as well as large pore volume, mesoporous materials have exhibited excellent performance in both controlled drug delivery with sustained release profiles and formulation of poorly aqueoussoluble drugs with enhanced bioavailability. Compared with other bulk excipients, mesoporous materials could achieve a higher loading of active ingredients and a tunable drug release profile, as the high surface density of surface hydroxyl groups offered versatility to be functionalized. With drug molecules stored in nano sized channels, the pore openings could be modified using functional polymers or nano-valves performing as stimuli-responsive release devices and the drug release could be triggered by environmental changes or other external effects. In particular, mesoporous silica nanoparticles (MSN) have attracted much attention for application in functional target drug delivery to the cancer cell. The smart nano-vehicles for drug delivery have showed obvious improvements in the therapeutic efficacy for tumor suppression as compared with conventional sustained release systems, although further progress is still needed for eventual clinical applications. Alternatively, unmodified mesoporous silica also exhibited feasible application for direct formulation of poorly water-soluble drugs to enhance dissolution rate, solubility and thus increase the bioavailability after administration. In summary, mesoporous materials offer great versatility that can be used both for on-demand oral and local drug delivery, and scientists are making great efforts to design and fabricate innovative drug delivery systems based on mesoporous drug carriers.

In vitro and in vivo evaluation of biodegradable embolic microspheres with tunable anticancer drug release

Natural polymer-derived materials have attracted increasing interest in the biomedical field. Polysaccharides have obvious advantages over other polymers employed for biomedical applications due to their exceptional biocompatibility and biodegradability. None of the spherical embolic agents used clinically is biodegradable. In the current study, microspheres prepared from chitosan and carboxymethyl cellulose (CMC) were investigated as a biodegradable embolic agent for arterial embolization applications. Aside from the enzymatic degradability of chitosan units, the cross-linking bonds in the matrix, Schiff bases, are susceptible to hydrolytic cleavage in aqueous conditions, which would overcome the possible shortage of enzymes inside the arteries. The size distribution, morphology, water retention capacity and degradability of the microspheres were found to be affected by the modification degree of CMC. An anticancer drug, doxorubicin, was successfully incorporated into these microspheres for local release and thus for killing cancerous cells. These microspheres demonstrated controllable degradation time, variable swelling and tunable drug release profiles. Co-culture with human umbilical vein endothelial cells revealed non-cytotoxic nature of these microspheres compared to monolayer control (P>0.95). In addition, a preliminary study on the in vivo degradation of the microspheres (100–300μm) was performed in a rabbit renal embolization model, which demonstrated that the microspheres were compatible with microcatheters for delivery, capable of occluding the arteries, and biodegradable inside arteries. These microspheres with biodegradability would be promising for embolization therapies.

Tunable drug release profiles from salicylate-based poly(anhydride-ester) matrices using small molecule admixtures.

Poly(anhydride-esters) with salicylic acid, a nonsteroidal anti-inflammatory drug, chemically incorporated into the polymer backbone provide high inherent drug loading. These poly(anhydride-esters) hydrolytically degrade to release salicylic acid over extended time periods (>30 days); however, an initial lag period of no salicylic acid release is observed. This lag period could be unfavorable in applications where immediate salicylic acid release is desired. Poly(anhydride-esters) with short (2 days) and long (11 days) lag periods were admixed with various small molecules as a means to shorten or eliminate the lag period. Salicylic acid, larger salicylic acid prodrugs, and 1:1 combinations of the two were physically admixed, each at 1%, 5%, and 10% (w/w). All admixtures resulted in immediate salicylic acid release and a decrease in glass transition temperatures compared to polymer alone. By varying the amounts of salicylic acid and salicylic acid prodrugs incorporated into the polymer matrix, immediate and constant salicylic acid release profiles over varied time periods were achieved.

Designing multilayered particulate systems for tunable drug release profiles

Triple-layered microparticles comprising poly(d,l-lactide-co-glycolide, 50:50) (PLGA), poly(l-lactide) (PLLA) and poly(ethylene-co-vinyl acetate, 40wt.% vinyl acetate) (EVA) were fabricated using a one-step solvent evaporation technique, with ibuprofen drug localized in the EVA core. The aim of this study was to investigate the drug release profiles of these triple-layered microparticles in comparison to double-layered (PLLA/EVA and PLGA/EVA) (shell/core) and single-layered EVA microparticles. Double- and triple-layered microparticles were shown to eliminate burst release otherwise observed for single-layered microparticles. For triple-layered microparticles, the migration of acidic PGA oligomers from the PLGA shell accelerated the degradation of the PLLA mid-layer and subsequently enhanced drug release in comparison to double-layered PLLA/EVA microparticles. Further studies showed that drug release rates can be altered by changing the layer thicknesses of the triple-layered microparticles, and through specific tailoring of layer thicknesses, a zero-order release can be achieved. This study therefore provides important mechanistic insights into how the distinctive structural attributes of triple-layered microparticles can be tuned to control the drug release profiles.