Polymeric Micelles For Drug Delivery Research Articles

Recent Progress in Proteins-Based Micelles as Drug Delivery Carriers

Proteins-derived polymeric micelles have gained attention and revolutionized the biomedical field. Proteins are considered a favorable choice for developing micelles because of their biocompatibility, harmlessness, greater blood circulation and solubilization of poorly soluble drugs. They exhibit great potential in drug delivery systems as capable of controlled loading, distribution and function of loaded agents to the targeted sites within the body. Protein micelles successfully cross biological barriers and can be incorporated into various formulation designs employed in biomedical applications. This review emphasizes the recent advances of protein-based polymeric micelles for drug delivery to targeted sites of various diseases. Most studied protein-based micelles such as soy, gelatin, casein and collagen are discussed in detail, and their applications are highlighted. Finally, the future perspectives and forthcoming challenges for protein-based polymeric micelles have been reviewed with anticipated further advances.

Zwitterionic doxorubicin loaded micelles based on polyethyleneimine for enhanced antitumor therapy in vivo

Zwitterionic groups of doxorubicin loaded micelles enhanced their antitumor performance in vivo.

Applications of Polymeric Micelles for Drug Delivery

Polymeric micelles have attracted more and more attention in the biomedical field due to their controlled synthesis and sustained drug release, where a diverse of different drug carriers based on the polymeric micelles have been developed in recent years. This research will analyze the application and development of polymeric micelles that derived from block copolymers in biomedicine. There are three processes in drug delivery of drug carriers prepared by polymeric micelles, including micellar drug loading, micellar drug release and targeted therapy. In the polymeric micelles system, the reason why the solubilization and stabilization of drugs are improved is that the hydrophobic interaction and forming of hydrogen bond between micelles-system and drugs. This research also gives basic mechanism for polymeric micelles for passive and active drug targeting. What makes micelles ideal hosts for hydrophobic anti-cancer drugs or other targeted drugs is the hydrophobic nature of its core. This can make the drug more stable. In addition, this research is written to cover the latest information on polymeric micelles and methods of synthesis for applications. The advantages and disadvantages of its use as a drug carrier are also included. And it highlights the conditions that polymeric micelles need to meet as specific delivery tools in various targeting situations.

Reversible Cross-Linked Mixed Micelles for pH Triggered Swelling and Redox Triggered Degradation for Enhanced and Controlled Drug Release.

Good stability and controlled drug release are important properties of polymeric micelles for drug delivery. A good candidate for drug delivery must have outstanding stability in a normal physiological environment, followed with low drug leakage and side effects. Moreover, the chemotherapeutic drug in the micellar core should also be quickly and “on-demand” released in the intracellular microenvironment at the tumor site, which is in favor of overcoming multidrug resistance (MDR) effects of tumor cells. In this work, a mixed micelle was prepared by the simple mix of two amphiphilic copolymers, namely PCL-SS-P(PEGMA-co-MAEBA) and PCL-SS-PDMAEMA, in aqueous solution. In the mixed micelle’s core–shell structure, PCL blocks were used as the hydrophobic core, while the micellar hydrophilic shell consisted of two blocks, namely P(PEGMA-co-MAEBA) and PDMAEMA. In the micellar shell, PEGMA provided hydrophilicity and stability, while MAEBA introduced the aldehyde sites for reversible crosslinking. Meanwhile, the PDMAEMA blocks were also introduced in the micellar shell for pH-responding protonation and swelling of the micelle. The disulfide bonds between the hydrophobic core and hydrophilic shell had redox sensitive properties. Reversible cross-linked micelles (RCLMs) were obtained by crosslinking the micellar shell with an imine structure. RCLMs showed good stability and excellent ability against extensive dilution by aqueous solution. In addition, the stability in different conditions with various pH values and glutathione (GSH) concentrations was studied. Then, the anticancer drug doxorubicin (DOX) was selected as the model drug to evaluate drug entrapment and release capacity of mixed micelles. The in vitro release profiles indicated that this RCLM had controlled drug release. In the simulated normal physiological environment (pH 7.4), the drug release of the RCLMs was restrained obviously, and the cumulative drug release content was only 25.7 during 72 h. When it came to acidic conditions (pH 5.0), de-crosslinking of the micelles occurred, as well as protonation of PDMAEMA blocks and micellar swelling at the same time, which enhanced the drug release to a large extent (81.4%, 72 h). Moreover, the drug release content was promoted further in the presence of the reductant GSH. In the condition of pH 5.0 with 10 mM GSH, disulfide bonds broke-up between the micelle core and shell, followed by shedding of the shell from the inner core. Then, the micellar disassembly (degradation) happened based on the de-crosslinking and swelling, and the drug release was as high as 95.3%. The MTT assay indicated that the CLSMs showed low cytotoxicity and good biocompatibility against the HepG2 cells. In contrast, the DOX-loaded CLSMs could efficiently restrain the proliferation of tumor cells, and the cell viability after 48 h incubation was just 13.2%, which was close to that of free DOX. This reversible cross-linked mixed micelle with pH/redox responsive behaviors is a potential nanocarrier for chemotherapy.

In vitro investigation of hyaluronan-based polymeric micelles for drug delivery into the skin: The internalization pathway

In our previous research, we concluded that polymeric micelles based on hyaluronic acid are able to penetrate into the deeper layers of skin tissue. The aim of this work was to characterize the mechanisms involved in the uptake by skin cells, which is important for understanding the influence of the carrier composition on the drug penetration.To reach this goal, we used micelles encapsulating curcumin made of oleyl-hyaluronan (HAC18:1) and hexyl-hyaluronan (HAC6) covalently linked with fluorescent Nile Blue. This labeling enabled us to track the micelle-forming derivative and also micelle payload into the keratinocytes and fibroblasts by fluorescent microscopy and flow cytometry. The regulation of both the passive and active cellular uptake was used to determine the mechanism of micelle internalization. Furthermore, the changes of membrane fluidity were measured for these derivatives by FRAP. Using these methods we concluded that carriers entered the cells using both active and passive transport. Passive transport was facilitated by the affinity of the carrier to the cell membrane, especially in the case of HAC18:1 carrier, which changed significantly the membrane fluidity. The active transport was dependent on cell type, but mainly driven by the clathrin-mediated endocytosis and macropinocytosis. Surprisingly, the main HA receptor, CD44, was not involved in the uptake. We can conclude that these carrier systems could be used for the local transport of active substances or hydrophobic drugs into the skin cells using the advantage of passive transport of oleyl-HA derivative.

Synthesis of high drug loading, reactive oxygen species and esterase dual-responsive polymeric micelles for drug delivery

Stimulus-responsive, controlled-release systems are of great importance in medical science and have drawn significant research attention, leading to the development of many stimulus-responsive materials over the past few decades. However, these materials are mainly designed to respond to external stimuli and ignore the key problem of the amount of drug loading. In this study, exploiting the synergistic effect of boronic esters and N-isopropylacrylamide (NIPAM) pendant, we present a copolymer as an ROS and esterase dual-stimulus responsive drug delivery system that has a drug loading of up to 6.99 wt% and an entrapment efficiency of 76.9%. This copolymer can successfully self-assemble into polymer micelles in water with a narrow distribution. Additionally, the measured CMC hinted at the good stability of the polymeric micelles in water solution, ensuing long circulation time in the body. This strategy for increasing the drug loading on the basis of stimulus response opens up a new avenue for the development of drug delivery systems.

Stimuli-responsive polymeric micelles for drug delivery and cancer therapy.

Polymeric micelles (PMs) have been widely investigated as nanocarriers for drug delivery and cancer treatments due to their excellent physicochemical properties, drug loading and release capacities, facile preparation methods, biocompatibility, and tumor targetability. They can be easily engineered with various functional moieties to further improve their performance in terms of bioavailability, circulation time, tumor specificity, and anticancer activity. The stimuli-sensitive PMs capable of responding to various extra- and intracellular biological stimuli (eg, acidic pH, altered redox potential, and upregulated enzyme), as well as external artificial stimuli (eg, magnetic field, light, temperature, and ultrasound), are considered as “smart” nanocarriers for delivery of anticancer drugs and/or imaging agents for various therapeutic and diagnostic applications. In this article, the recent advances in the development of stimuli-responsive PMs for drug delivery, imaging, and cancer therapy are reviewed. The article covers the generalities of stimuli-responsive PMs with a focus on their major delivery strategies and newly emerging technologies/nanomaterials, discusses their drawbacks and limitations, and provides their future perspectives.

A Simple Dual-pH Responsive Prodrug-Based Polymeric Micelles for Drug Delivery.

To precisely deliver drug molecules at a targeted site and in a controllable manner, there has been great interest in designing a synergistical drug delivery system that can achieve both surface charge-conversion and controlled release of a drug in response to different stimuli. Here we outline a simple method to construct an intelligent drug carrier, which can respond to two different pH values, therefore achieving charge conversion and chemical-bond-cleavage-induced drug release in a stepwise fashion. This drug carrier comes from the self-assembly of a block copolymer-DOX conjugate synthesized through a Schiff base reaction between poly(2-(diisopropylamino)ethyl methacrylate-b-poly(4-formylphenyl methacrylate-co-polyethylene glycol monomethyl ether methacrylate) (PDPA-b-P(FPMA-co-OEGMA)) and DOX. The surface charge of the BCP-DOX micelles reversed from negative to positive when encountering a weakly acidic environment due to the protonation of PDPA segments. In vitro cellular uptake measurement shows that the cellular uptake and internalization of the BCP-DOX micelles can be significantly enhanced at pH ∼ 6.5. Moreover, this drug carrier exhibits a pH-dependent drug release owing to the cleavage of the imine bond at pH < 5.5. With this dual-pH responsive feature, these micelles may have the ability to precisely deliver DOX to the cancer cells.

Novel polymeric micelles for drug delivery: Material characterization and formulation screening

A rising number of new chemical entities that exhibit only poor aqueous solubility are identified in drug discovery processes. Polymeric micelles composed of block copolymers (BP) facilitate the delivery of such lipophilic molecules in drug therapy. Consequently, a rational screening and selection procedure for novel BP was established. Further, the interplay of polymer structure, micelle formation and drug binding was studied. Therefore seven polymers (BP001 to BP007) were synthesized from different monomer compositions resulting in nanocarriers varying in surface decoration and lipophilicity. These polymers were characterized by H1-NMR and SEC. The molecular weight was ranging between 13 and 37kDa. The critical micelle concentration and micellar integrity in presence of human plasma were determined. Micelles were loaded with dexamethasone and characterized with regards to their size, morphology and surface charge. Polymeric micelles with a size of 49.21–236.37nm were obtained. A half-life of 11h was determined for five of the copolymers in presence of human plasma. Two nanocarrier formulations (BP006 and BP007) were exhibiting optimal micellar integrity in vitro and a modified release profile under biorelevant conditions. Strongest drug-polymer interaction was observed for nanocarrier compositions providing benzyl and carboxylic groups and were composed of BP006 and BP007.

Characteristic of core materials in polymeric micelles effect on their micellar properties studied by experimental and dpd simulation methods

Polymeric micelles are one important class of nanoparticles for anticancer drug delivery, but the impact of hydrophobic segments on drug encapsulation and release is unclear, which deters the rationalization of drug encapsulation into polymeric micelles. This paper focused on studying the correlation between the characteristics of hydrophobic segments and encapsulation of structurally different drugs (DOX and β-carotene). Poly(ϵ-caprolactone) (PCL) or poly(l-lactide) (PLLA) were used as hydrophobic segments to synthesize micelle-forming amphiphilic block copolymers with the hydrophilic methoxy-poly(ethylene glycol) (mPEG). Both blank and drug loaded micelles were spherical in shape with sizes lower than 50nm. PCL-based micelles exhibited higher drug loading capacity than their PLLA-based counterparts. Higher encapsulation efficiency of β-carotene was achieved compared with DOX. In addition, both doxorubicin and β-carotene were released much faster from PCL-based polymeric micelles. Dissipative particle dynamics (DPD) simulation revealed that the two drugs tended to aggregate in the core of the PCL-based micelles but disperse in the core of PLLA based micelles. In vitro cytotoxicity investigation of DOX loaded micelles demonstrated that a faster drug release warranted a more efficient cancer-killing effect. This research could serve as a guideline for the rational design of polymeric micelles for drug delivery.

Polymeric micelles for acyclovir drug delivery

Polymeric prodrug micelles for delivery of acyclovir (ACV) were synthesized. First, ACV was used directly to initiate ring-opening polymerization of ɛ-caprolactone to form ACV-polycaprolactone (ACV-PCL). Through conjugation of hydrophobic ACV-PCL with hydrophilic methoxy poly(ethylene glycol) (MPEG) or chitosan, polymeric micelles for drug delivery were formed. 1H NMR, FTIR, and gel permeation chromatography were employed to show successful conjugation of MPEG or chitosan to hydrophobic ACV-PCL. Through dynamic light scattering, zeta potential analysis, transmission electron microscopy, and critical micelle concentration (CMC), the synthesized ACV-tagged polymeric micelles were characterized. It was found that the average size of the polymeric micelles was under 200nm and the CMCs of ACV-PCL-MPEG and ACV-PCL-chitosan were 2.0mgL−1 and 6.6mgL−1, respectively. The drug release kinetics of ACV was investigated and cytotoxicity assay demonstrates that ACV-tagged polymeric micelles were non-toxic.

Lactic acid- and carbonate-based crosslinked polymeric micelles for drug delivery

Our objective was to synthesize and evaluate lactic acid- and carbonate-based biodegradable core- and core-co- rona crosslinkable copolymers for anticancer drug delivery. Methoxy poly(ethylene glycol)-b-poly(carbonate-co-lactide-co- 5-methyl-5-allyloxycarbonyl-1,3-dioxane-2-one) (mPEG-b-P(CB- co-LA-co-MAC)) and methoxy poly(ethylene glycol)-b-poly(acry- loyl carbonate)-b-poly(carbonate-co-lactide) (mPEG-b-PMAC-b- P(CB-co-LA)) copolymers were synthesized by ring-opening polymerization of LA, CB, and MAC using mPEG as an macroi- nitiator and 1,8-diazabicycloundec-7-ene as a catalyst. These amphiphilic copolymers which exhibited low polydispersity and critical micelle concentration values (0.8-1 mg/L) were used to prepare micelles with or without drug and stabilized by crosslinking via radical polymerization of double bonds introduced in the core and interface to improve stability. mPEG114-b-P(CB8-co-LA35-co-MAC2.5) had a higher drug encap- sulation efficiency (78.72% 6 0.15%) compared to mPEG114-b- PMAC2.5-b-P(CB9-co-LA39) (20.29% 6 0.11%). 1 H NMR and IR spectroscopy confirmed successful crosslinking (� 70%) while light scattering and transmission electron microscopy were used to determine micelle size and morphology. Crosslinked micelles demonstrated enhanced stability against extensive dilution with aqueous solvents and in the presence of physio- logical simulating serum concentration. Furthermore, bicaluta- mide-loaded crosslinked micelles were more potent compared to non-crosslinked micelles in inhibiting LNCaP cell prolifera- tion irrespective of polymer type. Finally, these results suggest crosslinked micelles to be promising drug delivery vehicles for chemotherapy. V C 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 000: 000-000, 2012

Guanosine-based antiviral acyclovir incorporated in ring-opening polymerization of ɛ-caprolactone

Disease prevention, diagnosis and treatment are constantly being advanced thanks to many possible offerings from nanoscale technologies. Nanoparticles encompass a wide variety of devices including but not limited to: carbon nanotubes, self-assembled polymeric nanoconstructs and nanobiosensors which can mimic or alter biological processes. Due to the fact that nanoparticles can be prepared using a variety of polymers, biodegradable polymers have been studied extensively. Considerable research has been conducted in the preparation of a variety of biodegradable polymeric nanoparticles for drug delivery. Polymeric nanoparticles are a choice delivery system because they can easily be manipulated and tailored to a drug or delivery sites’ specific needs. At the very least, a good drug carrier requires at least two criteria: first, is the ability to enhance a drug’s bioavailability and second, is controlled release of the drug. Ideal polymer nanocarriers therefore require multiple components which together enhance the drug’s efficiency. Acyclovir (ACV), commercially known as Zovirax, is a guanosine-based drug most commonly used for the treatment of infections caused by herpes simplex virus (HSV) type 1 and 2, varicella zoster virus and to a lesser extent cytomegalovirus and Epstein-Barr virus. Therapeutic benefits of using ACV to treat ocular infections and cutaneous infections caused by HSV type 1 and 2 have been extensively studied. In addition, studies have shown that ACV is an effective prodrug for gene-directed enzyme prodrug therapy (GDEPT), particularly, in regards to herpes simplex type-1 thymidine kinase (HSV-tk). Delivery of ACV to the basal epidermis, ophthalmic epithelium or even to cancer cells for GDEPT has proven difficult due to ACV’s poor water solubility and ensuing low bioavailability. Methods reported to increase the solubility of ACV are by coupling it to a biocompatible hydrophilic polymer (i.e., poly(ethylene glycol)) or polysaccharide (i.e. dextran). Alternative approaches to improve delivery efficiency of ACV to the targeted cells is through biocompatible drug delivery systems in a nano-sized platform such as polymeric micelles. Polycaprolactone (PCL), due to its low toxicity, biodegradability and biocompatibility, has been widely used in biomedical applications such as tissue engineering and drug delivery systems. Hydrophobic polyester PCL is commonly synthesized via ring-opening polymerization of e-caprolactone (e-CL) initiated by the primary hydroxyl group of an alcohol in the presence of a metal catalyst. Direct activation of monomer at the carbonyl oxygen with Sn(II)2-ethylhexanoate (Sn(Oct)2) is the mechanism for lactone polymerization. Using Sn(Oct)2 as a catalyst is favored for a variety of reasons, including its low cost, low toxicity and high efficiency. As a first step towards the formation of ACV-containing polymeric micelles for drug delivery, we developed in this study a novel technique for direct synthesis of ACV-PCL through the ring-opening polymerization of e-CL initiated by the primary hydroxyl group on ACV. Through H NMR, FTIR and GPC analysis, the structure of newly synthesized ACV-PCL was characterized and confirmed.

Mesoscopic simulations on the aggregation behavior of pH-responsive polymeric micelles for drug delivery

Computer simulations, dissipative particle dynamics (DPD) and mesoscopic dynamics (MesoDyn), are performed to study the aggregation behavior of pH-sensitive micelles self-assembled from amphiphilic polymer poly(methyl methacrylate- co-methacrylic acid)- b-poly(poly-(ethylene glycol) methyl ether monomethacrylate), P(MMA- co-MAA)- b-PPEGMA. Ibuprofen (IBU) is selected as the model drug. It can be seen from DPD simulations that P(MMA- co-MAA)- b-PPEGMA and IBU form spherical core–shell micelles at certain compositions, and IBU molecules distribute inside the core formed by hydrophobic MMA. The polymer molecules aggregate first, and then IBU diffuses into the aggregate, forming drug-loaded nanoparticles. With different compositions of polymer and IBU, aggregate morphologies in water are observed as sphere, column and lamella. From MesoDyn results, with less hydrophobic MMA beads, the polymer chains are more difficult to form ordered aggregates, and the order parameters get equilibrated in a longer time. The pH value also affects the aggregate process. At pH < 5, the polymer could form traditional core–shell micelles. But at pH > 5, the morphology of micelles is found to be anomalous and loose for releasing drug. MAA aggregates on the surface, instead of the inside. The simulation results are qualitatively consistent with the experimental results.

Micellar carrier based on methoxy poly(ethylene glycol)-block-poly(ε-caprolactone) block copolymers bearing ketone groups on the polyester block for doxorubicin delivery

Block copolymers of Methoxy poly(ethylene glycol)-block-poly(epsilon-caprolactone) bearing ketone groups (MPEG-b-P(CL-co-OPD)) are synthesized and evaluated for its potential to form micelles containing doxorubicin (DOX), a representative anticancer drug, by using an in vitro method based on membrane dialysis to emulate drug release in vivo. The (1)H NMR spectra of the prepared block copolymers in D(2)O solution exhibit peaks due to the P(OPD-co-CL) in decreased intensity, indicates that the polymers form micelle particles containing the hydrophilic segments in their external parts. The CMC of the copolymer decrease with an increase in the content of ketone groups in the hydrophobic chain. Drug-free and drug-loaded solutions of structurally related copolymers indicate the polymeric aggregation into micellar-type constructs. The size of the drug-loaded micelles is found to be larger than corresponding drug-free micelles. The release rate of MPEG-b-PCL micelles is faster than MPEG-b-P(OPD-co-CL) micelles in pH 7.4 buffered solution and they have a similar release rate in pH 5.0 buffered solution. This study, therefore, confirms the potential of a novel functional block copolymers, Methoxy poly(ethylene glycol)-block-poly(epsilon-caprolactone) bearing ketone Groups, for the formation of polymeric micelles for drug delivery.

ChemInform Abstract: RAFT Polymerization: An Avenue to Functional Polymeric Micelles for Drug Delivery

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Editorial for Theme Section on Polymeric Micelles for Drug Delivery

Editorial for Theme Section on Polymeric Micelles for Drug Delivery

RAFT polymerization: an avenue to functional polymeric micelles for drug delivery

RAFT (Reversible addition fragmentation chain transfer) polymerization is demonstrated as a versatile tool to obtain functional and crosslinked micelles for drug delivery purposes.

Polymeric Micelles for Drug Delivery

Polymeric micelles are nanoscopic core/shell structures formed by amphiphilic block copolymers. Both the inherent and modifiable properties of polymeric micelles make them particularly well suited for drug delivery purposes. An emphasis of this review has been placed on both the description and characterization techniques of the physical properties of polymeric micelles. Relevant properties discussed include micellar association, morphology, size and stability. These properties and characterization techniques are included to provide context for the known advantages and applications of polymeric micelles for drug delivery. The advantages and applications discussed include solubilization of poorly soluble molecules, sustained release and size advantages, and protection of encapsulated substances from degradation and metabolism. The three most widely studied block copolymer classes are characterized by their hydrophobic blocks, and are poly(propylene oxide), poly(L-amino acid)s and poly(ester)s. These three classes of block copolymers are reviewed with multiple examples of current research in which formulation techniques with polymeric micelles have been applied to some of the most challenging molecules in the pharmaceutical industry. The polymeric micelles used for drug delivery in these examples have shown the abilities to attenuate toxicities, enhance delivery to desired biological sites and improve the therapeutic efficacy of active pharmaceutical ingredients.

Polymeric micelles for drug delivery

Polymeric micelles have been the subject of many studies in the field of drug delivery for the past two decades. The interest has specifically been focused on the potential application of polymeric micelles in three major areas in drug delivery: drug solubilisation, controlled drug release and drug targeting. In this context, polymeric micelles consisting of poly(ethylene oxide)-b-poly(propylene oxide), poly(ethylene oxide)-b-poly(ester)s and poly(ethylene oxide)-b-poly(amino acid)s have shown a great promise and are in the front line of development for various applications. The purpose of this manuscript is to provide an update on the current status of polymeric micelles for each application and highlight important parameters that may lead to the development of successful polymeric micellar systems for individual delivery requirements.