Micelles For Drug Delivery Research Articles

Dendrimeric Micelles for Controlled Drug Release and Targeted Delivery

This review highlights the developments in dendrimer-based micelles for drug delivery. Dendrimers, the perfectly branched monodisperse macromolecules, have certain structural advantages that make them attractive candidates as drug carriers for controlled release or targeted delivery. As polymeric micelle-based approaches precede the work in dendrimers, these are also discussed briefly. The review concludes with a perspective on possible applications of biaryl-based dendrimeric micelles that exhibit environment-dependent conformations, in drug delivery.

Synthesis of a novel PEG- block-poly(aspartic acid- stat-phenylalanine) copolymer shows potential for formation of a micellar drug carrier

A novel functionalised copolymer with three polymeric components, poly(ethylene glycol)- block-poly(aspartic acid- stat-phenylalanine), PEG-P(asp-phe), was synthesised and investigated for its potential to form micelles via ionic interactions with a model water-soluble drug, diminazene aceturate. Drug-free solutions of structurally related PEG-P(asp-phe) 5:6:4 and PEG-P(asp-phe) 5:4:6 copolymers indicated polymeric aggregation into micellar-type constructs. The size of PEG-P(asp-phe) 5:6:4 micelles was found to be pH and drug content-dependent. The drug-loaded systems existed as discreet units and were fairly uniform in size and shape. More drug could be included in the PEG-P(asp-phe) 5:6:4 micelles as compared to if only interaction with carboxyl groups from aspartic acid units was responsible for micelle formation, indicating the augmentative role of phenylalanine moieties in drug-incorporation. The slower in vitro drug release from PEG-P(asp-phe) 5:6:4 micelles as compared to PEG-Pasp (AB) micelles indicated the role of the phenylalanine moiety in controlling drug release. This study, therefore, confirmed the potential of a novel tri-component copolymer structure, PEG-P(asp-phe), for the formation of polyionic micelles for drug delivery.

Stabilization and acoustic activation of polymeric micelles for drug delivery

Methods are disclosed in which a micelle is stabilized against degradation upon dilution. The micelle comprises molecules of a block polymer having a hydrophobic block and a hydrophilic block. The hydrophobic block forms a core of the micelle with corona from the hydrophilic block. The methods for stabilizing the core are (1) by chemically cross-linking, (2) incorporating a hydrophobic oil (vegetable oil) in the core to render it more hydrophobic and stable, and (3) incorporating a cross-linked interpenetrating network of a stimuli-responsive hydrogel into the core. The hydrogel is responsive to any stimuli, but preferably temperature or pH. A substance such as drugs can be incorporated into the dense inner core of the micelles. When subjected to ultrasound, the micelles release the substance, and then reversibly revert to a stable dense core and re-encapsulating the substance when the ultrasound is turned off. By pulsing the ultrasound, it is therefore, to controllably release the substance in a pulsed manner corresponding to the ultrasound signal.

Development of acid-sensitive copolymer micelles for drug delivery

Abstract In recent years, supramolecular micellar assemblies formed from amphiphilic block copolymers have been receiving attention as potential drug carriers. The size of the carriers is ideal for avoiding rapid renal exclusion and reticuloendothelial uptake, and enables them to be targeted to certain tissues such as tumors. One important issue determining the effectiveness of a micellar drug carrier is the ability to control the time over which drug release takes place, or to possibly trigger drug release at a specific location or time. The mildly acidic pH encountered in tumor and inflammatory tissues as well as in the endosomal and lysosomal compartments of cells has inspired the development of micellar carriers capable of releasing their drug load in response to small changes in pH. One approach to the development of these systems has been to incorporate “titratable” groups such as amines and carboxylic acids into the copolymer backbone, thus altering the solubility of the polymer upon protonation and disrupting micelle formation. Another approach has been to incorporate acid-degradable linkages into the copolymer, either for direct attachment of the drug, or to cause a structural change of such magnitude that micellar integrity is lost and the drug is released.

A polymeric micellar carrier for the solubilization of biphenyl dimethyl dicarboxylate.

A polymeric micelle drug delivery system was developed to enhance the solubility of poorly-water soluble drug, biphenyl dimethyl dicarboxylate, DDB. The block copolymers consisting of poly(D,L-lactide) (PLA) as the hydrophobic segment and methoxy poly(ethylene glycol) (mPEG) as the hydrophilic segment were synthesized and characterized by NMR, DSC and MALDI-TOF mass spectroscopy. The size of the polymeric micelles measured by dynamic light scattering showed a narrow monodisperse size distribution with the average diameter less than 50 nm. The MW of mPEG-PLA, 3000 (MW of mPEG, 2 K; MW of PLA, 1 K), and the presence of hydrophilic and hydrophobic segments on the polymeric micelles were confirmed by MALDI-TOF mass spectroscopy and NMR, respectively. Polymeric micelle solutions of DDB were prepared by three different methods, i.e. the matrix method, emulsion method and dialy-sis method. In the matrix method, DDB solubility was reached to 13.29 mg/mL. The mPEG-PLA 2K-1 K micelle system was compared with the poloxamer 407 micelle system for their critical micelle concentration, micelle size, solubilizing capacity, stability in dilution and physical state. DDB loaded-polymeric micelles prepared by the matrix method showed a significantly increased aqueous solubility (>5000 fold over intrinsic solubility) and were found to be superior to the poloxamer 407 micelles as a drug carrier.

A new approach towards acid sensitive copolymer micelles for drug delivery.

A new micellar system capable of selective release of its contents under mildly acidic conditions is described.

Incorporation and Release of Hydrophobic Probes in Biocompatible Polycaprolactone-block-poly(ethylene oxide) Micelles: Implications for Drug Delivery

Block copolymer micelles have shown high potential as hydrophobic drug carriers. The loading efficiency, partition coefficient, and release profile all play critical roles in micellar drug delivery. As part of a series of studies on these polycaprolactone-block-poly(ethylene oxide) (PCL-b-PEO) micelles in drug delivery, we investigated the solubilization and release of the hydrophobic probes, benzo[a]pyrene and Cell-Tracker CM-DiI (DiI) from these micelles using fluorescence spectroscopy. The same method was also used to determine the partition coefficients of each probe between the core and the exterior solution, which were calculated at different solvent compositions and extrapolated to 100% water. The maximum loading efficiencies of DiI and benzo[a]pyrene were 87% and 32%, respectively. The large difference in the loading efficiency is related to the values of the partition coefficients, which were calculated to be 5800 for DiI and 700 for benzo[a]pyrene. DiI is more highly miscible with the polycaprolactone core compared to benzo[a]pyrene. The release of the hydrophobic probes from the micelles showed a biphasic profile under “perfect sink” conditions; there is an initial burst release, followed by a slow and prolonged release until, eventually, complete release is achieved. The release of the probes from the micelles is under diffusion control as shown by the linearity of the release as a function of the square root of time. Approximate diffusion constants of the order of 10-15 cm2/s for DiI and benzo[a]pyrene were obtained. We demonstrate that the type and the concentration of the incorporated agent influence the loading and the release from PCL-b-PEO micelles. In addition to providing new information on the incorporation and release of benzo[a]pyrene and DiI from these micelles, this study also demonstrates the importance of probe−micelle compatibility in the evaluation of a micellar drug delivery system.

Poly(ethylene oxide)- block-poly( l-amino acid) micelles for drug delivery

Block copolymer micelles encapsulate water insoluble drugs by chemical and physical means, and they may target therapeutics to their site of action in a passive or active way. In this review, we focus on micelles self-assembled from poly(ethylene oxide)- block-poly( l-amino acid) (PEO- b-PLAA). A common theme in these studies is the chemical modification of the core-forming PLAA block used to adjust and optimize the properties of PEO- b-PLAA micelles for drug delivery. Micelle-forming block copolymer–drug conjugates, micellar nanocontainers and polyion complex micelles have been obtained that mimic functional aspects of biological carriers, namely, lipoproteins and viruses. PEO- b-PLAA micelles may be advantageous in terms of safety, stability, and scale-up.

Optimizing pH-responsive Polymeric Micelles for Drug Delivery in a Cancer Photodynamic Therapy Model

Different pH-sensitive, randomly- and terminally-alkylated N -isopropylacrylamide (NIPAM) copolymers were synthesized and used to prepare pH-responsive polymeric micelles (PM). These copolymers were modified from previously-studied copolymers by incorporating an additional hydrophilic monomer, N- vinyl-2-pyrrolidone (VP) to decrease uptake by the mononuclear phagocyte system (MPS) and improve localization in tumors. VP lowered the phase transition pH of the copolymers but did not affect the onset of micellization. The in vitro cytotoxicity of the copolymers was evaluated on EMT-6 mouse mammary tumor cells in comparison to Cremophor EL (CRM). The anticancer photosensitizer aluminum chloride phthalocyanine (AlClPc) was loaded into the PM with a standard dialysis procedure. Biodistribution and in vivo photodynamic activity were then evaluated in Balb/c mice bearing intradermal EMT-6 tumors. All NIPAM copolymers demonstrated substantially lower cell cytotoxicity than the control surfactant CRM. In vivo, similar AlClPc tumor uptake was observed for the PM and CRM formulations. However, the PM appeared to exhibit greater activity in vivo than CRM formulation at an AlClPc subtherapeutic dose. Therefore, NIPAM-based copolymers containing VP units represent promising alternatives for the formulation of poorly water-soluble phthalocyanines.

Drug–polyionic block copolymer interactions for micelle formation: physicochemical characterisation

While covalent attachment of small drug molecules to AB copolymers for the formation of polymeric micelles for drug delivery has been investigated, few studies have focused on non-covalent interactions. The aim of this study was therefore to explore the potential of non-covalent interactions between an AB copolymer, Poly(aspartic acid)–poly(ethylene glycol) (Pasp–PEG), with anionic pendant groups and diminazene aceturate, a small molecular weight cationic drug. Micelles were prepared by mixing solutions of Pasp–PEG and diminazene in 25 mM Tris–HCl buffer. At all Pasp–PEG concentrations studied, the micelles appeared to be water soluble with a unimodal size distribution and ranged in size from approximately 22 to 60 nm. The polyionic micelles also displayed similar and small absolute zeta potential values at various drug:monomer molar ratios which confirmed stabilisation by the PEG corona. The scattering intensity was maximal and remained unchanged, while particle size increased slightly at pH range from 3.4 to 7.2. At this pH range both the polymer and drug would be ionised and ionic interactions possible to drive micellar formation. An increase in size and scattering intensity with addition of NaCl to the micelles was attributed to dehydration of the PEG corona which may have led to aggregation of the micelles. The absence of micellar dissociation upon addition of salt was attributed to the dominance of hydrogen bonding between Pasp and diminazene aceturate, as assessed by isothermal titration microcalorimetry. Morphological evaluation of these constructs showed them to be discrete and fairly uniform in size and shape. This study was therefore successful in confirming the potential of non-covalent interactions using an AB copolymer to form polyionic micelles for drug delivery.

Block copolymer micelles for drug delivery: design, characterization and biological significance

Recently, colloidal carrier systems have been receiving much attention in the field of drug targeting because of their high loading capacity for drugs as well as their unique disposition characteristics in the body. This paper highlights the utility of polymeric micelles formed through the multimolecular assembly of block copolymers as novel core–shell typed colloidal carriers for drug and gene targeting. The process of micellization in aqueous milieu is described in detail based on differences in the driving force of core segregation, including hydrophobic interaction, electrostatic interaction, metal complexation, and hydrogen bonding of constituent block copolymers. The segregated core embedded in the hydrophilic palisade is shown to function as a reservoir for genes, enzymes, and a variety of drugs with diverse characteristics. Functionalization of the outer surface of the polymeric micelle to modify its physicochemical and biological properties is reviewed from the standpoint of designing micellar carrier systems for receptor-mediated drug delivery. Further, the distribution of polymeric micelles is described to demonstrate their long-circulating characteristics and significant tumor accumulation, emphasizing their promising utility in tumor-targeting therapy. As an important perspective on carrier systems based on polymeric micelles, their feasibility as non-viral gene vectors is also summarized in this review article.

Thermo-responsive self-assembled polymeric micelles for drug delivery in vitro

Cholic acid (CA) was coupled with amine-terminated poly ( N-isopropylacrylamide) (ATPNIPAAm) using N,N′-dicyclohexyl carbodiimide as a coupling agent. Self-assembled CA/PNIPAAm conjugate (abbreviated as CN) micelles were prepared by diafiltration method in water. The CN micelles exhibited the lower critical solution temperature (LCST) at 31.5°C. The CN micelles were observed as spherical shapes and their dried sizes were ranged between 30 and 50 nm by the transmission electron microscope (TEM) images. Hydrated micelle sizes measured by photon correlation spectroscopy (PCS) were ranged 337.5±67.8 nm. And reversible size changes of CN micelles were observed with two point temperature 10 and 40°C, respectively. From the fluorescence spectra, fluorescence intensity of pyrene in the CN micelles was increased and red-shifted as the concentration of CN increased, indicating the formation of self-assembled polymeric micelles in water. The critical micelle concentration (CMC) was evaluated as 8.9×10 −2 g/l. Much more indomethacin (IN) was released from the CN micelles at 10 than at 40°C due to the thermo-sensitivity of the PNIPAAm in the CN polymer.

The Role of Mixed Micelles in Drug Delivery. I. Solubilization

The present study revealed that the solubilization of a poorly soluble drug, Amphotericin-B (AmB) can be improved by lipid-bile salt mixed micelles and it was also noted that mixed micellar systems are thermodynamically stable relative to micellar systems. It was observed that the degradation or precipitation of AmB was significantly reduced when stored at 8°C. The mixed micellar systems composed of sodium desoxycholate with monoolein increased the solubilization of AmB by more than seven-fold as compared to nonmicellar systems.

Block copolymer micelles for drug delivery: loading and release of doxorubicin

Micelles of poly(ethylene oxide)- block-poly(β-benzyl- l-aspartate) (PEO-PBLA) were loaded with doxorubicin (DOX) and were characterized in relation to their use as drug vehicles. First, an oil-in-water emulsion method was developed to load DOX in PEO-PBLA micelles. The level of DOX in PEO-PBLA micelles was 5–12% w/w. Whereas the mean diameter of unloaded, PEO-PBLA micelles was ca., 19 nm, the mean diameter of PEO-PBLA micelles loaded with DOX was ≈37 nm. Minimal chemical degradation of DOX occurred as a result of loading in PEO-PBLA micelles. In addition, DOX in PEO-PBLA micelles was less susceptible to chemical degradation than free DOX in aqueous solution. There was evidence for retention of DOX in PEO-PBLA micelles even after freeze-drying and reconstitution in water. Lastly, PEO-PBLA micelles served as drug depots, slowly releasing DOX (days), even in the presence of 10% w/v serum albumin. The results suggest a number of pharmaceutical advantages of PEO-PBLA micelles for the delivery of DOX.

Mixed micelles in drug delivery

Large disk-like mixed micelles composed of a drug and biological lipid are thermodynamically stable and represent a novel drug delivery system. Their unique physical properties are reflected in a significantly improved therapeutic index.