European Journal of Pharmaceutics and Biopharmaceutics
Review articlePolymeric micelles – a new generation of colloidal drug carriers
Introduction
In order to improve the specific delivery of drugs with low therapeutic index several drug carriers such as liposomes [1], microparticles [2], nano-associates [3], nanoparticle [4], drug polymer-conjugates [5] and polymeric micelles [6], have been developed. In recent years, polymeric micelles have been the object of growing scientific attention. They have emerged as a potential carrier for poorly water soluble drugs because they can solubilize those drugs in their inner core and they offer attractive characteristics such as a generally small size (<100 nm) and a propensity to evade scavenging by the mononuclear phagocyte system (MPS) [7]. They were first proposed as drug carriers by Bader et al. in 1984 [8]. Micelles are often compared to natural occurring carriers such as viruses or lipoproteins [9], [10]. All three carriers demonstrate a similar core-shell structure that allows for their content to be protected while it is transported to the target cell, whether it is DNA for viruses or water-insoluble drugs for lipoproteins and micelles.
Lipoproteins were proposed as a vehicle for the targeting of antitumor compounds to cancer cells because tumors express an enhanced need for low density lipoproteins [11]. However, their efficiency as carriers has been questioned, mainly because drug-incorporated lipoproteins would also be recognized by healthy cells and because they would have to compete with natural lipoproteins for receptor sites on tumors [12]. On the other hand, viral carriers are mainly used for the delivery of genetic material and may have optimal use in applications that do not require repeated application of the delivery vehicle, since they are likely to elicit an immune response [13].
At the present time, polymeric micelles seem to be one of the most advantageous carriers for the delivery of water-insoluble drugs, although some questions may arise regarding their stability in plasma. The present work briefly reviews the preparation, characterization and potential applications of polymeric micelles as drug carriers.
Section snippets
Chemical nature of polymeric micelles
Polymeric micelles are characterized by a core-shell structure. Pharmaceutical research on polymeric micelles has been mainly focused on copolymers having an A-B diblock structure with A, the hydrophilic (shell) and B, the hydrophobic polymers (core), respectively (Fig. 1, left part). Multiblock copolymers such as poly(ethylene oxide)–poly(propylene oxide)–poly(ethylene oxide) (PEO–PPO–PEO) (A–B–A) can also self organize in micelles [14], [15] and have been described as potential drug carriers
Characterization
The use of polymeric micelles as drug carriers requires the determination of several important parameters. In this section the micellization process is briefly described and some methods commonly used for the characterization of polymeric micelles are reviewed.
Drug loading procedures
Insoluble drugs can be incorporated in micelles by chemical conjugation or by physical entrapment through dialysis or emulsification techniques (Fig. 4). The simple equilibration of the drug and micelles in water may not result in high levels of incorporated drug [72], [73]. Chemical conjugation implies the formation of a covalent bond, such as an amide bond, between specific groups on the drug and the hydrophobic polymer of the core. Such bonds are resistant to enzymatic cleavage mainly
Pharmaceutical applications
Theoretically, polymeric micelles may find practical applications in a variety of pharmaceutical fields, from oral delivery to sustained release and site-specific drug targeting. However, until now polymeric micelles have been almost exclusively evaluated for the parenteral administration of anticancer drugs. This section briefly analyses the recent advances in the delivery of drugs using polymeric micelles, and the reader is referred to the recent review by Yokoyama [6] for a more
Conclusion
Because of their distinct advantages, such as small size, high solubility, simple sterilization, controlled release of drugs, polymeric micelles seem to be the prototype of an ideal carrier for poorly water soluble drugs. However, the physical stability of this carrier is a critical issue since rapid release of the incorporated drug may occur in vivo. Still little is known about the interaction of polymeric micelles with plasmatic and cellular components, and much work remains to be done in
Acknowledgements
S. Guirguis is acknowledged for her critical reading of the manuscript.
References (102)
- et al.
microparticles for the delivery of polypeptides and proteins
Adv. Drug Deliv. Syst.
(1993) - et al.
Self-assembled hydrogel nanoparticle of cholesterol-bearing pullulan as a carrier of protein drugs: complexation and stabilization of insulin
J. Control. Rel.
(1998) - et al.
Polymeric micelles as new drug carriers
Adv. Drug Deliv. Rev.
(1996) - et al.
Surface activity and association of ABA polyoxyethylene-polyoxypropylene block copolymers in aqueous solution
J. Colloid Interface Sci.
(1979) - et al.
The neuroleptic activity of haloperidol increases after its solubilization in surfactant micelles
FEBS Lett.
(1989) - et al.
Preparation and characterization of the micelle-forming polymeric drug indomethacin-incorporated poly(ethylene oxide)-poly(β-benzyl l-aspartate) block copolymer micelles
J. Pharm. Sci.
(1996) - et al.
Biodistribution of immunoliposomes
Biochim. Biophys. Acta
(1986) - et al.
Introduction of cisplatin into polymeric micelles
J. Control. Rel.
(1996) - et al.
An AB block copolymer of oligo(methyl methacrylate) and poly(acrylic acid) for micellar delivery of hydrophobic drugs
J. Control. Rel.
(1998) - et al.
Use of polyethylene-lipid conjugates as long-circulating carriers for delivery of therapeutic and diagnostic agents
Adv. Drug Deliv. Rev.
(1995)
Thermo-responsive polymer nanoparticles with a core-shell micelle structure as site-specific drug carriers
J. Control. Rel.
Reversibly thermo-responsive alkyl-terminated poly(N-isopropylacrylamide) core-shell structures
Colloids Surfaces (B: Biointerfaces)
Effect of molecular architecture of hydrophobically modified poly(N-isopropylacrylamide) on the formation of thermoresponsive core-shell micellar drug carriers
J. Control. Rel.
Improved synthesis of adriamycin-conjugated poly(ethylene oxide)-poly(aspartic acid) block copolymer and formation of unimodal micellar structure with controlled amount of physically entrapped adriamycin
J. Control. Rel.
Development of amphiphilic diblock copolymers as micellar carriers of taxol
Int. J. Pharm.
Determination of surfactant micelle concentration by a novel fluorescence depolarization technique
J. Biochem. Biophys. Methods
Interaction studies of styrene-ethylene oxide block copolymers with ionic surfactants in aqeuous solution
Colloids Surf.
Incorporation of water-insoluble anticancer drug into polymeric micelles and control of their particle size
J. Control. Rel.
Preparation and characterization of thermally responsive block copolymer micelles comprising poly(N-isopropylacrylamide-b-dl-lactide)
J. Control. Rel.
Polymeric micelles for drug delivery: solubilization and haemolytic activity of amphotericin B
J. Control. Rel.
Methoxy poly(ethylene glycol) and ϵ-caprolactone amphiphilic block copolymeric micelle containing indomethacin
II. Micelle formation and drug release behaviors, J. Control. Rel.
Influencing factors on in vitro micelle stability of adriamycin-block copolymer conjugates
J. Control. Rel.
Block copolymer micelles for drug delivery: loading and release of doxorubicin
J. Control. Rel.
Remarkable increase in nuclease resistance of plasmid DNA through supramolecular assembly with poly(ethylene glycol)-poly(l-lysine) block copolymer
J. Pharm. Sci.
Characterization of physical entrapment and chemical conjugation of adriamycin in polymeric micelles and their design for in vivo delivery to a solid tumor
J. Control. Rel.
Enhanced tumor accumulation and prolonged circulation times of micelle-forming poly(ethylene oxide-aspartate) block copolymer-adriamycin conjugates
J. Control. Rel.
Delivery of molecular and cellular medicine to solid tumors
Adv. Drug Deliv. Rev.
Human plasma distribution of free paclitaxel and paclitaxel associated with diblock copolymers
J. Pharm. Sci.
In vitro dissociation of antifungal efficacy and toxicity for amphotericin B-loaded poly(ethylene oxide)-block-poly(β-benzyl-l-aspartate) micelles
J. Control. Rel.
Copolymers of N-isopropylacrylamide can trigger pH sensitivity to stable liposomes
FEBS Lett.
Phosphatidylethanolamine liposomes: drug delivery, gene transfer and immunodiagnostic applications, Biochim
Biophys. Acta
Doxorubicin in sterically stabilized liposomes
Nature
émann
R. Gurny, E. Doelker, Drug loaded nanoparticles – Preparation methods and drug targeting issues, Eur. J. Pharm. Biopharm.
Drug-polymer conjugates: potential for improved chemotherapy
Anti-Cancer Drugs
Novel passive targetable drug delivery with polymeric micelles
Water soluble polymers in medicine
Angew. Makromol. Chem.
Block copolymer micelles as vehicles for drug delivery
J. Control. Rel.
Polyethyleneglycol based micelles as carriers of therapeutic and diagnostic agents
S.T.P. Pharma Sciences
Low density lipoprotein for cytotoxic drug targeting: improved activity of elliptinium derivative against B16 melanoma in mice
Br. J. Cancer
Low-density lipoprotein as a vehicle for targeting antitumor compounds to cancer cells
Bioconjugate Chem.
Liposome delivery systems
Self-assembly in aqueous block copolymer solutions
Macromolecules
Methoxy poly(ethylene glycol)/ϵ-caprolactone amphiphilic block copolymeric micelle containing indomethacin
I. Preparation and characterization, J. Control. Rel.
Characterization and anticancer activity of the micelle-forming polymeric anticancer drug adryamicin-conjugated pol(ethylene glycol)-poly(aspartic acid) block copolymer
Cancer Res.
Preparation of micelle-forming polymer-drug conjugates
Bioconjugate Chem.
Novel polyion complex micelles entrapping enzyme molecules in the core: preparation of narrowly-distributed micelles from lysozyme and poly(ethylene glycol)-poly(aspartic acid) block copolymer in aqueous medium
Macromolecules
Spontaneous formation of polyion complex micelles with narrow distribution from antisense oligonucleotide and cationic block copolymer in physiological saline
Macromolecules
Formation of polyion complex micelles in an aqueous milieu from a pair of oppositely-charged block copolymers with poly(ethylene glycol) segments
Macromolecules
Fluorescence probe techniques used to study micelle formation in water-soluble block copolymers
Langmuir
Multiple morphologies of ‘crew-cut’ aggregates of polystyrene-b-poly(acrylic acid) block copolymers
Science
Cited by (1157)
Current paradigms in employing self-assembled structures: Drug delivery implications with improved therapeutic potential
2024, Colloids and Surfaces B: BiointerfacesImmunoregulatory effects of nanocurcumin in inflammatory milieu: Focus on COVID-19
2024, Biomedicine and PharmacotherapyHerbal approach for treatment of cancer using curcumin as an anticancer agent: A review on novel drug delivery systems
2023, Journal of Molecular LiquidsCancer treatment and toxicity outlook of nanoparticles
2023, Environmental ResearchDevelopment and Evaluation of Polymeric Mixed Micelles Prepared using Hot-Melt Extrusion for Extended Delivery of Poorly Water-Soluble Drugs
2023, Journal of Pharmaceutical Sciences