Review article
Polymeric micelles – a new generation of colloidal drug carriers

https://doi.org/10.1016/S0939-6411(99)00039-9Get rights and content

Abstract

Polymeric micelles have recently emerged as a novel promising colloidal carrier for the targeting of poorly water soluble and amphiphilic drugs. Polymeric micelles are considerably more stable than surfactant micelles and can solubilize substantial amounts of hydrophobic compounds in their inner core. Due to their hydrophilic shell and small size they sometimes exhibit prolonged circulation times in vivo and can accumulate in tumoral tissues. This review examines the chemical nature of polymeric micelles as well as the methods used to characterize them with regard to drug delivery. Special emphasis is put on the determination of critical micelle concentration and on drug loading procedures. Potential medical applications, especially in cancer chemotherapy, are described and discussed.

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.

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