Elsevier

Progress in Polymer Science

Volume 34, Issue 9, September 2009, Pages 893-910
Progress in Polymer Science

Thermo-sensitive polymeric micelles based on poly(N-isopropylacrylamide) as drug carriers

https://doi.org/10.1016/j.progpolymsci.2009.05.002Get rights and content

Abstract

Amphiphilic copolymers are well developed as precursors for the preparation of micellar drug carriers. Poly(N-isopropylacrylamide) (PNIPAAm) is one of the most extensively studied thermo-sensitive polymers that exhibits a lower critical solution temperature (LCST) at around 33 °C in aqueous solution. Over the past decade, considerable efforts have been devoted to design and preparation of PNIPAAm-based thermo-sensitive polymeric micelles as delivery vehicles for controlled drug release. Present review highlights the recent developments in this field, and focuses on two categories of PNIPAAm-based copolymer micelles as smart drug delivery systems, i.e. micelles with PNIPAAm as hydrophilic shell-forming segments below the LCST and micelles with PNIPAAm as hydrophobic core-forming segments above the LCST.

Introduction

Over the past decade, micelles formed by self-assembly of amphiphilic copolymers combining hydrophilic and hydrophobic segments for drug delivery have attracted much attention because they possess many advantages over other particulate drug carriers [1], [2], [3], [4]. For example, the hydrophobic micelle core creates a microenvironment for the incorporating of lipophilic drugs, resulting in significantly enhanced solubility of hydrophobic drugs to achieve improved bioavailability. At the same time, the hydrophilic shell provides a stabilizing interface between the hydrophobic core and the aqueous medium, which enhances dispersion and inhibits aggregation and interactions with other hydrophobic components. In addition, the hydrophilic shell could stabilize the drug-loaded micelles in the bloodstream to achieve the long circulation in the body when the concentration of the polymer is higher than low critical micelle concentration (CMC). Besides, the nano-scaled micelles with a small size (<200 nm) reduce non-selective uptake by the reticuloendothelial system (RES), and show the enhanced permeability and retention effect (EPR effect) at solid tumor tissue sites, which is defined as passive targeting [5], [6], [7], [8], [9], [10].

However, traditional micelles are unable to sense a signal and respond by changing their structures. To develop stimuli-responsive micelles sensitive to environmental changes, the polymers with stimuli-responsive properties were synthesized by introducing stimulus-responsive moiety into the polymer structure [11], [12], [13]. To date, numerous distinctive intelligent nano-scaled micelles, such as temperature [14], [15], [16], pH [17], [18] and magnetic field [19], [20] responsive micelles have been reported in drug delivery applications.

Temperature sensitivity is one of the most interesting properties in stimuli-responsive polymers. The most extensively investigated temperature sensitive polymer, poly(N-isopropylacrylamide) (PNIPAAm), exhibits a lower critical solution temperature (LCST) of approximately 33 °C in aqueous solution, below which PNIPAAm is water soluble and above which it becomes water insoluble [21], [22]. Based on the thermo-sensitive property of PNIPAAm, many PNIPAAm contained copolymers have been developed, which were utilized to prepare thermo-sensitive micelles as drug carriers [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77], [78], [79], [80], [81], [82], [83], [84], [85], [86], [87], [88], [89], [90], [91], [92], [93]. The strategy to use thermo-sensitive polymeric micelles aims at achieving temporal drug delivery control, i.e. changing the temperature of the environment slightly above or below the LCST can result in destabilization of the micelles and trigger a burst-like release of the encapsulated drug [2]. In other words, the drug release could be controlled by local heating or cooling during a particular time period. In addition, it is worth pointing out that the LCST of PNIPAAm-based polymers can be facilely tuned via copolymerization with hydrophilic or hydrophobic monomers.

This review highlights the very recent advances in PNIPAAm-based temperature sensitive polymeric micelles, with the emphasis on their applications in drug delivery. Since the thermo-sensitive PNIPAAm segments can be incorporated to either micelle shells or cores, the present review classifies the polymeric micelles based on PNIPAAm as smart drug delivery systems into two categories, i.e. micelles with PNIPAAm as hydrophilic shell-forming segments below the LCST and micelles with PNIPAAm as hydrophobic core-forming segments above the LCST. Additionally, a brief outlook into academic research as well as future practical applications in this fast developing realm is addressed at the end of this review.

Section snippets

Micelles with PNIPAAm as shell-forming segments

The copolymers consisting of PNIPAAm segments and hydrophobic segments can form core–shell micellar structure with a hydrophilic outer shell composed of hydrated PNIPAAm segments below the LCST of PNIPAAm and a hydrophobic inner core. The inner core domain can be loaded with hydrophobic drugs, while the PNIPAAm outer shell plays the role in aqueous solubilization as well as temperature responsiveness. The hydrophilic PNIPAAm outer shell, which prevents the inner core from interacting with

Micelles with PNIPAAm as core-forming segments

Double hydrophilic block copolymers (DHBCs), as a new class of amphiphilic block copolymers, have received considerable attention within the past decade due to their important roles and potential applications in diverse fields such as drug delivery, coatings, interface mediators, rheology modifiers, sensors, soft actuators/valves, catalysis and templates for the preparation of nanomaterials. Under a proper adjustment of external conditions such as pH, temperature, and ionic strength, one of the

Prospects

With the major goal of developing multifunctional micelles, thermo-sensitive polymeric micelles based on PNIPAAm have been extensively reported and their thermo-sensitivity has been frequently combined with other stimuli-responsibilities, such as pH-sensitivity, as well as biodegradability. In addition, other important strategies which have been employed to prepare multifunctional micelles include (i) chemical cross-linking of the micellar core or shell to improve the stability of resulting

Acknowledgments

The authors are grateful for the financial support from National Key Basic Research Program of China (2005CB623903), National Natural Science Foundation of China (50633020) and Ministry of Education of China (Cultivation Fund of Key Scientific and Technical Innovation Project 707043).

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