pH-sensitive micelles self-assembled from multi-arm star triblock co-polymers poly(ε-caprolactone)-b-poly(2-(diethylamino)ethyl methacrylate)-b-poly(poly(ethylene glycol) methyl ether methacrylate) for controlled anticancer drug delivery
Graphical abstract
Introduction
Due to the heterogeneity and adaptations of cancerous cells cancer therapy remains a tremendous challenge and great efforts have been devoted to cancer therapy over the past several decades. Chemotherapy plays an important role in cancer therapy and has become one of the most widely used tools in combating cancer. However, there are still various intrinsic limitations of anticancer agents, such as poor water solubility, uncontrolled pharmacokinetic processes (short duration in the circulation and improper biodistribution), and the possible occurrence of severe side-effects, which will considerably decrease the therapeutic efficacy [1], [2], [3].
Recently novel drug delivery approaches (e.g., nanoparticles, liposomes, hydrogels and polymeric micelles) have been investigated to obtain higher antitumor efficiency with reduced toxicity by altering the biodistribution of anticancer drugs [4], [5], [6], [7], [8], [9]. In addition, nanoparticles with a hollow structure have also been attracting attention because they can encapsulate drugs with high efficacy [10], [11], [12], [13]. Polymeric micelles with nanoscopic core–shell structures formed by amphiphilic co-polymers demonstrate a series of attractive properties as anticancer drug carriers, providing a high loading capacity of poorly water soluble drugs, improving the apparent water solubility, providing both passive and active targeting capabilities, altering the pathways of drug biocirculation, reducing uptake by the reticuloendothelial system (RES), prolonging the in vivo circulation duration and increasing specific accumulation within tumor tissues, thus affording enhanced therapeutic efficacy and negligible adverse effects [14], [15], [16], [17].
However, the formation of polymeric micelles is thermodynamically favorable only above the critical micelle concentration (CMC) of the amphiphilic molecules and they are relatively unstable in infinitely dilute environments. Once introduced into the bloodstream by intravenous administration polymeric micelles become thermodynamically unstable when the concentration of amphiphilic polymers drops below the CMC by severe dilution. The disruption of micellar structures might lead to the burst release of physically encapsulated drugs, which may cause serious side-effects, mostly due to large fluctuations in the drug concentration [18], [19]. All these characteristics may reduce the effectiveness of drug delivery and limit the in vivo application of polymeric micelles.
In contrast to the classical linear polymers, one promising approach to improving the thermodynamic stability of micelles is to develop star-shaped amphiphilic polymers which mimic the morphology of polymeric micelles. Star-shaped polymers, a form of dendritic polymer, present unique properties and advantages, such as a small hydrodynamic radius, a large number of arms, which are capable of forming a stable micelle structure, a low intrinsic viscosity and crystallinity, high functionality and simple synthesis, owing to their particular well-defined architecture with multiple polymer chains radiating from the central core [2], [20], [21], [22], [23]. Thus amphiphilic star-shaped co-polymers could be promising candidates for anticancer drug delivery [24], [25], [26], [27], [28], [29].
Considering the tumor targeting drug delivery field, an ideal anticancer drug carrier should retain the drug molecules in the micellar core in the bloodstream and normal tissues and release them at the specific tumor sites. So the production of pH-responsive star polymers could significantly expand the application of these polymers [26], [30], [31], [32], [33]. Compared with the normal physiological environment of pH 7.4, the extracellular pH values in tumorous tissues have been determined to be around 6.5–7.0, and the intracellular pH of the endosomal and lysosomal environments is typically acidic (pH 5.0 and 4.5–5.0) [34], [35], [36]. Poly(2-(diethylamino)ethyl methacrylate) (PDEAEMA), a cationic polyelectrolyte with a pKb of 6.9, making it soluble in acidic solution by protonation of the pendant amine groups but hydrophobic at around neutral pH, is a promising pH-sensitive material for tumor-targeted drug delivery [34], [37]. Well-defined four arm poly(ethylene oxide)-b-poly(2-(diethylamino)ethyl methacrylate) (four arm PEO-b-PDEAEMA) has been synthesized and its pH-responsive self-assembly examined. The results showed that the micelles shrank due to electrostatic charge screening of the protonated DEAEMA groups at high pH and dissociated into unimers at low pH [38]. Furthermore, four arm PEO-b-PDEAEMA micelles possessed a high gene transfection efficiency for the delivery of DNA [39]. A co-micelle drug delivery system of a star block co-polymer poly(ε-caprolactone)-block-poly(diethylamino)ethyl methacrylate (S(PCL-b-PDEAEMA)) and a linear block cpolymer methoxy poly(ethylene glycol)-block-poly(ε-caprolactone) (mPEG-b-PCL) was developed to enhance the micelle stability and improve the pH-sensitive release behavior [40].
However, the relationship between the molecular structure of the star polymers and the drug release performance has still not been clearly elaborated and the drug delivery performance of these pH-sensitive star polymeric micelles was still far from satisfactory. Thus enhancing the accuracy of the response to a stimulus and the drug delivery effectiveness and bioavailability, and forming an integrated understanding of the mechanism of drug release from star polymeric micelles are imperative [41]. We herein report pH-sensitive three layer micelles self-assembled from amphiphilic 4- and 6-arm star triblock poly(ε-caprolactone)-b-poly(2-(diethylamino)ethyl methacrylate)-b-poly(poly(ethylene glycol) methyl ether methacrylate) (4/6AS-PCL-b-PDEAEMA-b-PPEGMA) for efficient intracellular anticancer drug delivery. These micelles have a hydrophobic poly(ε-caprolactone) (PCL) to encapsulate the anticancer drug, a pH-responsive middle poly(2-(diethylamino)ethyl methacrylate) (PDEAEMA) layer and a poly(ethylene glycol) (PEG) outer layer. The pH-responsive PDEAEMA layer is hydrophobic and collapses on the core at physiological pH (7.4), which can prevent premature burst drug release, but becomes highly positively charged by protonation of the pendant tertiary amine groups and leads to the micelles being adsorbed onto negatively charged cell membranes and subsequently endocytosed by tumor cells at tumor extracellular pH. Once internalized and transferred to lysosomes the further charged PDEAEMA leads to faster release of the entrapped drug into the cytoplasm and nucleus [34]. The hydrophilic PPEGMA with short side-chains, known to be non-immunogenic, non-antigenic and non-toxic, is distributed on the surface of the self-assembled micelles and provides a compact protective layer maintaining the stability of the micelles in the circulation [42], [43]. Doxorubicin (DOX), one of the most potent anticancer drugs [44], was used as a model drug encapsulated in the 4/6AS-PCL-b-PDEAEMA-b-PPEGMA micelles. The influence of the PCL and PDEAEMA contents, and the 4- or 6-arm topological structure on the micellar physico-chemical properties and release performance, as well as the final anticancer activity, were explored in depth.
Section snippets
Materials
ε-Caprolactone (ε-CL) (99% pure, Aldrich) was dried over calcium hydride and distilled under reduced pressure before use. 2-(Diethylamino)ethyl methacrylate (DEAEMA) (TCI-EP) was distilled from calcium hydride, and stored under argon at −20 °C. Poly(ethylene glycol) methyl ether methacrylate (PEGMA) (Mn 475 Da, 99% pure, Aldrich) was purified by passage through a column filled with neutral alumina to remove inhibitor. Pentaerythritol and dipentaerythritol was dried under reduced pressure
Synthesis and characterization of 4/6AS-PCL-b-PDEAEMA-b-PPEGMA
The 4/6AS-PCL-b-PDEAEMA-b-PPEGMA were synthesized via ROP of ε-CL to produce 4- and 6-arm PCL, with subsequent continuous ARGET ATRP of DEAEMA and PEGMA as shown in Fig. 1 [47], [48]. In the first step star-shaped hydroxyl-terminated poly(ε-caprolactone) (4/6AS-PCL) were synthesized using pentaerythritol (for 4AS-PCL) or dipentaerythritol (for 6AS-PCL) as initiators in the presence of a catalytic amount of Sn(Oct)2 at 100 °C. Then the end hydroxyl groups of the 4/6AS-PCL were fully converted to
Conclusions
In the current work amphiphilic 4- and 6-armed star triblock co-polymers 4/6AS-PCL-b-PDEAEMA-b-PPEGMA and their self-assembled three layer micelles were developed for controlled delivery of hydrophobic anticancer drugs. The polymers showed extremely low CMC values which could markedly improve micelle stability and extend the range of applications in controlled drug delivery. The average sizes of the DOX-incorporating micelles were 120–230 nm, with a spherical shape. The in vitro release of DOX
Acknowledgements
This work was financially supported by the National Natural Science Foundation of China (Grants nos. 21176090 and 21206045), Team Project of Natural Science Foundation of Guangdong Province, China (Grant S2011030001366), Project of International Cooperation and Exchanges of Guangdong Province, China (Grant 2011B050400016) and the Research Fund for the Doctoral Program of Higher Education of China (Grant 20110172120013).
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