Drug releasing behavior of hybrid micelles containing polypeptide triblock copolymer

doi:10.1016/j.biomaterials.2008.09.010

Biomaterials

Volume 30, Issue 1, January 2009, Pages 108-117

https://doi.org/10.1016/j.biomaterials.2008.09.010 Get rights and content

Abstract

We report a new type of hybrid polymeric micelles for drug delivery applications. These micelles consist of PLGA (PLGA: poly(l-glutamic acid)) and PEG (PEG: polyethylene glycol) mixed corona chains. In acidic condition, PLGA undergoes a transformation from water-soluble random coils to water-insoluble α-helix, leading to microphase separation in micelle coronas and formation of PEG channels. These channels connect the inner core and the outer milieu, accelerating the diffusion of drugs from micelles. The micelles were prepared through a co-micellization of PLGA-b-PPO-b-PLGA (PPO: poly(propylene oxide)) and PEG-b-PPO in water. During the self-assembly, the PPO blocks of both block copolymers aggregated into cores that were surrounded by mixed corona chains of PLGA and PEG blocks. We confirmed this structure by using a number of characterization techniques including nuclear magnetic resonance spectroscopy, zeta potential, circular dichroism, and dynamic light scattering. We also performed molecular dynamics (MD) simulations to verify the models of the hybrid micelle structure. One advantage of the hybrid micelles as drug carriers is their tunable release rate without sacrificing colloidal stability. The rate can be tuned by either micelle structures such as the composition of the mixture or external parameters such as pH.

Introduction

Amphiphilic block copolymers are able to self-assemble in water into micelles at nanometer scale. All of the micelles have core–shell structures with water-insoluble blocks forming cores and water-soluble blocks acting as coronas. One promising application of this type of aggregates is for drug delivery [1], [2], [3], [4], [5], [6], [7], [8], [9]. Usually, hydrophobic drugs can be loaded in the cores of the micelles to lower its toxicity in human body, and to prolong their circulation time in blood [10]. In addition, the nanostructure of micelles may help the aggregates penetrate through cell membrane to deliver drug at subcellular level [11], [12], [13], [14], [15], [16], [17], [18], [19].

Because most pathological processes exhibit a decrease in pH [20], it has become an interesting research topic to design micellar carriers with pH-regulated releasing rate, but without loosing colloidal stability. Contrary to the normal blood pH of 7.4, the extracellular pH values in tumorous tissues are determined to be around 6.5–7.0, and the intracellular environment is typically acidic (pH 5.0–6.0). Therefore, if a carrier can retain the drug at pH 7.4 and quickly release it at a relative lower pH will be ideal for clinical treatments.

Although pH-responsive block copolymer micelles have been extensively studied and suggested for the application of drug delivery [21], [22], [23], it is still highly demanded to design carriers which can vary drug releasing rate within a narrow pH window from 7.4 to 5.0 without loosing the integration of the particles [18]. Recent researches into hybrid micelles self-assembled from two block copolymers provide an opportunity for the design of this type of aggregates [24], [25], [26], [27], [28], [29], [30], [31]. Jerome et al. prepared water-soluble micellar complexes of P2VP-b-PEG (P2VP: poly(2-vinylpyridinium); PEG: poly(ethylene oxide)) and PMAA-b-PEG (PMAA: polymethacrylic acid) [30]. This hybrid micelle consists of an interpolyelectrolyte complex core formed by the association of the PMAA and P2VP blocks surrounded by a corona of PEG blocks. Shi et al. prepared complex micelles from the self-assembly of PtBA-b-PNIPAM (PtBA: poly(tertbutyl acrylate), PNIPAM: poly(N-isopropylacrylamide)) and PtBA-b-P4VP (P4VP: poly(4-vinylpyridine)) [31]. The hydrophobic PtBA blocks of the two polymers associated together to form a dense core protected by the mixed P4VP/PNIPAM corona chains. These micelles with mixed corona chains are interesting and have a wide range of structure variation, because the solubility of P4VP and PNIPAM is sensitive to pH and temperature, respectively.

The new features of hybrid micelles offer the flexibility for further manipulating the desirable functions of drug carriers, especially releasing profile [32], [33], [34], [35]. For the hybrid micelles with mixed corona chains, it is especially interesting to understand how these mixed corona blocks influence drug release, whether the mixed chains in the corona can provide an advantage for the manipulation of releasing rate that micelles with single type of corona chains cannot afford. Unfortunately, there barely are reports to answer these questions.

In this paper, we report a new type of hybrid micelles self-assembled from PLGA-b-PPO-b-PLGA (PLGA: poly(l-glutamic acid); PPO: poly(propylene oxide)) and PEG-b-PPO in water to form micelles with mixed corona chains of PLGA and PEG. We are interested in this system for several reasons: (1) all the polymer blocks in the system have good biocompatibility and low toxicity which have potential for clinical treatments. (2) PLGA is a polypeptide segment which possesses a conformation transformation between coil and helix depending on pH of the solution, which has shown significant advantages in controlling both the function and supramolecular structures of bio-inspired self-assemblies [36], [37], [38], [39], [40]. (3) It is especially interesting to investigate how the conformation change of PLGA in the mixed corona chains can be used to manipulate drug releasing profiles of drug carriers.

The hybrid micelles were characterized by ¹H NMR, zeta potential measurements and dynamic light scattering (DLS). In addition to the experimental studies, we also performed molecular dynamics (MD) simulations using a Brownian dynamics to further verify the structures. The MD simulations offered a microscopic understanding of the thermodynamic properties and a detailed picture of the self-assembled aggregates [41], [42], [43], [44], [45]. Following the micelle characterization, we studied their behavior as drug carriers. Particularly we investigated the effect of mixed corona chains of PLGA and PEG on the drug releasing functions.

Section snippets

Materials

Tetrahydrofuran (THF), hexane and 1,4-dioxane were refluxed with sodium and distilled immediately before use. Doxorubicin hydrochloride (DOX-HCl) was obtained from Zhejiang Hisun Pharmaceutical Co., Ltd. α-Amino-ω-amino poly(propylene oxide) (NH₂–PPO₆₉–NH₂) and poly(ethylene glycol)₃₁-b-poly(propylene oxide)₁₀ (PEG-b-PPO) were purchased from Sigma–Aldrich Co., Inc. NH₂–PPO–NH₂ was dissolved in toluene in a flame-dried reaction bottle, followed by removing the toluene in high vacuum to obtain

Results and discussion

This paper consists three sections: in the first section, PLGA-b-PPO-b-PLGA and PEG-b-PPO were used to prepare hybrid micelles. Once micelles prepared, we characterized the structure and also studied their stimuli-responsive properties. In the second section, we simulated the aggregation behavior using molecular dynamics (MD) to verify the experimental observations. In the last section, we investigated drug loading and releasing profiles of the micelles as functions of micelle structures and

Conclusions

We prepared hybrid micelles through the self-assembly of PLGA-b-PPO-b-PLGA and PEG-b-PPO. The resulting micelles contain hydrophobic PPO cores and mixed coronas of PLGA and PEG. This structure was characterized by using ¹H NMR, zeta potential measurements, DLS and verified by using MD simulations. Further studies of this type of micelles as drug carriers led to the discovery that the mixed corona chains containing PLGA and PEG play an important role in tuning drug releasing rate. For the

Acknowledgements

This work was supported by National Natural Science Foundation of China (50673026, 20574018). Supports from Doctoral Foundation of Education Ministry of China (Grant No. 20050251008) and Projects of Shanghai Municipality (06SU07002, 0652nm021, 082231, and B502) are also appreciated. XSW thanks EPSRC for a Roberts Academic Award.

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