Dendronized heparin−doxorubicin conjugate based nanoparticle as pH-responsive drug delivery system for cancer therapy
Introduction
Nanoparticles, as drug delivery vehicles for cancer therapy, are rapidly progressing and are being implemented to overcome the limitations of conventional chemotherapeutic agents such as nonspecific biodistribution and targeting in the body, poor water solubility and low therapeutic indices [1], [2]. Nanoscale drug delivery vehicles provide enhanced antitumor efficacy and reduced side effects, owing to their properties such as higher accumulation in tumors via the enhanced permeability and retention (EPR) effect and active cellular uptake [1], [3]. Among the emergent nanoparticles, lipids (liposomes) and polymers (polymeric nanoparticles, micelles and dendrimers) likely have the great potential clinical impact for the foreseeable future [4], [5], [6], [7]. However, although those lipids and polymers based nanoparticles demonstrate many advantages as drug delivery systems, there are still many limitations to address such as instability in circulation, inadequate tissue distribution and toxicity.
Dendrimers with nanometer dimensions have provided potential drug delivery vehicles due to their features such as their precise and monodisperse size, low polydispersity, modifiable surface functionality, water solubility and multivalency, resulting in a number of possible advantages, such as pharmacokinetic advantages of typical colloidal or macromolecular delivery systems [8], [9]. The fate of injected nanoparticles, including dendrimer based drug delivery, suitable for cancer therapy depends on their sizes and surface characteristics [1], [10], [11], [12], [13], [14]. However, this kind of drug delivery with ideal antitumor properties in vivo has not been sufficiently achieved, since the reported dendrimers with size less than 10 nm are rapidly cleared from the circulation through extravasation or renal clearance [10]. Increasing generation and surface modification can increase the sizes of the dendrimers, which leads to longer blood circulation and higher antitumor efficacy. However, it's not easy to prepare higher generation dendrimers due to the steric hindrance to chemical reactions [15]. Simultaneously, the high generation dendrimer leads to side effects due to their slow degradation [15], [16].
In order to prepare dendrimer or dendritic polymer based nanoparticles with larger sizes and well–defined molecular objects, dendronization strategy has been utilized to prepare nanoscopic objects via connecting dendron to polymer [17], [18], in which polymer was used as a polyfunctional and polydisperse core, and the new polymers with this architecture were referred to as ‘dendronized polymers’ [19], [20]. The dendronized polymers can self–assemble into nanoparticles taking advantage of dendrimer and linear polymer [21], [22]. The dendronization and self–assembly can overcome the synthetic challenges associated with preparation of dendrimer based nanoparticles with satisfied sizes.
Heparin, a non-cytotoxic, biodegradable, rich in animal tissues and water–soluble natural polysaccharide belonging to the family of glycosaminoglycans [23], has been widely used as an anticoagulant drug owing to its ability to accelerate the rate at which antithrombin inhibits serine proteases in the blood coagulation cascade [24], [25], as well as antitumor drug delivery carriers due to its ability to inhibiting tumor growth and metastasis by interacting with tumor related factors such as selectins, heparanases, and growth factors [26], [27], [28], [29], [30], [31], [32]. The antitumor drug was conjugated to heparin or encapsulated into the heparin nanoparticles [33], [34], [35], [36], [37], [38], [39]. However, the major problems are the unsuitable particle sizes for cancer therapy and poor stability. Based on above observations, our question here was if the dendronized heparin–DOX conjugate can self–assemble into nanoparticle and be suitable as nanoscale drug delivery with significant antitumor efficacy as well as good biosafety by combination of the features of dendrimer and heparin. However, currently, few studies on dendronized heparin based nanoparticles as antitumor drug delivery has been reported.
In this study, we described the preparation and characterization of dendronized heparin–DOX conjugate as pH-stimuli and nanoscale drug delivery system for breast tumor therapy. Its antitumor efficacy and biosafety were assessed well. The heparin was dendronized with low generation dendron via click reaction; DOX was conjugated to the surface of dendron through pH-sensitive hydrazone bond, resulting in compact nanoparitcle via the self–assembly, as shown in Fig. 1. The in vitro and in vivo characteristics of nanoparticle as pH-stimuli drug delivery system, such as size, zeta potential, drug release, antitumor efficacy, antiangiogenic effect and toxicity, were evaluated, which showed the dendronized heparin–DOX conjugate based nanoparticle provide a potential drug delivery vehicle for breast cancer therapy.
Section snippets
Materials and measurements
N,N,N′,N′–tetramethyl–(1H–benzotriazol–1–yl)uronium hexafluorophosphate (HBTU), 1–hydroxybenzotriazole (HOBt), propargylamine, N,N–diisopropylethylamine (DIPEA), trifluoroacetic acid (TFA) and doxorubicin hydrochloride were purchased from Sigma–Aldrich and used without further purification. Boc–l–Lys(Boc)–OH was purchased from GL Biochem (Shanghai) Ltd. N–Hydroxysulfosuccinimide sodium salt (Sulfo–NHS) and N–(3–dimethylaminopropyl)–N′–ethylcarbodiimide hydrochloride (EDC·HCl) were obtained from
Design and preparation of dendronized heparin–DOX conjugate based nanoparticle
In our previous studies, peptide dendrons/dendrimers have been used as drug/gene delivery vehicles and magnetic resonance imaging probes taking advantage of dendrimer's multivalency [15], [43], [44], [45], [46], [47], [48], [49]. However, the dendrimer based drug delivery system can be easily cleaned up form body due to the small size [10]. Despite the high generation dendrimer showed higher size, it resulted in toxicity in vitro and in vivo [15], and it was also associated with synthesis
Conclusion
In summary, we have shown an example of amphiphilic dendron and linear polymer conjugate based nanoparticle as drug delivery vehicle that combined the polymer hybrid framework by dendronization and self-assembly. The anticancer drug doxorubicin was conjugated to the dendronized heparin block via an acid–labile hydrazone linkage. The dendronized heparin–DOX conjugate based nanoparticles showed a pH-sensitive drug release property. In aqueous solution, the conjugate can self–assemble into compact
Acknowledgments
The work was supported by National Basic Research Program of China (National 973 program, No. 2011CB606206), National Natural Science Foundation of China (51133004, 81101099 and 30970730) International Collaboration Project of Ministry of Science & Technology (2010DFA51550), International Cooperation Project of Sichuan Province (2009HH0001) and the Excellent Young Teachers Program of Sichuan University (2012SCU04A06).
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She W C. and Li N. contributed equally to this work.