The potential of self-assembled, pH-responsive nanoparticles of mPEGylated peptide dendron–doxorubicin conjugates for cancer therapy
Introduction
Chemotherapy has been heavily investigated for the treatment of numerous cancers. However, one of the biggest challenges in this field is the lack of highly efficient and safe drug delivery vehicles. Nanoparticles, as nanoscale drug delivery vehicles [1], [2], are emerging as a class of therapeutics for cancer, suggesting enhanced efficacy, while simultaneously reducing side effects, owing to properties such as higher accumulation in tumors via the enhanced permeability and retention (EPR) effect and active cellular uptake [1], [3]. Among the emergent nanotechnology platforms, liposomes and polymer technologies likely have the great potential clinical impact for the foreseeable future [4]. Currently, natural polymers and synthetic polymers [5], [6], [7], such as dendritic polymers [8], have been widely prepared as nanoscale drug delivery vehicles for cancer therapy.
Dendritic polymers [9], [10], including dendrimers and dendrons [11], [12], [13], [14], have provided a potential alternative route to the development of drug delivery vehicles due to their versatility, precise nanostructure, low polydispersity, controllable molecular size, highly adaptable surface chemistry and chemically stable molecular entities with great flexibility [13], [15], [16], which have demonstrated a number of possible advantages, such as drug targeting and pharmacokinetic advantages of typical colloidal or macromolecular delivery systems [16], [17]. Recently, peptide dendritic polymers with attractive characteristics are currently under investigation as drug delivery systems due to their properties similar to proteins, such as good biocompatibility, water solubility and resistance to proteolytic digestion. However, the development of dendrimer–drug conjugates with ideal antitumor properties in vivo has not been sufficiently addressed, since the reported dendrimer based conjugates with size less than 10 nm are rapidly cleared from the circulation through extravasation or renal clearance [18].
The nanoparticles, including dendrimer/dendron-based drug delivery systems, suitable for cancer therapy depend on the size and surface properties [1], [9], [18], [19], [20], [21]. For dendrimers or dendrons, two methods, including increasing generation and surface modification via covalently connection, can be used to increase molecular weights and sizes of the dendrimers, which lead 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 [22]. Simultaneously, the high generation dendrimer (over 5 generation) can cause side effects due to their slow degradation [22], [23]. In order to enhance the blood circulation of dendrimers, as well as biocompatibility, polyethylene glycol (PEG), which can extend retention time in blood by decreasing non-specific interactions with endogenous components and macrophages, has been used to modified the surface of dendrimers to form a new kind of dendritic structures. The PEGylated dendrimers [24], [25], as drug delivery [26], [27], [28], [29] or imaging probes [30], have demonstrated increased drug loading and solubility, longer blood circulation and high accumulation in tumor tissue via the enhanced permeability and retention (EPR) effect [24]. In addition, PEGylation is one preferred method for avoiding premature clearance of nanoparticles by the reticuloendothelial system (RES) [5].
Another important issue regarding the development of dendritic polymers for specific applications is their ability to self-assemble into nanostructures [31], [32], [33], [34], [35], [36], [37], [38]. After encapsulation of drug, the nanostructures provided potential as drug delivery vehicles. The self-assembly can overcome the synthetic challenges associated with preparation of dendrimer [36]. In our group [39] and others [40], the degradable dendrimers/dendrons were aggregated to nanocarriers for gene delivery, demonstrated the dendrimers/dendrons self-assembly significantly enhanced DNA binding and efficiency at transporting DNA into cells compared to dendrimer or dendron alone. Based on above observations, our question here was if the mPEGylated peptide dendron–DOX conjugate can aggregate to nanoparticle and be suitable as nanoscale drug delivery with good biosafety as well as significant antitumor efficacy. However, currently, few studies on peptide dendron based nanoparticles as antitumor drug delivery have been reported.
In this study, we described the preparation and characterization of mPEGylated peptide dendron–DOX conjugate as pH-stimuli drug delivery system for breast tumor therapy. Its biosafety and antitumor efficacy were assessed well. The tail of protected dendron synthesized by divergent strategy in liquid phase with high yield was modified with mPEG via click reaction; DOX, as a widely used antitumor chemotherapeutic drug, was conjugated to another tail of the dendron through pH-sensitive hydrazone bond, resulting in compact nanoparitcle via the self-assembly governed by dendron–DOX itself, as shown in Fig. 1. The in vitro and in vivo characteristics of nanoparticle as pH-stimuli drug delivery system, such as size and morphology, zeta potential, drug release, antitumor efficacy and toxicity, were evaluated, which showed the mPEGylated peptide dendron–DOX conjugate based nanoparticle may be as a potential drug delivery vehicle for breast cancer therapy.
Section snippets
Materials and measurements
N,N-Diisopropylethylamine (DIPEA), 1-hydroxybenzotriazole (HOBt), N,N,N',N'-tetramethyl-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), propargylamine, trifluoroacetic acid (TFA) and methoxy poly(ethylene glycol) (mPEG, 2 Ka) were purchased from Sigma–Aldrich and used without further purification. Boc–l-Lys(Cbz)–OH, h-l-Glu(OBzl)–OBzl·TsOH and Boc–l-Lys(Boc)–OH were purchased from GL Biochem (Shanghai) Ltd. Azido methoxy poly(ethylene glycol) (mPEG–N3) [41], [42], 4-(N'-tert
Design and preparation of mPEGylated dendron–DOX conjugate based pH-stimuli nanoparticle
In our previous studies, peptide dendrons/dendrimers have been used as drug/gene delivery vehicles and magnetic resonance imaging contrast agents, showing good biocompatibility [22], [30], [39], [45], [46], [47], [48]. However, the dendrimer based drug delivery system with small size can be easily cleaned up form body [18]. Although the dendrimer with high generation showed higher size, the higher generations resulted in toxicity in vitro and in vivo [22]. Recently, PEG was used to modify
Conclusion
In summary, we have shown an example of amphiphilic comb-dendritic copolymer drug conjugate that combined the dendritic framework with the multivalent functionality at the two tails of peptide dendron. The anticancer drug doxorubicin was conjugated to the mPEGylated peptide dendron via an acid-labile hydrazone linkage. The peptide dendron–DOX conjugate showed a pH-sensitive drug release feature. In aqueous solution, the conjugate can self-assemble into spherical and compact nanoparticle, where
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 50830105), International Collaboration Project of Ministry of Science & Technology (2010DFA51550) and International Cooperation Project of Sichuan Province (2009HH0001).
References (58)
- et al.
Nanoparticle-based targeted drug delivery
Exp Mol Pathol
(2009) - et al.
In vivo evaluation of safety and efficacy of self-assembled nanoparticles for oral insulin delivery
Biomaterials
(2009) - et al.
Dendrimers and dendritic polymers in drug delivery
Drug Discov Today
(2005) - et al.
Preparation, cellular transport, and activity of polyamidoamine-based dendritic nanodevices with a high drug payload
Biomaterials
(2006) - et al.
Targeted intracellular codelivery of chemotherapeutics and nucleic acid with a well-defined dendrimer-based nanoglobular carrier
Biomaterials
(2009) - et al.
Plasmid pORF-hTRAIL and doxorubicin co-delivery targeting to tumor using peptide-conjugated polyamidoamine dendrimer
Biomaterials
(2011) - et al.
Design of interior-functionalized fully acetylated dendrimers for anticancer drug delivery
Biomaterials
(2011) - et al.
Nanoparticles for drug delivery: the need for precision in reporting particle size parameters
Eur J Pharm Biopharm
(2008) - et al.
Effects of particle size and surface coating on cellular uptake of polymeric nanoparticles for oral delivery of anticancer drugs
Biomaterials
(2005) - et al.
Functional dendritic polymer architectures as stimuli-responsive nanocarriers
Biochimie
(2010)
Arginine functionalized peptide dendrimers as potential gene delivery vehicles
Biomaterials
In vitro cytotoxicity testing of polycations: influence of polymer structure on cell viability and hemolysis
Biomaterials
Partly PEGylated polyamidoamine dendrimer for tumor-selective targeting of doxorubicin: the effects of PEGylation degree and drug conjugation style
Biomaterials
PEGylated poly(amidoamine) dendrimer-based dual-targeting carrier for treating brain tumors
Biomaterials
Development of efficient acid cleavable multifunctional prodrugs derived from dendritic polyglycerol with a poly(ethylene glycol) shell
J Control Release
Dendrimers of citric acid and poly(ethylene glycol) as the new drug-delivery agents
Biomaterials
RGD-modified PEG-PAMAM-DOX conjugates: in vitro and in vivo studies for glioma
Eur J Pharm Biopharm
Gadolinium-labeled peptide dendrimers with controlled structures as potential magnetic resonance imaging contrast agents
Biomaterials
Self-assembly of pH-responsive fluorinated dendrimer-based particulates for drug delivery and noninvasive imaging
Biomaterials
Effective strategy for the systematic synthesis of hydrazine derivatives
Tetrahedron
Peptide dendrimers as efficient and biocompatible gene delivery vectors: synthesis and in vitro characterization
J Control Release
Multifunctional gadolinium-based dendritic macromolecules as liver targeting imaging probes
Biomaterials
Dendrimers: relationship between structure and biocompatibility in vitro, and preliminary studies on the biodistribution of 125I-labelled polyamidoamine dendrimers in vivo
J Control Release
pH-triggered injectable hydrogels prepared from aqueous N-palmitoyl chitosan: in vitro characteristics and in vivo biocompatibility
Biomaterials
Influence of PAMAM dendrimers on human red blood cells
Bioelectrochemistry
Effects of nanomaterial physicochemical properties on in vivo toxicity
Adv Drug Deliv Rev
Nanoparticle therapeutics: an emerging treatment modality for cancer
Nat Rev Drug Discov
Therapeutic nanoparticles for drug delivery in cancer
Clin Cancer Res
Impact of nanotechnology on drug delivery
ACS Nano
Cited by (259)
Active targeting tumor therapy using host-guest drug delivery system based on biotin functionalized azocalix[4]arene
2024, Journal of Controlled ReleaseIn vitro and in vivo anti-tumor extrapolation of one pot engineered stimuli-responsive poly(ethylenimine) and (phenylthio) acetic acid ion pair micelles for smart delivery of doxorubicin and indocyanine green
2023, Journal of Drug Delivery Science and TechnologyDevelopment and evaluation of finasteride niosomes targeting to hair follicles for the management of androgenic alopecia
2023, Journal of Drug Delivery Science and TechnologyA prestin-targeting peptide-guided drug delivery system rearranging concentration gradient in the inner ear: An improved strategy against hearing loss
2023, European Journal of Pharmaceutical Sciences