Multifunctional superparamagnetic nanocarriers with folate-mediated and pH-responsive targeting properties for anticancer drug delivery
Introduction
A major challenge to successful cancer chemotherapy is achieving specific drug accumulation at the tumor sites. Most of the available anticancer agents cannot distinguish between cancerous and healthy cells, leading to systemic toxicity and undesired side effects. Solutions to this problem have focused on the development of nanoscale tumor-targeted delivery systems. Various nanocarriers including liposomes, polymeric nanoparticles, block copolymer micelles, and dendrimers have been developed for the targeted delivery of therapeutics to cancerous tissues [1], [2], [3], [4], [5]. Nanocarriers are also used to deliver imaging agents (e.g. superparamagnetic iron oxide nanoparticles as magnetic resonance imaging (MRI) contrast agent) for diagnostics and real-time particle tracking in the body. Long-circulating nanocarriers such as poly(ethylene glycol) (PEG)- and poly(ethylene oxide) (PEO)-modified nanocarrier systems can preferentially accumulate in the tumor sites through the leaky tumor neovasculature by the enhanced permeability and retention (EPR) effect, known as the passive targeting [6], [7].
To further improve delivery efficiency and cancer specificity, active targeting strategies are currently under wide investigation. One of the most common such strategies involves coupling the nanocarrier surface with a specific ligand that is recognizable by cells present at the disease site [8]. Various specific receptors (e.g. vitamins and sugar receptors) overexpressed on the cancer cell surface have served as useful targets. Folate receptors are selectively overexpressed on brain, kidney, lung, and breast cancer cells. Folate (vitamin M) has a low molecular weight and a high receptor affinity (Kd = 1 × 1−10 M) [9], [10]. Nanocarriers conjugated with folate can be targeted to and internalized into target cells though receptor-mediated endocytosis [11], [12], [13], [14].
Another promising targeting approach is the use of stimuli-responsive delivery systems that are sensitive to changes in biological and environmental signals such as pH, temperature, and specific enzymes [15], [16], [17]. Ideal drug delivery systems should be stable with a long circulation time, and should keep the loaded drugs unreleased during circulation in the bloodstream or in normal tissues. Upon reaching and accumulating in tumor tissues by passive and active targeting, and after being taken up by cancer cells, the systems should release the drugs rapidly in response to the local environment.
Smart drug delivery systems have been developed in which the drug is loaded by acidic pH-induced cleavable covalent bonds. For example, adriamycin (ADR) can be attached to the side chain of a core-forming segment by an acid-labile hydrazone bond. This bond is stable at physiological pH (7.0–7.4) but degraded at the lower pH of endosomal/lysosomal compartments (pH 5.0–5.5) [18], [19]. Drugs may otherwise be loaded into the core of polymeric micelles by non-covalent interactions, in most cases, hydrophobic [20], [21], or ionic interactions [22], [23]. Recently, our group successfully loaded drugs with ionizable groups and hydrophobic moieties into nanocarriers by the combined action of ionic bonding and hydrophobic interactions [24], [25]. The use of non-covalent interactions resulted in a high loading affinity at a neutral pH (7.4), preventing premature release into the bloodstream. The loaded drugs released with good kinetics at an acidic pH, which breaks the ionic bonding.
In this paper, we report the development of multifunctional nanocarriers with a superparamagnetic Fe3O4 core, carboxyl-containing inner shell with adjustable hydrophobicity, biocompatible PEG outermost shell, and a small amount of surface-conjugated folate. The multifunctional nanocarriers were prepared by coating a superparamagnetic Fe3O4 core with a mixture of the triblock copolymer methoxy poly(ethylene glycol)-b-poly(methacrylic acid-co-n-butyl methacrylate)-b-poly(glycerol monomethacrylate) (denoted MPEG-b-P(MAA-co-nBMA)-b-PGMA) and the folate-conjugated block copolymer folate-poly(ethylene glycol)-b-poly(glycerol monomethacrylate) (denoted FA-PEG-b-PGMA) (Scheme 1). As a model drug with an amine group and a hydrophobic moiety, ADR was loaded into the nanocarrier at pH 7.4 by ionic bonding and hydrophobic interactions. The nanocarrier possessed a superparamagnetic Fe3O4 nanoparticle core, which may serve as MRI contrast agent and hyperthermic agent, folate conjugation on the surface, which was recognized by HeLa cells, and property of pH-responsive release of the loaded drug.
Section snippets
Materials
Methoxy poly(ethylene glycol) (MPEG-OH, 2000 Da, Aldrich) and poly(ethylene glycol) (HO-PEG-OH, 3000 Da, Fluka) were dehydrated by azeotropic distillation of water in toluene, precipitated with cold ethyl ether, filtered, washed with ether, and vacuum-dried. tert-Butyl methacrylate (tBMA, Acros) and normal-butyl methacrylate (nBMA, Acros) were distilled over CaH2 under reduced pressure before use. 1,1,4,7,7-Pentamethyldiethylenetriamine (PMDETA) was purchased from Acros. 2-Bromoisobutyryl
Preparation and characterization of the nanocarriers
Block copolymers containing PMAA, PGMA, and PnBMA segments were synthesized by copolymerization of the corresponding tBMA, SMA, and nBMA monomers. Synthesis was initiated by PEG macroinitiators and performed by ATRP, followed by deprotection of the PtBMA and PSMA segments [24], [26], [27]. The block copolymer structure is shown in Table 1. Chain lengths of the PtBMA, PnBMA and PSMA segments were determined by 1H NMR using the MPEG or PEG segment as a reference.
In preparing the macroinitiator
Conclusions
Nanoparticles with an Fe3O4 core and MPEG-b-P(MAA19-co-nBMA4)-b-PGMA25/FA-PEG-PGMA34 shell were prepared as a tumor-targeted drug delivery system. As a model drug, ADR was loaded into the carboxyl-containing inner shell composed of P(MAA-co-nBMA) by a combination of ionic bonding and hydrophobic interactions at pH 7.4. The release of the loaded drugs from the nanocarriers was pH-responsive. At endosomal/lysosomal acidic pH (<5.5), the protonation of the polycarboxylate anions of PMAA broke the
Acknowledgements
This work was supported by the National Natural Science Foundation of China (Grant No. 20974052), the National Key Technologies R & D Program for New Drugs of China (Grant No. 2009ZX09301-002), and the Natural Science Foundation of Tianjin Municipality (Grant No. 09JCZDJC22900).
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