pH-Sensitive tumor-targeted hyperbranched system based on glycogen nanoparticles for liver cancer therapy

Highlights

• Glycogen nano-system targets liver cancer and releases drug under pH response.

• Glycogen nano-system minimizes drug leakage in normal organs.

• The system enhances drug accumulation at tumor site and inhibits tumor growth effectively.

Abstract

A multifunctionalized nanodevice based on natural hyperbranched glycogen nanoparticles had been fabricated for tumor therapy. Glycogen nanoparticles were decorated with liver cancer cell-targeted agent β-galactose and anticancer drug doxorubicin via schiff-base reaction. It was found that the glycogen nanocarrier could be taken by liver cancer cell selectively owing to galactose-ASGPR binding. After endocytosis, drug could be released from nanoparticles due to the cleavage of hydrazone-based bond at acidic tumor cell environment. The in vivo study demonstrated that this glycogen based drug delivery system minimized uptake and drug leakage in normal organs, enhanced accumulation and efficient drug release at tumor sites, inhibiting tumor growth with only slight retention in normal liver tissues. This strategy on exploiting glycogen nanoparticles as anticancer drug vehicle provides alternative platform for on-demand and targeted cancer therapy.

Introduction

Carbohydrate functionalized nanoparticles, polymers, dendrimers and liposomes have been served as multivalent scaffolds for improving the efficiency of targeting carbohydrate binding proteins [[1], [2], [3], [4]]. Through multiple receptor-ligand interactions in high affinity, these glyconanomaterials can potentially mediate various biological activities, including cell-cell communication, bacterial infections, immune response and virus invasion, which are desirable for recognition studies and therapeutic applications [[5], [6], [7], [8]]. Thus, glyconanomaterials were widely explored as drug delivery vehicle for tumor therapy [9,10]. Ideally, except meeting the target capability, drug delivery system also needs to the requirements of prolonged blood circulation, controlled dissociation and release of cargo under intracellular stimuli, as well as nontoxic degradation products [11,12]. In these, biosourced polysaccharide have been extensively developed as drug carriers, such as chitin [13], hyaluronic acid [14], dextran [15], cellulose [16] and so on. They not only carry multiple copies of carbohydrate components themselves, but also possess excellent properties of hydrophilicity, nontoxicity, degradability and nonimmunogenicity [17]. While, most of these natural saccharides are liner polymers, carrying limited functionalized sites. Herein, glycogen, the hyperbranched polysaccharide like natural dendrimer, is concerned by us and its therapeutic applications are explored.

Glycogen consists of α-D-(1–4) and α-D-(1–6) glycosidic bonds, presenting as nanoparticles in microscopic morphology [18,19]. Glycogen nanoparticles present innate characters of dendritic and hyperbranched structure without being structured by chemical synthesis [20]. Besides, the modified sites of glycogen nanoparticles are not only confined to the outer sphere but distributed in the interior space, which contribute to the modification of periodate oxidation [21], alkylation [22] and electrification [23] in high efficiency. Additionally, glycogen tends to aggregate at liver, where it is very popular to conduct metabolic activities [24]. This inherent characteristic endows glycogen the capability of “fusion targeting” as cargo vehicle. Besford et al. successfully developed lactose-functionalized glycogen, which exerts high affinity to peanut agglutinin (PNA) and interacts with galectin-1 that is overexpressed in prostate cancer cells, highlighting the targeted imaging effect to prostate cancer cells [25]. Bergkvist [23] and Caruso group [26] extended the use of glycogen nanoparticle as siRNA carrier that can bring gene silencing effect in multicellular tumor spheroids. These research broadened the applications of glycogen in drug delivery system, while we found that the delivery capabilities of the reported glycogen vehicles were not yet complete. While, the ideal drug carriers need to meet specific criteria in one system for successful cancer therapy in vivo, including prolonged blood circulation, special accumulation in tumor, release of drug cargo under stimuli as well as nontoxic degradation products [27]. Therefore, a strategy for glycogen modification must be devised to fully exploit all potential benefits of glycogen nanoparticles.

Herein, we exploited glycogen as a smart vehicle for targeted transporting hydrophobic drug to liver cancer and releasing drug under pH response (Scheme 1). Glycogen was oxidized and conjugated with doxorubicin through schiff-base reaction, thus forming the pH responsive drug release model [[28], [29], [30]]. To enhance the liver targeted efficiency, we grafted glycogen with galactose derivate, which showed high sensitivity and specificity to the asialoglycoprotein receptor (ASGPR) on hepatic parenchymal cells [31]. The structure characterization and pH sensitive drug release behavior of the resulting systems were studied in detail. Their cytotoxicity and targeting activity were assessed against normal cell Cos 7 and liver cancer cell Hep G2 through intracellular drug release. Furthermore, the anticancer capability of these glycogen based drug delivery system were unambiguously investigated in vivo. We hypothesized that the evaluating intracellular uptake, drug distribution and glycogen based drug delivery system could be used as a potential platform of treating liver tumor.