Cyclic RGDfK- and Sulfo-Cy5.5-functionalized mPEG-PCL theranostic nanosystems for hepatocellular carcinoma
Graphical abstract
In this article, we evaluated the targeted theranostic efficacy of multifunctional polymeric nanoparticles (NPs) for hepatocellular carcinoma in vitro and in vivo.
Introduction
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers that leads the fourth most common cause of cancer-related death worldwide [1]. The treatment of HCC varies depending on the stage of the disease. Surgical resection or liver transplantation could be the best options to treat early-stage HCC. If the patient has a few small tumors, minimally-invasive treatments such as ablation or embolization are recommended as alternatives to surgery. If HCC is too advanced to undergo surgery or local therapy, systemic chemotherapy may be a consideration [2], [3], [4]. However, most anticancer drugs do not exhibit strong anticancer effects on HCC. Although chemotherapeutic agents such as doxorubicin [5], cisplatin, and 5-fluorouracil are often used alone or in combination for the treatment of HCC; these drugs shrink only a small number of tumors, and their effects are short-lasting [6], [7].
Sorafenib (SF) is a unique drug that can be used as the first treatment for advanced HCC, as approved by the FDA in 2007 [8]. It functions as a multikinase inhibitor that suppresses tumor cell proliferation and angiogenesis and promotes tumor cell apoptosis [9], [10]. SF has significantly extended the median survival time of HCC patients [11]. However, the benefits of SF are often balanced by its adverse effects [12]. A variety of off-target effects are elicited by SF, manifesting in other pathways or other kinases, which may negatively influence the regulation of physiological function and disrupt homeostasis in patients, leading to life-threatening situations; these effects may eventually result in the discontinuation of SF administration [13]. Therefore, there is an urgent need to develop new strategies that can selectively deliver the optimum dose of SF to affected liver cells.
The integrin ανβ3 can be a key player in targeting SF to HCC because the adhesion and the migration of HCC cells are mainly implicated through ανβ3 integrin [14]. Therefore, the integrin ανβ3 can be regarded as the targeted site for drug carriers to target HCC. As an integrin-specific peptide, arginine–glycine–aspartic acid (RGD) can be specifically recognized by the integrin ανβ3 [15], [16] and has been demonstrated as a potent targeting ligand of tumors [17] possessing ανβ3-overexpressing cells [18], [19]. Thus, the drug delivery system conjugated with the ανβ3-specific RGD peptide could be a novel strategy for selective delivery of SF to HCC.
In this work, the multifunctional polymeric theranostic nanosystems were prepared for HCC treatment (Scheme 1). Methoxy polyethylene glycol-polycaprolactone (mPEG-PCL) was selected as an amphiphilic diblock copolymer where the hydrophobic PCL core can encapsulate SF through self-assembly, increasing solubility; the hydrophilic PEG shell may prolong its blood circulation time [20], [21]. Cyclic RGDfK (cRGD) was conjugated to the end of PEG-PCL (cRGD-PEG-PCL) as a ligand for interaction with HCC. In addition, S-Cy5.5 was incorporated into PEG-PCL for fluorescence imaging (S-Cy5.5-PEG-PCL). A series of hybrid NPs (S-Cy5.5-cRGD-PEG-PCL) consisted of mPEG-PCL, cRGD-PEG-PCL, and S-Cy5.5-PEG-PCL were prepared by the solvent evaporation method, and their theranostic effects through specific integrin-mediated cellular uptake and diagnostic efficiency with fluorescence imaging were systemically investigated in vitro and in vivo.
Section snippets
Materials
Methoxy polyethylene glycol-polycaprolactone (mPEG-PCL) and amine-polyethylene glycol-polycaprolactone (H2N-PEG-PCL) diblock copolymers (PEG: 2 kDa, PCL: 2 kDa) were obtained from Creative PEGWorks (Chapel Hill, NC, USA). The cyclic arginine–glycine–aspartic acid-d-phenylalanine-lysine (cRGDfK, abbreviated as cRGD) peptide was synthesized at Peptron Inc. (Daejeon, Korea). Sulfo-Cyanine5.5-COOH (S-Cy5.5) was purchased from Lumiprobe (Hunt Valley, MD, USA). Sorafenib (SF) was bought from LC
Conjugation of cRGD-PEG-PCL and S-Cy5.5-PEG-PCL
The conjugation of cRGD and S-Cy5.5 to H2N-PEG-PCL was confirmed by 1H NMR (Fig. 1B). In Fig. 1B-a, the signals of PEG appeared at 3.44 and 3.35 ppm, and the signals of PCL were observed at 3.97–4.09, 2.24–2.29, 1.49–1.57, and 1.29–1.33 ppm. A characteristic peak of cRGD that corresponds to the −CH peak of d-phenylalanine was assigned to 7.13 ppm. In Fig. 1B-b, the −CH peak of S-Cy5.5 appeared at 7.75 ppm. The degree of substitution (DS) of cRGD and S-Cy5.5 was calculated by comparison of the
Conclusion
In this study, biocompatible and multifunctional NPs consisted of cRGD-PEG-PCL, S-Cy5.5-PEG-PCL, and mPEG-PCL with SF were successfully prepared by the solvent evaporation method. The prepared NPs were smaller than 100 nm with a high EE and a sustained release capacity. In vitro tests exhibited that the incorporation of cRGD led to the improved cellular uptake of SF into Hep3B cells through receptor-mediated endocytosis. In addition, the incorporation of S-Cy5.5 into NPs has successfully
Conflict of interest
There are no conflicts of interest to declare.
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgments
This work was supported by a grant of Ministry of Trade, Industry and Energy (MOTIE) (Grant no. 10047811).
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