Targeted osteosarcoma chemotherapy using RGD peptide-installed doxorubicin-loaded biodegradable polymeric micelle
Introduction
Osteosarcoma, which is the most frequent occurring malignant bone cancer mostly in children and adolescents between 10 and 20 years of age, ranking among the leading causes of cancer-related death in the pediatric age group [1], [2], [3], [4], [5]. Osteosarcoma is arising from mesenchymal bone forming tissue and its histological hallmark is the production of malignant osteoid [6]. In clinical practices, surgery followed by chemotherapy regimens of high-dose methotrexate with leucovorin rescue, doxorubicin (DOX), cisplatin, and ifosfamide is the standard treatments for osteosarcoma, which could achieves a 5-year event-free survival of 60–70% in extremity [7]. It should be noted, however, associated toxic side-effects of these chemotherapeutic drugs, have extremely limited its therapeutic indexes [8], [9].
Recently, nanoparticulate drug delivery system (NDDS), especially ligand-directed targeted NDDS, has been widely studied as a powerful platform for treatment of cancer [10], [11], [12], and achieved great success. Targeted NDDS loaded with chemotherapeutic drugs could not only reduces the toxic side-effects of chemotherapeutic agents by minimizing non-specific normal tissue accumulation, but also strengthens tumor targeting by enhanced permeation and retention (EPR) effect [13], [14], [15], and improving affinity between nanoparticles and membranes of treated cells. Taking the merits of targeted NDDS, several ligand-installed nanosystems with loading of chemotherapeutic drugs have been designed and explored for osteosarcoma treatment. For example, Kopecek’s group used d-aspartic acid octapeptide as both hydrophilic micellar corona and effective targeting agent, forming targeted pH-sensitive DOX conjugate micelles as potential osteosarcoma therapeutics [16]. Anada et al. explored a novel type of calcium phosphate-binding liposome by conjugation of bisphosphonates as bone-targeting ligand and achieved reduced human osteosarcoma MG-63 cells viability [17]. Ni et al. described a salinomycin-loaded polymeric nanoparticle conjugated with CD133 aptamers, demonstrated active cell targeting ability and significantly inhibited the osteosarcoma growth by killing CD133+ osteosarcoma cancer stem cells [18].
Arg-Gly-Asp (RGD), a cell-affinitive peptide is able to interact with αvβ3 and αvβ5 integrins, which are widely expressed in osteosarcoma cell lines such as MG-63 and MNNG/HOS cells [19], [20]. The affinity of RGD towards osteosarcoma cells brings inspiration to Sun et al. [21] and Grigore et al. [22] incorporated RGD motifs into hydrogels to generate cellular adhesion sites to enhance osteocytes (MG-63 was used as model cell line in their reports) spreading and differentiation for guiding tissue formation, as well as Haubner et al. used 18F-labeled RGD-containing glycopeptide for murine osteosarcomas imaging [23]. However, to the best of our knowledge, few RGD-associated nanosystems were explored for targeted chemotherapy of osteosarcoma. Herein, in this study, we designed and developed DOX-loaded targeted polymeric micelle self-assembled from RGD-terminated poly (ethylene glycol)-block-poly (trimethylene carbonate) (RGD-PEG-PTMC) amphiphilic block copolymer, for high-efficiency targeted osteosarcoma chemotherapy (Fig. 1). PEG-PTMC defines as excellent biodegradable and biocompatible biomedical polymer and was successful developed as micellar nanomedicine for a library of cancer chemotherapy [24], [25], [26]. Intriguingly, our results in in vitro studies showed that this RGD-installed DOX-loaded polymeric micelle (RGD-DOX-PM) displayed enhanced cell uptake ability relative to its non-targeted counterpart (DOX-PM), leading to increased osteosarcoma cells death and demonstrating high potential for targeted chemotherapy of osteosarcoma.
Section snippets
Materials
Methoxy poly(ethylene glycol) (MeO-PEG-OH, Mn = 5.0 kg/mol, PDI = 1.03, Fluka) and Maleimide activated poly(ethylene glycol) (Mal-PEG-OH, Mn = 5.0 kg/mol, PDI = 1.02, Jenkem technology Co., Ltd, China) were dried by azeotropic distillation from anhydrous toluene. Toluene and dichloromethane (DCM) were dried by refluxing over CaH2 and distilled prior to use. Trimethylene carbonate (TMC, Duoyu biotechnology Co., Ltd., China) was recrystallized by ethyl acetate before polymerization. Diphenyl phosphite
Synthesis of PEG-PTMC and RGD-PEG-PTMC block polymers
The ring-opening polymerization of TMC using MeO-PEG-OH (Mn = 5.0 kg/mol) as a macro-initiator and diphenyl phosphiteas a catalyst yielded PEG-PTMC block polymer (Fig. 2). 1H NMR showed that signals at δ 3.65 attributable to the methylene protons of PEG block, and peak at δ 3.38 belongs to terminal methoxy group of PEG. Besides that, resonances at δ 4.24 and 2.06 owing to the methylene protons of PTMC block (Fig. 3A). The comparison of the integrals of signals at δ 2.06 (methylene protons of TMC)
Acknowledgements
The work was financially supported by the Natural Science Foundation of Health and Family Planning Commission of Wuhan City (WZ14D06), and Natural Science Foundation of Municipal Commission of Science and Technology of Wuhan City (201060938370).
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These authors contributed equally to this work.