pH-triggered small molecule nano-prodrugs emulsified from tryptamine-cinnamaldehyde twin drug for targeted synergistic glioma therapy
Graphical abstract
Introduction
Gliomas are characterized by high morbidity and mortality owing to their localization, infiltration to brain parenchyma and injury to neurological functions [1]. At present, surgical resection followed by radiotherapy and chemotherapy is the standard therapy strategy to inhibit gliomas growth and prolong the survival time [2]. However, most patients have still faced the threat of death resulted from high recurrence within 1 to 2 years, despite they have taken a full course of treatment [1,3]. This poor prognosis is due primarily to the limited delivery of chemotherapeutics across the blood brain barrier (BBB), difficult accumulation of drugs in the gliomas area, and off-target toxicity. Hence, these drawbacks force us to develop an efficient drug with highly targeted therapy to prevent gliomas from recurrence.
Cinnamaldehyde (CA) as a hydrophobic natural product can promote tumoral ROS-mediated apoptosis while being low toxicity or non-toxicity to normal cells [[4], [5], [6], [7]]. Nevertheless, its easy oxidation property and poor water solubility restrict further application [8,9]. Tryptamine (Try) as a hydrophobic analogue of serotonin (5-HT) endows specific gliomas cytotoxicity via multiple effects such as inhibition of tryptophanyl-tRNA synthetase (TrpRS), degeneration of mitochondria and intercalation into nucleic acids [[10], [11], [12], [13]]. Moreover, Try is more easily internalized by gliomas cells via the overexpressed 5-HT receptors (5-HT1A, 5-HT2) on the cell membrane, in comparison with other normal astrocytes [14,15]. Therefore, Try is a promising drug for glioma therapy based on its selective and efficient cytotoxicity. However, it can be metabolized by monoamine oxidase (MAO-A and MAO-B) in the body [16,17], thereby shortening its half-life and decreasing the accumulation at gliomas. Hence, it is highly desirable to develop a special dosage form to maximize the effects of CA and Try while decreasing their disadvantages appealing for significantly synergistic gliomas therapy and easy clinical transition.
Nanomedicines have emerged as promising candidates for cancer treatment [18,19]. They can enhance pharmacokinetics and tumor accumulation while decreasing the side effect [20]. However, only a few nanotherapeutics have hit the market in the past few decades, because traditional polymeric nanomedicines suffer from some inherent defects, such as undefined structure, complex preparation, and low drug loading ratio [21]. Carrier-free nano-prodrugs derived from anticancer small molecule twin drugs have been paid tremendous attention in recent years. They not only retain nanoscale advantages, but also undergo facile synthesis, precise structure, extraordinary drug loading capacity (100 %), and defined metabolism pathway [22]. Therefore, it’s a viable strategy to construct an ideal carrier-free nano-prodrug for gliomas chemotherapy via the combination of CA and Try.
Notably, CA and Try can easily bond together to form twin drug via the aldimine condensation between aldehyde group in CA and amino group in Try. The hydrophobic twin drug could further construct the small molecule nano-prodrug via the O/W emulsion solvent evaporation method [23], therefore achieving the long-term storage and circulation stability via the steady physicochemical property, ease to cross BBB in the form of hydrophobic nanospheres [24,25], selective target to gliomas cells via the overexpressed 5-HT receptors, and enhanced release and synergetic cytotoxicity of CA and Try via the intracellular endosomal acidolysis of Schiff bases and protonation of imidazole rings in the Try [26,27] (Scheme 1). Herein, we focus on the investigation of storage and circulation stability, pH-triggered charge reversal, size transition and drug release, lipid solubility-driven brain accumulation, Try-mediated cellular uptake, selectively synergistic cytotoxicity, inhibition on SH-SY5Y MCs, and biosafety based on pH-triggered small molecule nano-prodrugs emulsified from tryptamine-cinnamaldehyde twin drug.
Section snippets
Materials
Ethanol (99.7 %), dichloromethane (AR), tryptamine (Try, 98 %), cinnamaldehyde (CA, 98 %), sodium laurylsulfonate (SDS, 98 %), hydrogen peroxide (H2O2, 30 %), coumarin 6 (98 %) and plasma amine oxidase (PAO) were purchased from Macklin. 4′,6-diamidino-2-phenylindole (DAPI), poly(2-hydroxyethyl methacrylate) (Mw 300,000), poly(vinyl alcohol) (PVA, Mw 13,000-23,000, 87–89 %), and 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenyl-formazan (MTT, 98 %) were obtained from Energy Chemical. Try/CA was yielded
Synthesis and characterization of twin drug (Try-CA)
As shown in Scheme 1, Try-CA was easily synthesized through aldimine condensation between aldehyde group in CA and amino group in Try. The feeding molar ratio between CA and Try was kept 1:1.1, so that the crude product was easily purified to remove redundant Try by water precipitation. 1H-NMR, 13C-NMR and MS were used to confirm the structure of Try-CA. As displayed in Fig. 1, the Schiff base was successfully formed via the disappearance of proton peaks at 1.26 ppm (h’, Try-NH2, Fig. 1a) and
Conclusions
In summary, the Try-CA twin drug could be synthesized via aldimine condensation and further formed small molecule nano-prodrugs by using the O/W emulsion solvent evaporation method. Try-CA-NPs showed the stability in H2O2 and plasma amine oxidase for 24 h, and in PBS (pH 7.4) and 1% sodium dodecyl sulfate for 7 days, suggesting their long-term storge and circulation stability. Try-CA-NPs also exhibited intracellular endosomal pH-triggered charge reversal, large-to-small size transition and
CRediT authorship contribution statement
Zhexiang Wang: Data curation, Writing - original draft. Jinzhu Yao: Visualization. Zhaoyuan Guan: Project administration. Haifang Wu: Writing - review & editing. Huazheng Cheng: Supervision. Guoqing Yan: Software, Validation. Rupei Tang: Investigation, Conceptualization, Methodology.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (No. 51803001 and 51603001), the Research Foundation of Education Department of Anhui Province of China (No. KJ2018ZD003, KJ2018A0006 and KJ2019A0015), and the Academic and Technology Introduction Project of Anhui University (AU02303203).
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