br Acta Materialia Inc Published by Elsevier Ltd
2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
⇑ Corresponding authors.
E-mail addresses: [email protected] (F. Liu), [email protected] (W. Zeng), [email protected] (S. Sun). 1 These two authors contributed equally to this work.
Cancer remains as the leading cause of death worldwide, and chemotherapy continues to be one of the best techniques for cancer treatment [1,2]. Drug delivery nanocarriers that can transport an effective dosage of drug molecules to targeted CCK-8 and tissues have been extensively designed to overcome the adverse side effects and
low effectiveness of conventional chemotherapy drugs [3–7]. How-ever, it should be noted that most of nanocarriers, such as traditional inorganic biomaterials (e.g., silica- and carbon-based nanocarriers), are quite difficult to be biodegraded , leading to potential long-term toxic side effects. Especially, in the majority of these nanocar-riers, one nanocarrier could only load one specific drug, because dif-ferences in the properties of drugs such as hydrophilicity/ hydrophobicity, positive/negative charge usually overwhelm one nanocarrier to afford. However, tumor formation is a complex and multifactorial process, such that optional combination chemother-apy is more preferred over single-agent chemotherapy to overcome drug resistance and achieve synergistic therapeutic effect [9–14]. Theoretically, two or more nanocarriers can be employed to deliver different drugs to fulfill these requirements, but such combination is really complex and painstaking. Several issues that should be con-sidered are as follows: biodegradability of each nanocarrier; whether the metabolism of more than one nanocarrier will result in an overloaded burden of the metabolic system; possible effect of cellular uptake of different nanocarriers to each other; inconsis-tency of drug load and release efficiency of different nanocarriers, which may affect, even decrease, the synergistic treatment effect.
Thus, constructing biodegradable versatile nanocarrier that can carry various types of drugs, is in urgent need and more suitable for commercial production and clinical use. To achieve biodegrada-tion, nanocarriers should be able to be degraded into non-toxic products, such as essential or easily metabolized metal ions of body, through response to the special microenvironment of cancer-ous cells like pH and glutathione (GSH) [15–19]. While to realize versatility, drugs with different properties must be able to load controllably. Only if a nanocarrier owns both positive and negative charged parts, various drugs could be loaded simultaneously. Because positive-charged nanocarriers are limited to load negative-charged or electron-rich drugs, while, negative-charged nanocarriers are restricted to load positive-charged or electron-poor drugs. Layered nanomaterials, which own unique structures consisting of stacked nanosheets, provide an interesting opportu-nity to develop new hybrid materials with intentional and control-lable functionalities . As reported in our previous work and others [21,22], both the positive- and negative-charged basic units can be obtained through the exfoliation of corresponding biodegradable positive- and negative-charged layer materials sep-arately, and after delicate combination, they can be sequentially united into a positive- and negative-charged array like nanocarrier
through electrostatic interaction-induced layer-by-layer (LBL) self-assembly .
Based on this rational, as shown in Scheme 1, we designed a novel biodegradable versatile nanocarrier (CM) based on the self-assembly of delaminated CoAl-layered double hydroxides (LDHs) and manganese dioxide (MnO2), which acted as basic positive-charged and negative-charged units respectively. Then for better targeting of cancerous cells, folic acid (FA) molecules were cova-lently attached to CM yielding FA modified CM (FA-CM). The results indicated that FA-CM exhibited GSH and pH dual stimuli-response drug release and meanwhile could efficiently degrade into Co2+, Al3+ and Mn2+ in cancerous cells. It should be noted that Co is an essential trace element of human body and is a key con-stituent of vitamin B12 ; Al can be easily excreted from human body and there is evidence of no toxicity if it is consumed in amounts not greater than 40 mg/day per kg of body mass [25– 27]; Mn is an important element for human health, essential for development, metabolism, and the antioxidant system . There-fore, the degradation obstacle and resulting long-term toxic side effects to organisms existed in most nanocarriers could be avoided [29–32]. More importantly, FA-CM could optionally load not only positive-charged drugs (e.g., doxorubicin (DOX)) but also negative-charged drugs (e.g., sulforhodamine B (SRB)). To further determine the applicability of FA-CM, hydrophilic and hydrophobic drugs (DOX and paclitaxel (PTX) were chosen as models, which have been reported to possess synergistic therapeutic effect ) were co-loaded on FA-CM for synergistic combination chemother-apy. More efficacious anticancer effects using the co-loaded FA-CM were reached in an in vitro cytotoxicity evaluation and in a xeno-graft tumor model of hepatoma than free drug alone or corre-sponding cocktail solutions. In addition, the ratios of DOX and PTX loaded on FA-CM could be tuned as needed. Furthermore, FA-CM displayed high storage stability, excellent dispersibility and low cytotoxicity. These characteristics guarantee the further clinical applications of FA-CM.