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    2021-03-03


    Contents lists available at ScienceDirect
    Chemical Engineering Journal
    journal homepage: www.elsevier.com/locate/cej
    Black phosphorus nanosheets-based stable drug delivery system via drug- T self-stabilization for combined photothermal and chemo cancer therapy
    Gan Liua,b, Hsiang-I Tsaia, Xiaowei Zenga, Junyang Qia, Miaomiao Luoa, Xusheng Wanga, Lin Meia, , Wenbin Denga,b,
    a School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China
    b Department of Biochemistry and Molecular Medicine, School of Medicine, University of California at Davis, Sacramento, CA 95817, USA
    • BP-based stable drug delivery system was constructed through drug-self-stabilization.
    • BP nanosheets were proved to load DACHPt twice their weight.
    • BP/DACHPt released DACHP in acid-and NIR-responsive manner.
    • BP/DACHPt killed almost all the cancer Galactose 1-phosphate  by combined photo-thermal and chemo effects.
    • BP/DACHPt would exert tumor abla-tion in vivo.
    Keywords:
    Drug-self-stabilization Black phosphorus Platinum-based anticancer drugs Enhanced stability Combined cancer therapy 
    Black phosphorus (BP) nanomaterials have shown great potential as near-infrared (NIR) photothermal therapy agents and drug delivery systems for cancer therapy. However, their practical applications were still severely limited as their lack of stability under ambient conditions. Here we reported a strategy of using drug itself to stabilize BP. The active species of platinum-based anticancer drugs (DACHPt and Pt(NH3)2) were utilized to coordinate with BP nanosheets to form complex BP/DACHPt and BP/Pt(NH3)2 and improve their stability. BP nanosheets were proved to load DACHPt twice their weight and released it in acid- and NIR-responsive manner, indicating an excellent drug carrier. In vitro cytotoxicity results and apoptosis mechanism showed BP/DACHPt would almost kill all the cancer cells by combined photothermal and chemo effects. Finally in vivo results confirmed BP/DACHPt-PEG would accumulate efficiently in tumor and exert tumor ablation. Thus this novel strategy of using drug itself to stabilize BP, would not only evade the potential clinical application risks, but also construct stable BP-based drug delivery system for combined photothermal and chemo cancer therapy.
    1. Introduction cancer therapy [1–16]. As the new member of 2D materials with ex-
    cellent optical properties, atomic thin black phosphorus (BP) has been a Recently photothermal therapy (PTT), with high efficiency and rapid rising star as near-infrared (NIR) PTT agents for cancer therapy in
    minimal invasiveness, has been considered a new promising option for the last two years [17–25]. Being a layered semiconductor composed of
    Corresponding authors at: School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China (W. Deng). E-mail addresses: [email protected] (L. Mei), [email protected] (W. Deng).
    single P atom, BP exhibited quite wide absorption from the ultraviolet (UV) to infrared regions due to its layer-dependent bandgap varying from 0.3 eV (bulk BP) to 2.0 eV (monolayered BP) [17,26]. Another attractive quality of BP for biomedical applications is its inherent bio-compatibility and biodegradability. Experiments showed BP nanosheets could degrade to nontoxic phosphate and phosphonate in aqueous media, both of which are widespread in the human body [20,27]. Furthermore, recently BP nanomaterials were reported to load drugs that weight much more than themselves, allowing them work as effi-cient drug carriers for combined photothermal and chemo cancer therapy [21,28,29].
    Despite the great potential, a fundamental bottleneck impeding the practical adoption of BP is its instability in air-exposed water en-vironments including body circulation [30–32]. BP has been proved to readily react with oxygen and water under ambient conditions, causing compositional degradation and thus acute loss of optical performances [27,33]. Due to a puckered honeycomb structure, one phosphorus atom of BP is bonded to three other single-layer phosphorus atoms cova-lently, thereby exposing a pair of lone pair electrons [34]. The lone pair electrons is very reactive with oxygen to form PxOy, which would be removed by water, exposing the surface P0 for continue oxidation fol-lowed by BP degradation [30]. Thus, stabilizing the lone pair electrons would be a potential strategy to inhibit the BP degradation. Recently, several approaches including surface covalent functionalization [35], noncovalent functionalization [36–38] and coordination with transi-tional metal ion [39,40] were reported to stabilize the lone pair elec-trons of BP. However, in view of the biomedical applications in body, efficient and clinically prospective strategy for BP stabilization is still urgent.