Smart pH-responsive and high doxorubicin loading nanodiamond for in vivo selective targeting, imaging, and enhancement of anticancer therapy

Abstract

Nanodiamond as a carrier for transporting chemotherapy drugs has emerged as a promising strategy for treating cancer. However, several factors limited its extensive applications in biology, such as low drug loading, easily cluster and a high drug loss under physiological environment. In this work, to ensure high drug capacity and low drug leakage in physiological conditions, and especially ensure to be delivered to tumor region, a smart pH-responsive drug delivery system was designed and prepared by DOX adsorbed onto PEGylated nanodiamond in sodium citrate medium (ND-PEG-DOX/Na3Cit, NPDC). The system can significantly enhance cellular uptake to exert therapeutic effect in comparison to free drug. And more importantly, DOX was released in a sustained and pH-dependent manner and exhibits excellent stability under neutral conditions. In addition, NPDC could enter into cells via both clathrin and caveolae-mediated endocytosis pathway, and then dissociated DOX migrated into nucleus to block the growth of cancer cells. Furthermore, NPDC can significantly inhibit the cell migration and change the cell cycle. Excitingly, the NPDC system was very smart to enrich at the tumor site in vivo effectively and to enhance antitumor efficiency with low toxicity beyond conventional DOX treatment in cancer cells and nude mouse model. So this study introduces a simple and effective strategy to design a promising drug delivery platform for improving the biomedical applications of the smart nanodiamonds carriers. amount of loaded DOX is relative poor and the drug dissociation in physiological environment is slightly high. Scheme 1 Schematic illustration of the fabrication of an intracellular pHresponsive NPDC delivery system for cancer therapy.

Dual Loading of Doxorubicin and Magnetic Iron Oxide into PLA‐TPGS Nanoparticles: Design, in vitro Drug Release Kinetics, and Biological Effects on Cancer Cells

“…It was reported that when the MNDDS enter to the cell, Dox release could be affected partly by the endosomal and lysosomal lumen whose pH is maintained in a range of 6.5 to 4.5 [48] . Our results are consistent with those reported by Li et al., [49] the amount of Dox released from the Dox‐PEGylated nanodiamond system at acid pH (pH 5.5) faster than at neutral pH conditions (pH 6.5 or pH 7.4).…”

Optical Studies of Nanodiamond-Tissue Interaction: Skin Penetration and Localization

“…Negligible cytotoxicity has been demonstrated for the NDs used in this work (data not shown); note, that low or no cytotoxicity has been demonstrated before for different kinds of NDs elsewhere [27,50,55,60]. The NDs’ surface can be functionalized and modified with molecules of interest for interaction for further bio-applications [24,28,61].…”

“…Understanding the NP interaction with the skin is important for topical, local drug delivery, including nanoparticle-provided delivery of drugs [20,22], such as delivery via the topical application of a nanoparticle-drug system with slow controllable drug release [23]. Among the nanomaterials with demonstrated facilities of controlled drug release, nanodiamonds (NDs) are a promising candidate in the development of multiple applications [24,25]. However, the potential applications of NDs in transdermal drug delivery, as well as other theranostic applications, will depend on understanding the ND interaction with the skin and on the ability to detect and visualize the interaction with the skin.…”

“…NDs’ fluorescence [26,27,28], Raman scattering [27], and backscattered signal (differential interference and Hoffman modulation ‘space’ contrast microscopy techniques) [28] have been utilized for multimodal imaging and delivery monitoring. The surface properties of NDs allow the functionalization of the particles with molecules of interests for interaction with bio-targets [24,25,29]. Importantly, in anticancer therapy, ND-mediated delivery has been shown to increase the efficiency of drug treatment [30].…”

Nanodiamonds for In Vivo Applications

“…Another approach to combine doxorubicin with an additional molecule was shown by Li et al They attached doxorubicin onto diamond particles that were coated with polyethylene glycol (PEG). PEG is well known for its excellent properties when it comes to suppressing immune responses.…”