Multifunctional Eu³⁺/Gd³⁺ dual-doped calcium phosphate vesicle-like nanospheres for sustained drug release and imaging

Abstract

A facile room-temperature solution method is reported for the preparation of multifunctional Eu³⁺ and Gd³⁺ dual-doped calcium phosphate (CaP) (Eu³⁺/Gd³⁺−CaP) vesicle-like nanospheres in the presence of an amphiphilic block copolymer polylactide–block–monomethoxy(polyethyleneglycol) (PLA−mPEG). The photoluminescent (PL) and magnetic multifunctions of CaP vesicle-like nanospheres are realized by dual-doping with Eu³⁺/Gd³⁺ ions. Under the excitation at 393 nm, Eu³⁺/Gd³⁺−CaP vesicle-like nanospheres exhibit a strong near-infrared (NIR) emission at 700 nm, and the PL intensity can be adjusted by varying Eu³⁺ and Gd³⁺ concentrations. Furthermore, Eu³⁺/Gd³⁺−CaP vesicle-like nanospheres can be used as the drug nanocarrier and have a high drug loading capacity and ultralong sustained drug release using ibuprofen as a model drug. The drug release from the drug delivery system of Eu³⁺/Gd³⁺−CaP vesicle-like nanospheres can sustain for a very long period of time (more than 80 days). The as-prepared Eu³⁺/Gd³⁺−CaP vesicle-like nanospheres exhibit essentially inappreciable toxicity to the cells in vitro. The noninvasive visualization of nude mice with subcutaneous injection indicates that the Eu³⁺/Gd³⁺−CaP vesicle-like nanospheres are suitable for in vivo bio-imaging. In vivo imaging tests using the subcutaneous injection model of nude mice indicate that Eu³⁺/Gd³⁺−CaP vesicle-like nanospheres can be used as an imaging agent for the NIR luminescence imaging. Thus, the Eu³⁺/Gd³⁺−CaP vesicle-like nanospheres are promising for applications in the biomedical fields such as multifunctional drug delivery systems and tissue engineering scaffolds with bio-imaging guidance.

Introduction

Calcium phosphates (CaP) are the most important inorganic constituents of human hard tissues including bone and tooth [1], [2], [3]. Therefore, synthetic CaP materials have been recognized as promising biomaterials with a great value and significance, and have been investigated for applications in bone repair/tissue engineering, drug and gene delivery, and other biomedical areas [4], [5], [6], [7], [8]. CaP materials with different morphologies including nanorods, plate-like nanocrystals, nanoparticles, nanotubes and three-dimensional structures have been prepared [9], [10], [11], [12], [13], [14], [15]. The chemical composition, structure and properties of CaP materials are usually determined by their preparation process. The facile synthesis of CaP nanostructured materials with well-defined structure, size, morphology and multifunctions is of great significance and remains a great challenge. Recently, amphiphilic block polymers were used in the synthesis of CaP nanostructures which showed enhanced properties in the application of drug/gene delivery [16], [17], [18].

Luminescence imaging has become an important tool for biomedical applications, particularly in the region of near-infrared (NIR) spectrum [19], [20], in which low absorptivity by tissue chromophores can be used in deep-tissue imaging [21]. However, many fluorophores of organic molecules show low fluorescence quantum yield, solvatochromic effects, photobleaching, short half-life and in vivo instability, which limit their applications in vivo [22], [23], [24]. It has been reported that nanostructured CaP significantly increased brightness and prolonged signal intensity when organic fluorophores were encapsulated compared with the free fluorophores [25], [26].

Europium, with 4f–4f intra orbital electronic transitions which span both the visible and near-infrared ranges, leads to long lifetimes of the excited states, and allows the use of time-resolved detection, a definitive asset for bioassays and biological luminescence imaging [27], [28], [29]. Meanwhile, gadolinium can be used as a contrast agent to provide brighter magnetic resonance (MR) signal [30]. Furthermore, lanthanide ions including Eu³⁺ and Gd³⁺ are known functional mimics of Ca²⁺ ions and have been shown to affect the bone remodeling cycle, and have a potential for the treatment of bone density disorders such as osteoporosis [31], [32]. Recently, the research on lanthanide ions-doped calcium phosphate for biomedical applications has become a hot topic [33], [34], [35], [36], [37].

Herein, we report a facile room-temperature solution method for the preparation of multifunctional Eu³⁺ and Gd³⁺ dual-doped CaP (Eu³⁺/Gd³⁺−CaP) vesicle-like nanospheres in the presence of an amphiphilic block copolymer polylactide–block–monomethoxy(polyethyleneglycol) (PLA−mPEG). The multifunctions of photoluminescence (PL), magnetism and drug delivery are realized in Eu³⁺/Gd³⁺−CaP vesicle-like nanospheres. The Eu³⁺/Gd³⁺−CaP vesicle-like nanospheres are promising for applications in the biomedical fields such as multifunctional drug delivery systems and tissue engineering scaffolds with bio-imaging guidance.