A mesoporous silica nanoparticulate/β-TCP/BG composite drug delivery system for osteoarticular tuberculosis therapy

Abstract

A composite scaffold drug delivery system (CS-DDS) for osteoarticular tuberculosis therapy has been prepared by loading bi-component drugs into a mesoporous silica nanoparticles (MSNs)-coated porous β-TCP scaffold, which was followed by an additional bioactive glass coating. Such a CS-DDS showed high performances in the local and extremely sustained delivery of the bi-component antitubercular drugs and excellent biocompatibility. N₂ sorption isotherms indicated greatly increased surface area of the composites compared to pure β-TCP scaffold, and the mesopores were around 2.6 nm which were large enough to encapsulate drugs such as isoniazide and rifampicin. The in vitro and in vivo release tests demonstrated extra sustained co-release profiles of rifampicin and isoniazide from such a CS-DDS, and both drug concentrations kept higher than their effective values to kill mycobacterium tuberculosis for as long as 42 days. The hepatic and renal function tests indicated that the CS-DDS had neglectable long-term lesions to liver and kidney.

Introduction

With the rapid growth of floating population, the wide-spreading of AIDS all over the world and the emergence of multi-drug resistant mycobacteria, tuberculosis (TB) as a global health problem continues to present a formidable challenge. According to the World Health Organization, about one third of the overall population in the world was infected with the Mycobacterium tuberculosis, and there were millions of newly infected cases annually [1], [2], [3]. Recently, there has been a spurt in extrapulmonary TB (EPTB) [4], [5]. Thereinto, osteoarticular TB cases account for approximately 10–11% of EPTB, which are about 19–38 million in the world [6], [7], [8], [9], [10].

Strategies for treating TB, including osteoarticular TB, mainly consisted of multi-drug chemotherapy for an appropriate period, which prevented the apparent resistance of TB bacilli to single drugs. Though the optimal duration for such a chemotherapy has not been thoroughly known [11], [12], it was generally recommended that a total of 9 month treatment was acceptable for adults, while no less than 12 months for children, which were undoubtedly a heavy burden to patients [13], [14], [15]. Moreover, because of toxic side effects of the drugs [16], [17], [18], [19], degradation of drugs before reaching their target site and/or low permeability of the drugs and poor patient compliance, the effect of systematic multi-drug chemotherapy, including oral administration and intravenous injection, was unfortunately rather limited. As for osteoarticular TB, the osseous focus developed by tubercle bacillus is usually poor in blood supply, and it is difficult for antitubercular drugs carried in blood to arrive at the focus. Therefore the tubercle bacillus living in the osseous focus or survived through debridement operations were difficult to be killed completely by traditional systematic chemotherapy and easy to become latent bacillus which would reproduce rapidly once in co-morbid conditions.

Another general rule for osteoarticular TB treatment was surgical intervention [6], [20]. With the development of internal fixation materials and technology, debridement of the bone infection foci was inevitably suggested to be chosen by doctors [21]. However, apart from the surgery, antitubercular multi-drug therapy was unfortunately still indispensable. The current common regimen for treating osteoarticular TB was 1–4 weeks of pre-operative and 6–9 months of post-operative multi-drug chemotherapy in order to consolidate the curative effect.

To shorten or even avoid the drug therapy following debridement and reduce lesions to hepatic and renal functions, orthopedic surgeons and researchers have been showing more and more interest in controlled drug release systems [22], [23], which offer more effective and favorable methods to optimize drug dosage, deliver to specific sites or prolong delivery duration [24]. Nanoparticles [25], mesoporous materials [26], and lipids [27] were among the most investigated carriers for drugs [28], [29], [30]. Much attention has been paid to poly (lacticide-co-glycolicide) (PLGA) as a base compound of micro-particles for pulmonary delivery of anti-tuberculosis drugs. However, PLGA microspheres embedded into the bone defect caves would induce the significant decrease of pH values by the acidic degradation products of PLGA [31], [32], [33]. The decreased pH values could result in drug resistance of tubercle bacillus.

Alternatively, porous inorganic materials, such as mesoporous silica materials, may provide a more advantageous choice for controlled and localized antitubercular drug delivery without causing significant pH value decreases, which have been investigated as a drug delivery carrier for more than a decade, thanks to its extensive nanopore structure in mesoporous silica [26], [34], [35], [36]. The mesopore structure of 2–50 nm in diameter may render good bioactivity and biocompatibility. Compared with solid nanoparticles, the mesoporous silica nansparticles (MSNs) are apparently a more suitable drug delivery carrier due to its extensive mesoporous structure.

As far as antitubercular drugs are concerned, isoniazid (INH) and rifampicin (RFP) are two of the efficacious drugs against TB with the traditional duration of treatment [4], [37], [38]. With positive therapy effects to tuberculosis caused by susceptible strains, the co-encapsulation of INH and RFP had no effect on their respective virtues [39], [40].

After debridement of osteoarticular TB, the residual cavity, which could give rise to common bacterial infection and rapid propagation of the residual tuberculosis germs when it was filled by blood clot, should be filled. Porous beta-tricalcium phosphate (β-TCP) bioceramics have been regarded as one of the satisfactory bone tissue engineering scaffolds to recover the residual cavity. Osteochondral and large articular cartilage defects have been successfully repaired by porous β-TCP scaffolds seeded with autologous cells in an animal model [41], [42].

Therefore, a composite scaffold drug delivery system (CS-DDS) composed of the bioceramic β-TCP scaffold and coated MSNs on the inner macropore surface of the scaffold is highly promising to meet the requirements for advanced TB therapy. The composite system is expected to combine the merits of multi-drug loading and very sustained and localized drug co-release for effective osteoarticular treatment, and bioactivity for bone repairing. The purpose of this work was to design and fabricate such a CS-DDS made of β-TCP bioceramics scaffold and MSNs coating within the scaffold for simultaneously encapsulating INH and RFP. During the debridement of osteoarticular TB, this CS-DDS will supply both a sufficient filling to the bone defect area and effective anti-tuberculosis drug concentrations for the prolonged post-operative multi-drug chemotherapy to partly or even completely eradicate the residual tubercle bacillus.