Mesoporous silica nanoparticles in medicine—Recent advances

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Abstract

MSNs have attracted increasing interest as drug carriers due to promising in vivo results in small-animal disease models, especially related to cancer therapy. In most cases small hydrophobic drugs have been used, but recent in vitro studies demonstrate that MSNs are highly interesting for gene delivery applications. This review covers recent advances related to the therapeutic use of mesoporous silica nanoparticles (MSNs) administered intravenously, intraperitoneally or locally. We also cover the use of MSNs in alternative modes of therapy such as photodynamic therapy and multidrug therapy. We further discuss the current understanding about the biodistribution and safety of MSNs. Finally, we critically discuss burning questions especially related to experimental design of in vivo studies in order to enable a fast transition to clinical trials of this promising drug delivery platform.

Introduction

Nanomedicine seeks to offer nanotechnology-based solutions for medical problems with the main aims of enhancing the bioavailability of drugs and reducing side effects [1]. The ultimate goal is to enable more effective and patient friendly treatment regimes by reducing drug concentration and dosing frequency, by offering easier administrations and improving safety [2], [3]. Various approaches may open up for retained drug action and nanotechnology might enable personalized medicine [4]. In addition to these benefits there are clear commercial benefits such as the possibility for reformulation of drugs that have not made it to the clinic due to poor solubility or extensive side effects. Several different nanodevices have been suggested to provide a benefit to the drug delivery scene. However, despite high promises and exhaustive research activities during the last decades, surprisingly few nanotechnology-based drug formulations have reached the clinic. Delivery systems have been applied to prolong the circulation time and bioavailability of certain drug molecules but addressing the drug delivery vehicles to specific tissues or cells still lies in the future. Formulations based on liposomes are already on the market but a variety of other delivery systems are emerging. Mesoporous silica nanoparticles, (MSNs), the focus of this review belongs to this class [5], [6], [7]. MSNs have several advantages as drug delivery vehicles, as will be discussed in more detail below. The size and shape of the particles are easily tunable. The high pore volume and surface area allow for a high drug load. Due to the flexibility of the platform and the vast possibilities for further functionalizations they may offer targeted delivery and controlled release. Further, surface tailoring allows detailed engineering to circumvent unwanted biological interactions, facilitate bioavailability and cellular uptake, and to shift the platform away from immune-surveillance. Taken together this will open up for tailored pharmacokinetic release profiles, increased bioavailability, target delivery and thereby enhanced therapeutic efficacy. Detailed understanding of the biobehaviour of MSNs and exhaustive preclinical testing are needed to push the technology towards a clinical standard. Recently, the first silica based diagnostic nanoparticles in the form of “C-dots” (Cornell dots) [8] were FDA-approved for stage I human clinical trial. This represents an important step towards clinical acceptance of silica-based nanoparticles.

The interactions between nanoparticles and various cells and tissues of the human body will ultimately determine the medical applicability of the technology [9], [10]. The interactions between nanoparticle design and various levels of biological complexity are presented in Fig. 1. Compared to soluble molecules or drugs, using nanoparticulate drug carriers adds another level of complexity as these nanoparticles may dissolve, aggregate, and interact with biomolecules, cells and tissues according to their chemical composition, size, shape and physical properties. Hence a direct dose–response relationship obtained through standard testing in cellular systems cannot predict the behavior in the organism. Critical assessment of biodistribution, biocompatibility and toxicity in relation to the physico-chemical properties of the nanoparticles in well-established model systems in vivo is therefore needed before the technology can become a clinical reality. Dissolution rate and mechanism are important determinants of blood circulation times and the mode of elimination. Further, particle dissolution may release particle components that might cause adverse affects when in free form. Surface engineering or functionalization may offer targeted delivery, determine interactions with biomolecules, cells and tissues, enable controlled drug release and shift the safety profile of the particles. But the particle surface should stay intact and unchallenged until the particle reaches the target and the most critical parameter for efficacy in addition to safety might be degradation rate and mechanisms. Degradation needs to take place at the right time and at the right place. The heterogeneity of biological model systems adds to the complexity. In vitro studies using different cell types are therefore important to be able to determine particle behavior on a cellular level. Different cells may respond differently to any given particle. The cell type, origin and morphology as well as culturing conditions may determine uptake rate, uptake mechanism, intracellular routing, aggregation and further intracellular processing, degradation and elimination of the material. The targeted tissue and its morphology will thus influence the response to particle treatment. The administration route, whether systemic, oral, intraperitoneal or subcutaneous, is equally important to consider when designing the particles. Targeted systemic delivery is by far the most challenging where interactions with proteins, serum components and immune cells in the blood may affect the behavior of the particles [11], [12], [13]. Circulation time critically determined by size, degradation kinetics, surface functionalization, and the location and accessibility of the targeted tissue needs to be considered in the design. Particles including mesoporous silica, also show different toxicity based on the administration route. Native (non-functionalized) particles administered subcutaneously have shown less toxicity as compared to particles delivered intraperitoneally or systemically, especially at high doses [14]. In addition to the morphological challenges (size and shape), parameters such as recognition by biological systems, coronation (opsonization of proteins to the surface), communication of toxicity cues between cells, cell specific reactions and biodegradation influence therapeutic performance.

The considerations highlighted above are not restricted to any specific nanotechnology-based drug delivery system but pose a general challenge. This review focuses on recent advances related to MSNs for drug delivery, reflecting the considerations discussed above and highlighting future challenges with the main emphasis on preclinical in vivo testing of therapeutic efficacy and safety. We are especially focusing on therapeutic strategies where the delivery platform has shown to have had beneficial action, such as enhancing bioavailability, evading multidrug resistance or enabling the use of new drugs targeting molecular pathways in cancer. The vast literature on the performance of mesoporous silica nanoparticles as delivery devices in vitro has been recently discussed in a number of reviews by us [5], [6], [7] and others [15], [16], [17], [18], and is therefore largely omitted in this review. We give a brief overview of the carrier platform with focus on the control of particle size and shape, surface functionalizations, and methods for drug loading and controlled release. Recent technology advances broadening the therapeutic repertoire by for instance enabling gene delivery, and alternative targeting are also discussed.

Section snippets

Brief description of the technology platform

The synthesis of MSNs is typically relying on co-operative self-assembly of supramolecular surfactant assemblies, acting as structure directing agents, and oligomeric silica species [19], [20], [21]. Furthermore, controlled nucleation and growth allows for tailoring of particle size (10–1000 nm) (see for example [22]). By tuning the synthesis conditions and/or by variation of the reactants elongated MSNs with tunable aspect ratios can be synthesized, [23] providing yet another means for

Cargo loading and release from mesoporous silica

Due to the high surface area and pore volume of MSNs high drug loadings can be achieved, even exceeding 35 wt.%, but in most if not all biological studies published to date drug loadings lower than the maximum loadings have been used. There are two main means for drug loading into MSNs, in situ during synthesis or as post-sorption (either by physisorption or by chemisorption). We have covered the drug loading processes in detail recently, [7] and the interested reader is referred to this review

Improved efficacy and reduced side effects of anticancer drugs

Poor solubility, drug instability and poor cellular uptake of many cancer drugs hamper efficient therapy. Due to frequent occurrence of side effects, the therapeutic window of many drugs is narrow. Therefore, the development of delivery systems that can carry a high payload of drug, protect the drug from degradation, facilitate cellular uptake and target specific cell populations is necessary for the clinical applicability of many drugs. Mesoporous silica particles have been highlighted to be

Current status of MSNs' pharmacology development relative to major stages of clinical trials

The flexibility of MSNs highlights them as interesting drug delivery vehicles. Biological performance and applicability have been demonstrated by preclinical experimentation, but systematic testing of biodistribution, safety and therapeutic efficacy as related to various designs are still needed to bring the technology closer to the clinic. The current status of MSNs is presented in Fig. 3 and below we discuss current advances and future challenges to proceed on this path. We also emphasize the

Tissue accumulation and elimination of nanoparticles

For optimal therapy the nanoparticle should reach the tumors or diseased tissue but at the same time not have adverse effects in normal tissue. Preferably, particles that are not targeted to the site of action should be cleared from the body and not accumulate in healthy tissue. Although smaller particles are expected to more easily reach and penetrate the targeted tissue, they can also extravasate in most normal tissue. In addition to size, shape and surface modification also affect

Interaction with the immune system and impact on embryonic development

Only few studies have evaluated the effect of MSN on primary immune-competent cells and the immune system. The performed studies highlight MSN as a safe and biocompatible drug delivery system. Vallhov et al. [97] tested the effects of mesoporous silica nano- (270 nm) and microparticles (2.5 μm) on human monocyte-derived dendritic cells. They observed size- and concentration-dependent effects where the smaller particles and lower concentrations affected cells to a minor degree compared to the

Reactive oxygen species-MSNs

A lot of studies have been focusing on the generation of reactive oxygen species (ROS) upon cellular uptake of crystalline silica polymorphs, especially in relation to exposure through inhalation and subsequent potential development of, for example, silicosis or lung cancer as recently reviewed [104], [105]. The formation of ROS has in these studies been observed to be much higher for freshly cleaved crystalline silica surfaces containing Si+, Si–O+, Siradical dot, and Si–Oradical dot species, while ROS generation

Outlook

During the last years a number of proof-of-concept studies of the in vivo use of MSNs in drug delivery have been published. Most of this work focus on cancer treatment and have fuelled the hope for improved detection and enhanced therapeutic regimes and even targeted delivery to reduce or circumvent side effects. The process of MSN selection based on strict criteria is half the battle for successful preclinical trials. Nanoparticulate systems have to be compared not only to free drug, but also

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