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Published in final edited form as: Adv Drug Deliv Rev. 2012 Sep 4;65(1):93–99. doi: 10.1016/j.addr.2012.08.011

Inorganic Nanosystems for Therapeutic Delivery: Status and Prospects

Chang Soo Kim 1, Gülen Yesilbag Tonga 1, David Solfiell 1, Vincent M Rotello 1,*
PMCID: PMC3538170  NIHMSID: NIHMS409773  PMID: 22981754

Abstract

Inorganic nanomaterials have an array of structural and physical properties that can be used in therapeutic delivery systems. The sizes, shapes, and surfaces of inorganic nanomaterials can be tailored to produce distinct interactions with biological systems both in vitro and in vivo. Nanoparticle cores can likewise be engineered to possess unique opticophysical properties, including upconversion, size-dependent absorbance/emission as well as magnetic properties such as superparamagnetism. These properties make inorganic nanomaterials useful imaging agents for noninvasive diagnostics and remotely activated theragnostics. Taken together, these unique properties of inorganic nanomaterials make them promising delivery systems.

Keywords: inorganic nanomaterials, drug delivery, upconversion, theragnostic, multifunctional, imaging agent

1. Introduction

Inorganic nanomaterials are rapidly emerging tools for therapeutic delivery [1]. On the physical side, nanoparticle (NP) cores can be designed to retain unique optical properties that enable remote activation and imaging for theragnostic applications [2]. The cores of these materials also provide scaffolds featuring structural and dynamic properties difficult or impossible to access using other materials such as polymer and lipid-based delivery vectors. Taken together, these properties enable new strategies for the presentation and encapsulation of drugs, biomolecules, and imaging agents (Fig. 1).

Fig. 1.

Fig. 1

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Schematic presentation of inorganic nanomaterials with different sizes and shapes. The inorganic nanomaterials possess various physical, chemical properties and may be used in numerous applications in imaging, delivery, and theragnostic applications.

In this highlight, we discuss selected recent advances in engineered inorganic nanosystems for delivery, diagnostic and theragnostic applications. We have divided this review into three categories: optical and magnetic properties of inorganic nanomaterials, the interaction of inorganic nanomaterials with their environment and applications of inorganic nanomaterials in imaging, delivery and theragnostics [3,4].

2. Quantum properties of inorganic nanomaterials

Quantum confinement of excitons within nanoscale inorganic crystals is one of the unique properties that distinguishes nanomaterials from their corresponding bulk solids [5]. Some of the benefits of quantum dots (QDs) with respect to fluorescent organic dyes are broad absorption spectra with narrow, size-tunable emissions that possess superior signal brightness and greater resistance to photobleaching. QDs can be functionalized with synthetic ligands that simultaneously passivate the inorganic core and provide the particles with additional functionalities. Together, these properties make QDs versatile nanoscale scaffolds for designing multifunctional NPs with both imaging and therapeutic functions [6].

Beside quantum confinement, another noteworthy feature of inorganic materials is capacity for the upconversion (UC) of light energy. In upconversion, the particle emits higher energy photons after being excited by multiple lower-energy photons (usually near-infrared (NIR) or infrared IR radiation) [7]. Upconverting particles are typically designed to emit visible light upon NIR-light excitation. NIR-to-Vis UC imaging systems allow the light source to penetrate more deeply into living tissues than down-conversion luminescent materials that often suffer from low signal-to-noise ratios as a result of shallow tissue-penetration depth (Fig. 2) [8,9]. Recently, Li et al. have reported the first example of triplet-triplet annihilation (TTA)-based UC system used for in vivo whole-body imaging [8]. Both sensitizer (octaethylporphyrin Pd complex) and annihilator (9,10-diphenylanthracene) have been successfully embedded into a silica NP to obtain a water-soluble TTA-based UC NP. These NPs demonstrate low cytotoxicity and high photo-stability, and exhibit quantum yields of 4.5 % in pure water.

Fig. 2.

Fig. 2

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(a) Schematic illustration of upconversion luminescence of NPs triplet–triplet annihilation - upconversion nanophosphors NPs (TTA-UCNP), and chemical structures of building blocks for TTA-UCNP. (b) Energy level diagram of sensitized TTA process. (Reproduced with permission from [8], copyright by the American Chemical Society).

3. The interface between nanoparticles and biosystems

Many factors affect the interactions between NPs and biological systems. The interfacial forces between NPs and biological membranes can be expressed mathematically in terms of particle ‘wrapping time’. Wrapping time is related to particle size and shape, as well as membrane surface energy and elasticity [10]. Chan et al. have observed differences in cellular uptake in a number of cell lines (A549, HeLa and MDA-MB 435) as a function of several physical aspects of NPs, including size and shape [11, 12]. This same group has described a protein ‘corona’ effect in which NPs become surrounded by a protein coat after being exposed to serum or extracellular environments. Biological coatings of this kind mask the synthetic identity of nanomaterials and provide them with biological properties. Xia et al. have also investigated the dependence of physical parameters (size, shape, density and surface coating) on the cellular uptake of inorganic NPs employing an inverted cell culture system to minimize sedimentation effects [13]. Size-dependent distribution of water-soluble QDs in vivo has been investigated in real time by the simultaneous injection and imaging of QDs (Fig. 3) [14]. Multiphoton microscopy images demonstrate that QDs (< 60 nm) are able to extravasate and diffuse away from blood vessels while 125 nm QDs do not extravasate due to interstitial transport barriers (Fig. 3 b-c).

Fig. 3.

Fig. 3

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Real-time intravital imaging of size-dependent QDs distribution in a SCID mouse bearing a Mu89 melanoma. (a) Multiphoton microscopy image of the distribution of NPs at 30 min. (b) Multiphoton microscopy images of distribution of the NPs in the same region as (a) at 120 min post-injection. (c) Penetration depth analysis at 60 min post-injection. (Reproduced with permission from [14], copyright by the John Wiley and Sons)

The interaction between inorganic nanomaterials and biological systems is also strongly affected by surface chemistry with Rotello et al. observing strong interactions of cationic NPs with cells [15, 16].

4. Applications for inorganic nanomaterials

4.1. Imaging applications of inorganic nanomaterials

Noninvasive imaging technologies, such as magnetic resonance imaging (MRI), optical imaging, positron emission tomography (PET), computed X-ray tomography, photothermal heterodyne imaging and ultrasound, play a critical role in clinical diagnoses and treatment [17, 18]. Inorganic NPs provide multifunctional agents for noninvasive imaging applications as a result of their magnetic and optical properties. These optical properties can be tuned by controlling the assembly process of inorganic nanomaterials via programmable intermolecular interactions [19]. Superparamagnetic iron oxides (SPIO) NPs may be used as MRI contrast agents, and have been used to image a number of organs in mice, including bowel, liver, and spleen [20]. Improved contrast in cancer imaging has been achieved using surface functionalized inorganic NPs carrying tumor-specific targeting ligands [21]. Inorganic NP imaging agents can assist cancer treatments by providing surgeons with the means of identifying tumor margins for resection procedures [22].

Gold NPs (AuNPs) provide promising optical contrast agents as a result of their size and shape dependent optical properties as well as their general biocompatibility. Nanospheres, nanocages, nanorods and nanoshells made from AuNPs have all been used as contrast agents in preclinical investigations [21]. NP imaging agents can compliment traditional imaging methods when used in multimodal imaging strategies. For example, the shallow tissue penetration of photoacoustic imaging with NPs can be complimented by the low-resolution deep tissue imaging of ultrasound [23, 24]. In Fig 4., photoacoustic images (Fig. 4 b-f) were used to identify one of four cell groups from the ultrasound image (Fig. 4a) that have been labeled with targeted AuNPs [24]. Together, the two imaging modalities produce a highly informative image of the diseased site. Furthermore, multimodal imaging can be used to map the distribution and clearance of NPs. Prasad et al. synthesized organically modified silica NPs conjugated with near-infrared fluorophores for optical imaging with maximum tissue penetration [25]. In addition, the NPs were radiolabeled with 124I for PET imaging making accurate NP quantification within various target organs possible after injection in mice. Biodistribution results show accumulation of NPs in the major reticuloendothelial system organs (e.g., liver, spleen and stomach), and a clearance study indicates hepatobiliary excretion of NPs.

Fig. 4.

Fig. 4

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Block diagram of the combined ultrasound and photoacoustic imaging system (a), photoacoustic images (b,c) and ultrasound (d) of gelatin implants in mouse tissue ex vivo at various laser illumination wavelengths. The cells with targeted AuNPs (red), control cells (white), the cells mixed with mPEG-SH coated Au NPs (green), and NIR dye (blue) are shown on the ultrasound image (d). (Reproduced with permission from [24], copyright by the American Chemical Society)

4.2. Application of inorganic nanomaterials in drug delivery

Nanomaterial-based drug delivery systems are highly attractive platforms for the efficient delivery and release of drugs to targeted tissues and cells. There are two major strategies for conjugating drugs to NPs: covalent or non-covalent association [26, 27]. Mirkin et al. have employed a covalent attachment strategy to conjugate paclitaxel (a potent chemotherapeutic drug) to AuNPs via DNA linkers, thereby enhancing the solubility and overall effectiveness of the drug [28]. Also, Zubarev et al. have attached a flexible hexaethylene glycol linker to the C-7 position of paclitaxel to conjugate it to phenol-terminated Au NPs [29]. Using this strategy, 70 molecules of paclitaxel were able to be loaded onto an AuNP in a controlled manner.

Rotello et al. have used the hydrophobic interior of Au NP monolayers to non-covalently encapsulate and deliver a hydrophobic drug molecule [30]. Depending on the strategy used, the release of a drug from its carrier can be triggered by a wide range of stimuli, such as hydrophobicity, pH, temperature, magnetic fields, enzymes, UV, and NIR photoluminescence [30, 31, 32, 33, 34, 35]. For instance, Burda et al. have shown a photodynamic therapy (PDT) drug such as silicon phthalocyanine 4 could be successfully adsorbed on PEGylated AuNPs and used as an effective PDT drug delivery vector for both in vitro and in vivo applications [36]. Also, Sun et al. have reported that a hydrophobic drug (cisplatin) can be loaded and released in low pH (<6) using porous hollow Fe3O4 NPs [37].

Inorganic nanomaterials can be designed to improve drug efficacy through enhanced targeting delivery [38]. For instance, El-Sayed et al. have quantified the degree of tumor cell uptake of Au nanorods covalently conjugated to tumor-targeting peptides [39]. Cheon et al. have created a multifunctional “all-in-one” magnetic NP comprising a cell-specific targeting moiety, a fluorescent dye, and a therapeutic siRNA payload to target images, and diseased cells simultaneously [40].

Inorganic nanomaterials can also be used as therapeutic agents themselves. Rotello et al. have reported the use of synthetic host–guest chemistry involving diaminohexane-terminated AuNPs (AuNP–NH2) and complementary cucurbit[7]uril (CB[7]) to provide a triggered activation of a therapeutic system (Fig. 5) [41]. Cytotoxicity in this system is triggered by removal of CB[7] in the presence of 1-adamantylamine.

Fig. 5.

Fig. 5

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(a) Structure of the diaminohexane-terminated AuNP and cucurbit[7]uril (CB[7]). (b) Activation of AuNP–NH2–CB[7] cytotoxicity by dethreading of CB[7] from the NP surface by 1-adamatylamine. (Reproduced with permission from [41], copyright by the Nature Publishing Group)

4.3. Theragnostic applications of inorganic nanomaterials

The combination of imaging and therapeutic systems generates a hybrid delivery platform, called “theragnostics”. The inherent properties of inorganic NPs, such as a facile surface modification, high surface to volume ratios, controllable shape/size, and unique optical properties, make them excellent candidates for theragnostic applications [42]. El-Sayed et al. have designed multifunctional anti-cancer AuNPs that can act as targeted contrast agents for photothermal cancer therapy and as scaffolds for enhanced potent cancer drug delivery [43].

The ability to functionalize magnetic NPs with targeting, therapeutic, and imaging moieties makes magnetic NPs an ideal platform for theragnostics [44]. Additionally, the thermal energy from magnetic NPs can be used as an external and a remotely regulated trigger for controlled drug release. Zink et al. have described a novel material that incorporates zinc-doped iron oxide nanocrystals within a pseudorotaxane functionalized mesoporous silica framework for the delivery of the cargo, with release effected by magnetic heating [45]. Zhang et al. have reported the facile synthesis of a hydrophilic multifunctional dual imaging mode mesoporous nanorattles making use of both its UC luminescent and magnetic properties [46]. Upon application of an alternating magnetic field, the thermal energy generated by the magnetic particles releases the drug by opening the gates of mesoporous silica carriers (Fig. 6). The concept of theragnostic dual imaging NPs with external stimuli can be applied in many biomedical applications by engineering additional functionalities onto the NPs.

Fig. 6.

Fig. 6

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(a) Schematic presentation of targeting of doxorubicin (DOX) loaded magnetic upconversion oxide nanospheres (MUC-F-NR) to tumor cells assisted by an externally applied magnetic field (MF). (b) Tumor location intensity increases with 1 h magnetic field treatment. (c) The luminescence signal at 650 nm. (d) Changes in tumor volume of mice treated with saline, MUC-F-NR, DOX, and DOX loaded MUC-F-NR over 21 days in the absence and presence of MF. (Reproduced with permission from [46], copyright by the American Chemical Society)

5. Conclusions

The unique physical and chemical properties of inorganic nanomaterials contribute to their wide range of possible applications in imaging, drug delivery, and theragnostics. Quantum confinement, facile size/shape and surface modification, and tunable optical properties make inorganic nanoparticles versatile design platforms for multifunctional biomedical technologies. Taken together, inorganic particles provide excellent tools for fundamental research and candidates for therapeutic, imaging, and theragnostic applications.

Acknowledgements

This work was supported by grants from the NIH (EB014277 and GM077173).

Footnotes

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