Jessica M. Rosenholm

Targeting of Porous Hybrid Silica Nanoparticles to Cancer Cells

Mesoporous silica nanoparticles functionalized by surface hyperbranching polymerization of poly(ethylene imine), PEI, were further modified by introducing both fluorescent and targeting moieties, with the aim of specifically targeting cancer cells. Owing to the high abundance of folate receptors in many cancer cells as compared to normal cells, folic acid was used as the targeting ligand. The internalization of the particles in cell lines expressing different levels of folate receptors was studied. Flow cytometry was used to quantify the mean number of nanoparticles internalized per cell. Five times more particles were internalized by cancer cells expressing folate receptors as compared to the normal cells expressing low levels of the receptor. Not only the number of nanoparticles internalized per cell, but also the fraction of cells that had internalized nanoparticles was higher. The total number of particles internalized by the cancer cells was, therefore, about an order of magnitude higher than the total number of particles internalized by normal cells, a difference high enough to be of significant biological importance. In addition, the biospecifically tagged hybrid PEI-silica particles were shown to be noncytotoxic and able to specifically target folate receptor-expressing cancer cells also under coculture conditions.

Targeted intracellular delivery of hydrophobic agents using mesoporous hybrid silica nanoparticles as carrier systems.

Targeted nanoparticle-mediated intracellular delivery is demonstrated using two hydrophobic fluorophores as model drug cargo. The presented hybrid carrier system exhibits both cancer cell-targeting ability and capacity to retain a hydrophobic agent with subsequent specific release into the endosomal compartment. Furthermore, the incorporated agent is shown to be able to escape from the endosomes into the cytoplasm, making the particles promising candidates as carriers for targeted drug delivery for cancer treatment.

Towards establishing structure–activity relationships for mesoporous silica in drug delivery applications

Mesoporous silicas are currently widely studied carrier matrices in drug delivery applications. Surface functionalization of the silica is often employed in order to enhance the interaction between the drug and the support. However, in many cases the effectiveness of the introduced surface functions is much lower than what could be expected, and the release rate from surface functionalized silica is often not very different from that of the bare silica support, suggesting that the drug-support interactions are weaker than assumed under physiologically relevant conditions. We have therefore studied the adsorption of a model acidic drug, salicylic acid, to amino-functionalized mesoporous silica both from organic solvents, and from water as a function of pH, in order to rationalize these findings. It is shown that the nature of the organic solvent has a great influence on the loading degree, which however is more pronounced for the pristine silica materials due to absence of strong drug-support interactions. More importantly, the net effective surface charge of the adsorbent was found to control the adsorption process in water, and remaining silanols on the silica surface after functionalization have a marked influence on the drug-support interactions. The results can explain the relatively minor influence of amino groups on the release of acidic drugs reported in the literature, and gives a rational basis for optimization of support-drug interactions. The results are also of interest for optimization of drug immobilization and purification, as many medicinal and biologically active compounds are organic acids.

Nanoparticles in targeted cancer therapy: mesoporous silica nanoparticles entering preclinical development stage

Nanotechnology may help overcome persisting limitations of current cancer treatment and thus contribute to the creation of more effective, safer and more affordable therapies. While some nanotechnology-based drug delivery systems are already being marketed and others are in clinical trial, most still remain in the preclinical development stage. Mesoporous silica nanoparticles have been highlighted as an interesting drug delivery platform, due to their flexibility and high drug load potential. Although numerous reports demonstrate sophisticated drug delivery mechanisms in vitro, the therapeutic benefit of these systems for in vivo applications have been under continuous debate. This has been due to nontranslatable conditions used in the in vitro studies, as well as contradictory conclusions drawn from preclinical (in vivo) studies. However, recent studies have indicated that the encouraging cellular studies could in fact be repeated also in vivo. Here, we report on these recent advances regarding therapeutic efficacy, targeting and safety issues related to the application of mesoporous silica nanoparticles in cancer therapy.

Multifunctional Mesoporous Silica Nanoparticles for Combined Therapeutic, Diagnostic and Targeted Action in Cancer Treatment

The main objective in the development of nanomedicine is to obtain delivery platforms for targeted delivery of drugs or imaging agents for improved therapeutic efficacy, reduced side effects and increased diagnostic sensitivity. A (nano)material class that has been recognized for its controllable properties on many levels is ordered mesoporous inorganic materials, typically in the form of amorphous silica (SiO2). Characteristics for this class of materials include mesoscopic order, tunable pore dimensions in the (macro)molecular size range, a high pore volume and surface area, the possibility for selective surface functionality as well as morphology control. The robust but biodegradable ceramic matrix moreover provides shelter for incorporated agents (drugs, proteins, imaging agents, photosensitizers) leaving the outer particle surface free for further modification. The unique features make these materials particularly amenable to modular design, whereby functional moieties and features may be interchanged or combined to produce multifunctional nanodelivery systems combining targeting, diagnostic, and therapeutic actions. This review covers the latest developments related to the use of mesoporous silica nanoparticles (MSNs) as nanocarriers in biomedical applications, with special focus on cancer therapy and diagnostics.

Amino-functionalization of large-pore mesoscopically ordered silica by a one-step hyperbranching polymerization of a surface-grown polyethyleneimine.

A simple method for surface functionalization of large-pore mesoporous silica by hyperbranching polymerization resulting in a high loading of amine groups is presented.

Cancer-cell targeting and cell-specific delivery by mesoporous silica nanoparticles

Mesoporous silica nanoparticles (MSNs) have emerged as promising drug carriers. Here we highlight some recent developments related to cell-specific targeting and delivery using MSNs. Some key requirements for carrier design are discussed from a biological perspective, including a suggested experimental work-flow for the evaluation of active cell-specific targeting of nanoparticles.

Core-shell designs of photoluminescent nanodiamonds with porous silica coatings for bioimaging and drug delivery I: fabrication

A multifunctional core-shell nanocomposite platform consisting of a photoluminescent nanodiamond (ND) core with uniform porous silica coatings is presented. This design intended for drug delivery applications allows simultaneous stable fluorescent imaging with high loading capacity of bioactive molecules. Despite irregularly shaped starting cores, well-dispersed and uniformly shaped nanocomposite particles can be produced. Moreover, after optimization of the silica source-to-diamond ratio, the thickness of the porous layer can be tuned by adjusting the ethanol amount, allowing rational nanoparticle size control. The ND key property, photoluminescence, is not quenched regardless of coating with thick silica layers. The high loading capacity for incorporation of active agents, provided by the introduced porous layer, is demonstrated by adsorption of a hydrophobic model drug to the composite particles. The loading degree, as compared to a pure ND, increased by two orders of magnitude from 1 wt% for the ND to >100 wt% for the composite particles. Combining these two material classes, which both have well-documented excellent performance especially in biomedical applications, for the NDs with emphasis, but not exclusively, on imaging and mesoporous silica (MSN) on drug delivery, the advantages of both are shown here to be synergistically integrated into one multifunctional nanocomposite platform.

Shape engineering vs organic modification of inorganic nanoparticles as a tool for enhancing cellular internalization

In nanomedicine, physicochemical properties of the nanocarrier affect the nanoparticles pharmacokinetics and biodistribution, which are also decisive for the passive targeting and nonspecific cellular uptake of nanoparticles. Size and surface charge are, consequently, two main determining factors in nanomedicine applications. Another important parameter which has received much less attention is the morphology (shape) of the nanocarrier. In order to investigate the morphology effect on the extent of cellular internalization, two similarly sized but differently shaped rod-like and spherical mesoporous silica nanoparticles were synthesized, characterized and functionalized to yield different surface charges. The uptake in two different cancer cell lines was investigated as a function of particle shape, coating (organic modification), surface charge and dose. According to the presented results, particle morphology is a decisive property regardless of both the different surface charges and doses tested, whereby rod-like particles internalized more efficiently in both cell lines. At lower doses whereby the shape-induced advantage is less dominant, charge-induced effects can, however, be used to fine-tune the cellular uptake as a prospective ‘secondary’ uptake regulator for tight dose control in nanoparticle-based drug formulations.

On the complexity of electrostatic suspension stabilization of functionalized silica nanoparticles for biotargeting and imaging applications

Different means of attaching streptavidin to surface functionalized silica particles with a diameter of 240 nm were investigated with special focus on suspension stability for electrostatically stabilized suspensions. The influence of two different fluorescent dyes covalently linked to the streptavidin on suspension stability was also studied. The results clearly show that the stability of the suspensions is crucially dependent on all functional groups present on the surface. The surface functions may either directly affect the effective surface charge if the functions contain charged groups, or indirectly by affecting the relative concentration of charged groups on the particle surface. Poly(ethylene imine)-functionalized silica particles, where the polymer is grown by surface hyperbranching polymerization, are shown to be promising candidates for bioapplications, as the zeta-potential can remain strongly positive even under biologically relevant conditions.