Mika Lindén

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.

Mesoporous silica nanoparticles in medicine—Recent advances☆

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.

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.

Cancer‐Cell‐Specific Induction of Apoptosis Using Mesoporous Silica Nanoparticles as Drug‐Delivery Vectors

Targeted delivery of the chemotherapeutic agent methotrexate (MTX) to cancer cells using poly(ethyleneimine)-functionalized mesoporous silica particles as drug-delivery vectors is reported. Due to its high affinity for folate receptors, the expression of which is elevated in cancer cells, MTX serves as both a targeting ligand and a cytotoxic agent. Enhanced cancer-cell apoptosis (programmed cell death) relative to free MTX is thus observed at particle concentrations where nonspecific MTX-induced apoptosis is not observed in the nontargeted healthy cell line, while corresponding amounts of free drug affect both cell lines equally. The particles remain compartmentalized in endo-/lysosomes during the time of observation (up to 72 h), while the drug is released from the particle only upon cell entry, thereby inducing selective apoptosis in the target cells. As MTX is mainly attached to the particle surface, an additional advantage is that the presented carrier design allows for adsorption (loading) of additional drugs into the pore network for therapies based on a combination of drugs.

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.

Recent Advances in Nano- and Macroscale Control of Hexagonal, Mesoporous Materials

Nano- and macroscale control of siliceous MCM-41 type, hexagonal, mesoporous materials are discussed with reference to proposed mechanisms of formation and morphological manipulation. The complex interplay of surfactant silicate chemistry in the numerous synthetic strategies of MCM-41 type materials reported to date are examined. Recent advances in the growth of thin film mesoporous silicates from solid-liquid, air-liquid and liquid-liquid interfaces are reviewed. Extension into three-dimensional silicate structures is made possible through detailed control of shear flow conditions and reaction composition.