Targeted Cytosolic Delivery of Cell-Impermeable Compounds by Nanoparticle-Mediated, Light-Triggered Endosome Disruption

Abstract

Nanoparticle (NP)-mediated drug delivery typically relies on cargo release to occur passively or in response to environmental stimuli. Here we present a delivery method based on light-activated disruption of intracellular vesicles after internalization of biofunctionalized mesoporous silica nanoparticles loaded with cargo. This method combines the power of targeted delivery with the spatiotemporal control of light activation. As an example, we delivered a cell-impermeable fluorescent compound exclusively to the cytosol of multidrug resistant cancer cells in a mixed population. KeywordsMesoporous silica; nanoparticles; P-glycoprotein; drug delivery; photodynamic therapy; endosomeThe potential of nanomaterials for drug delivery has been extensively explored in recent years. [1][2][3][4] Such efforts have been driven to a large extent by the need to reduce side effects in anticancer drugs (such as doxorubicin's severe cardiotoxicity) via tissue-specific targeting. 5 Beyond enhanced targetability, NP-encapsulation of drugs may also provide protection against premature degradation and enable efficient delivery of substances with poor inherent solubility or membrane permeability. Important determinants of the success of NP-mediated drug delivery are biocompatibility, circulation time, immunogenicity, specific targeting, © 2010 American Chemical Society * To whom correspondence should be addressed. dclapham@enders.tch.harvard.edu. HHMI Author Manuscript HHMI Author Manuscript HHMI Author Manuscripttiming of cargo release and, ideally, access to intracellular compartments. Careful tuning of NP size, especially in the 10-100 nm range, enables control of circulation time, 6,7 as well as passive tumor accumulation due to the "enhanced permeability and retention" effect. 8 Particle size also affects NP cellular uptake. 9 A highly desirable feature of NP-based delivery platforms is precise temporal control of compound release. This can be regulated by incorporating release mechanisms triggered by environmental stimuli such as pH, 10 temperature, 11 or enzymatic reactions. 12 Another important way to control payload delivery for membrane-impermeable drugs is to regulate access to the cytosol, which usually requires escape from the endolysosomal compartment where particles are clustered following receptor-mediated endocytosis. Here we present a method for precise spatial and temporal control over cytosolic delivery of compounds that would otherwise be cell-impermeable by incorporating a light-triggered endosomal escape mechanism within a cell targetable mesoporous silica carrier.Among potential nanocarriers, mesoporous silicate materials 13-15 have demonstrated great potential for biomedical applications due to their biocompatibility, ease of functionalization, and large surface-to-volume ratio. 16 They have been successfully used to deliver drugs, 17,18 proteins 19 and nucleic acids. 20,21 Most recent efforts have been focused on their biological targeting in order to achieve site-specific delivery. 16,22 Size contro...

Tailoring the interplay between electromagnetic fields and nanomaterials toward applications in life sciences: a review

“…178 Also, some hybrid materials that combine photosensitizers and NPs have been described. [179][180][181][182] In all the above examples, PDT is achieved by direct light excitation of photosensitizers, which may be or may not be tagged on passive NPs, cf. Fig.…”

Polysaccharide-based nanoparticles for co-loading mitoxantrone and verapamil to overcome multidrug resistance in breast tumor

“…This certainly showed that DOX-VRPPENPs successfully reached the nucleus in significant quantities after getting into the cells, to ensure the cytotoxic role of DOX. 46,47 Overall, these results iterate that PENPs co-loaded with VRP have great potential for the delivery of cytotoxic drugs to overcome MDR in tumor treatments. …”

Smart Drug Delivery Systems

“…Febvay et al [88] designed a system based on this strategy, which involved the use of a mesoporous silica nanoparticle to house the drug system, whose surface is decorated with both PEG and antibodies for cell surface targeting. The drug in this case is a model compound, or an Alexa546 membrane impermeable dye to ensure that all fluorescence is attributed to internalized species from the nanoparticle drug delivery system (Fig.…”

“…After nanoparticle endocytosis (b), the cargo is released in the endosome (c). Exposure to light at the dye's excitation wavelength (546 nm) promotes ROS-mediated membrane damage (d) with cytosolic delivery of Alexa546 exclusively in the P-gp expressing cells [88] control over the route of drug delivery and begins to address another critically important question that lies largely unanswered. What can be done to effectively promote the intracellular activity of an internalized drug?…”

“…For these reasons, an opportunity exists to design a tandem system where a magnetoresponsive material is coupled to a thermoresponsive material. The bars represent SD [88] In this system, under alternating magnetic field, the magnetic particles would generate enough heat to shift the thermoresponsive material through its LCST and destabilize the self-assembled species to release the encapsulated drug.…”