Porous silicon advances in drug delivery and immunotherapy

Abstract

Biomedical applications of porous silicon include drug delivery, imaging, diagnostics and immunotherapy. This review summarizes new silicon particle fabrication techniques, dynamics of cellular transport, advances in the multistage vector approach to drug delivery, and the use of porous silicon as immune adjuvants. Recent findings support superior therapeutic efficacy of the multistage vector approach over single particle drug delivery systems in mouse models of ovarian and breast cancer. With respect to vaccine development, multivalent presentation of pathogen-associated molecular patterns on the particle surface creates powerful platforms for immunotherapy, with the porous matrix able to carry both antigens and immune modulators.

Figure 1. Schematic overview presenting porous silicon microparticle fabrication and applications in drug delivery and immunotherapy

The central image is a scanning electron micrograph showing a patterned pSi wafer prior to sonication-based release of the patterned particles. The multistage vector concept of drug delivery is shown to the left, with intravascular administration of pSi particles resulting in tumor-associated vascular accumulation based on geometric properties, charge or targeting ligands. Secondary nanoparticles, released from the porous matrix, migrate into the tumor tissue to deliver the therapeutic payload. Utilization of pSi for vaccine development is shown to the right. Particles, loaded with antigens and immune modulators, are surface-coated with pathogen-associated molecular patterns (PAMPs), leading to enhanced dendritic cell activation and particle internalization. Once internalized, the antigen cargo is processed, both within the endosomal pathway and within the proteasome, for presentation to lymphocytes in association with major histocompatibility class I and II molecules. Graphical images created by Mr. Matthew Landry, graphic artist in the Department of Nanomedicine at The Methodist Hospital Research Institute.

Figure 2. Porous silicon microparticles in varying geometries

The pseudo-colored scanning electron micrograph shows a variety of pSi microparticles, fabricated in diverse sizes, shapes, and porosities. Image taken at 17,500x magnification using the FEI Nova NanoSEM housed in the Methodist Hospital Research Institute SEM/AFM Imaging Core.

Figure 3. In vitro cellular association of pSi particles with endothelial cells and in vivo therapeutic efficacy of multistage vector delivery of EphA2 siRNA and paclitaxel

A. Confocal (single plane and z-stacked) and an electron micrograph show 2 μm pSi nanowires located within or in the process of being internalized by endothelial cells. Cells in the confocal images are labeled with nuclear (blue) and cytoskeleton (red actin and green microtubules) dyes. B. The scanning electron micrograph shows an endothelial cell with 3 μm hemispherical pSi particles associated with the cell surface. Particles are pseudo-colored in blue. Reproduced by permission of The Royal Society of Chemistry, Nanoscale, Serda et al.[50] C. Tumor weight 6 weeks after initiation of biweekly multistage vector (MSV) /EphA2 siRNA injections (intravascular) in combination with paxlitaxel (PTX; weekly; intraperitoneal) or monotherapy in a mouse model of ovarian cancer (2 mg/kg PTX; scr = scrambled siRNA; **p<0.01). Reprinted with permission from the American Association of Cancer Research, Clinical Cancer Research, Shen H, et al. [33]. D. Antitumor efficacy of MSV loaded with PTX in female nude mice bearing MDA-MB-468 breast cancer xenografts. Treatment groups included: (i) control micelles; (ii) PTX micelles; (iii) PTX Cremophor EL (CrEL, a polyethoxylated castor oil formulation); and (iv) PTX MSV (all were treated with a single dose at Day 0; PTX 15 mg/kg). Asterisks denote results in which the difference was statistically significant compared to the control group (*p<0.05; **p<0.01; ***p<0.001). Reproduced with permission from Elsevier, Cancer Letters, Blanco E, et al. [35].

Figure 4. In vitro association of pSi microparticles with dendritic cells and in vivo migration of the particle-loaded cells to the draining lymph node

A. The scanning electron micrograph shows a murine bone marrow-derived dendritic cell (BMDC) associating with three pSi microparticles, pseudo-colored in pink (cell false-colored blue). B. The transmission electron micrograph shows a BMDC with multiple internalized pSi particles (white boxes), associating with a T cell. C. Confocal micrographs of BMDC following 3 hr incubation with pSi microparticles. Particles are labeled with DyLight 594 and TLR-4 ligands, while cells are labeled with Oregon Green 488 phalloidin and DAPI for actin and nuclear visualization, respectively. D. In vivo percent of hock-injected CellTracker Orange-labeled BMDC migrating to the draining lymph nodes (LN) following stimulation by pSi microparticles with discrete surface functionalization (*p<0.001 compared to BMDC).Reproduced with permission from Molecular Pharmaceutics, Volume 8, Meraz et al, Activation of the Inflammasome and Enhanced Migration of Microparticle-Stimulated Dendritic Cells to the Draining Lymph Node, pages 1683-1696. Copyright 2012 American Chemical Society.