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Bombarding Cancer: Biolistic Delivery of Therapeutics using Porous Si Carriers
Adi Tzur-Balter, Neta Zilony, Orit Shefi, Ester Segal

Date: 2014-03-11 06:30 PM – 09:30 PM
Last modified: 2014-02-01

Abstract


SUMMARY

A new paradigm for an effective delivery of therapeutics into cancer cells is presented. Degradable porous silicon carriers, tailored to carry and release a model anticancer drug, are biolistically bombarded into in-vitro cancerous cultures. We demonstrate the ability to launch these highly porous microparticles by a pneumatic capillary gene gun, which is conventionally used to deliver cargos by non-degradable heavy metal carriers. By optimizing the gun parameters, we have successfully delivered the porous carriers, to reach deep targets and to cross a skin barrier in a highly spatial resolution. Our study reveals significant cytotoxicity towards the target cells, human breast carcinoma, following the delivery of drug-loaded carriers, while administrating empty particles results in no effect on cell viability. The unique combination of biolistics with the temporal control of payload release from porous carriers presents a powerful and non-conventional platform for designing new therapeutic strategies.

INTRODUCTION

Much effort is devoted to the development of new drug delivery methodologies, focusing on specificity and accuracy aspects. Biolistics has emerged as a promising non-invasive route for delivering payloads into both cells and tissue. In the biolistic method, originally developed for gene expression manipulations 1, molecules are carried by heavy metal particles, accelerated to high speeds by flow of a gas and launched into the target tissue. In the present study we show for the first time the application of biolistics for highly controlled delivery of therapeutic payloads carried by degradable porous Si (PSi) particles 2. We employ a modified version of the pneumatic capillary gene gun 3, which allows the application of high He pressures, to launch the PSi carriers into two- and three dimensional (2D, 3D) targets.

RESULTS AND DISCUSSION

In attempt to extend the biolistic delivery methodology into a powerful therapeutic tool, we have used a novel gene gun setup 3, 4 to bombard PSi microparticles into 2D and 3D targets. The design of our gun allows the application of extremely high He pressures to launch the “airy” particles (65% porosity) with no spatial damage to the target. In the current setup, negative vacuum pressure (through the ‘vacuum tube’, see Figure 1A) is applied to divert the He flow from the target to prevent gas shock damages.

 

 

 

Figure 1: (A) The biolistic setup. (B) HR-SEM micrographs of PSi microparticles. (C) Particle size distribution of PSi carriers. (D) A typical distribution curve of the number of PSi particles and (E) gold particles (1.6 μm) targeted to 2% agarose gel vs. the penetration depth, He pressures of 20/25 psi (particles/He tube).

 

By proper control of the bombardment conditions, the PSi microparticles, ranging in size between 2-18 μm with 74 wt% of particles in the range of 2-10 μm (Figure 1B and 1C), were launched to depths of ~2000 μm. A typical distribution of the penetration depths of the particles is depicted in Figure 1D. The applied bombardment conditions were also examined for the delivery of commercially available gold microparticles (commonly used in biolistic applications and are heavier by at least ~2 fold than the studied PSi particles), see Figure 1E. In these experiments, the penetration depths were notably lower (240 μm).

Drug-loaded PSi microparticles, designed to exhibit a sustained release of the anticancer drug Mitoxantrone (MTX) over several days5, were launched into MDA-MB-231 cell cultures. Viability studies were carried out following the bombardment of MTX-loaded PSi and Neat-PSi (empty) particles (See Figure 2). At all studied time points, cell viability was not affected by the bombardment of Neat-PSi particles, demonstrating that the biolistic administration may potentially allow non-invasive injection of PSi carriers into diseased tissues. The targeted delivery of MTX-loaded particles resulted in a profound cell death of ~40%, 48 h after bombardment. By administration of multiple doses, we have achieved a reduction of 95% in viable cancer cells, showing that the efficacy of this biolistic-mediated therapeutic route can be controlled and optimized.

Figure 2: Cell viability experiments following biolistic delivery of neat PSi and drug-loaded PSi6.

To demonstrate the feasibility of the biolistic methodology for non-invasive delivery of therapeutic cargos into tissues, we have bombarded fluorescently labeled PSi particles through freshly excised porcine skin into a 3D agarose gel (see Figure 3). Porcine skin is used to mimic the barrier function of the human stratum corneum7, due to its structural and functional resemblance to human skin. Obviously, the porcine skin barrier (~700 μm thick) hinders particles penetration and results in a maximal penetration depth of ~1 mm.

 

 

 

Figure 3: Delivery of PSi particles into a 3D set-up: (A) A schematic diagram of a porcine skin placed atop agarose gel. (B) The freshly excised porcine skin (C) PSi particles labeled with Texas Red as detected in the gel using confocal microscopy following biolistic delivery6.

CONCLUSIONS

The methodology presented in this work provides a new paradigm for an effective delivery of therapeutics into cancer cells. The use of biolistics to administer degradable PSi particles, which can practically be tailored to carry a variety of payloads with controlled release profiles, and the ability to cross skin barrier, offers a generic approach for advanced nanomedicine.


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