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. 2013 Oct 21;1(39):10.1039/C3TB20595A.
doi: 10.1039/C3TB20595A.

Bacteriophage Associated Silicon Particles: Design and Characterization of a Novel Theranostic Vector with Improved Payload Carrying Potential

Srimeenakshi Srinivasan  1 , Jenolyn F Alexander  1 , Wouter H Driessen  2 , Fransisca Leonard  1 , Hu Ye  1 , Xuewu Liu  1 , Wadih Arap  2 , Renata Pasqualini  2 , Mauro Ferrari  1 , Biana Godin  1
Affiliations

Bacteriophage Associated Silicon Particles: Design and Characterization of a Novel Theranostic Vector with Improved Payload Carrying Potential

Srimeenakshi Srinivasan et al. J Mater Chem B. .

Abstract

There has been extensive research on the use of nanovectors for cancer therapy. Targeted delivery of nanotherapeutics necessitates two important characteristics; the ability to accumulate at the disease locus after overcoming sequential biological barriers and the ability to carry a substantial therapeutic payload. Successful combination of the above two features is challenging, especially in solid porous materials where chemical conjugation of targeting entities on the particle surface will generally prevent successful loading of the therapeutic substance. In this study, we propose a novel strategy for decorating the surface of mesoporous silicon particles with targeting entities (bacteriophage) and gold nanoparticles (AuNP) while maintaining their payload carrying potential. The resulting Bacteriophage Associated Silicon Particles (BASP) demonstrates efficient encapsulation of macromolecules and therapeutic nanoparticles into the porous structures. In vitro targeting data show enhanced targeting efficiency with about four orders of magnitude lower concentration of bacteriophage. In vivo targeting data suggest that BASP maintain their integrity following intravenous administration in mice and display up to three fold higher accumulation in the tumor.

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Figures

Figure 1
Figure 1. Schematic presentation of BASP
showing the interaction of the three components: S1MP (grey), AuNP (yellow) and targeting peptide (red) displaying filamentous bacteriophage (orange). The inset shows the pores of S1MP loaded with S2NP (blue).
Figure 2
Figure 2. Visualization of the BASP formation
(A) Macroscopic view on network/gel formation corresponding to the association of AuNP-bacteriophage networks with S1MP to form BASP at serial dilutions of the bacteriophage starting from the concentration of 3.87×105 TU/μL; (B) Confocal microscopic image of BASP with BSA-FITC loaded S1MP(+) (Green) and Dylight 594 labeled phage (Red) showing the specific co-localization of the two; (C) TEM image of BASP showing the S1MP surrounded by AuNP (arrow heads) and bacteriophage (arrows).
Figure 3
Figure 3. Effect of porosity and surface zeta potential of S1MP on BASP formation
(A) SEM micrographs demonstrating the importance of porosity in the association of the AuNP-bacteriophage networks with S1MP having (i) 20–30nm pores, (ii) 40–60nm pores, (iii) nonporous surface; (B) Zeta potential of BASP and their components (inset) SEM image of BASP with S1MP(-) and S1MP(+) showing better adhesion of AuNP-bacteriophage networks to the S1MP(+) in comparison to S1MP(-); (C) Contact angle measurements of BASP showing an increase in hydrophilicity in comparison to AuNP or AuNP-bacteriophage.
Figure 4
Figure 4. Spectral characterization of BASP
(A) UV-Vis spectra of BASP show 2–3 fold increase in the NIR absorbance of BASP in comparison with the same concentration of AuNP; (B) Detection of BASP using NIR-SERS signal of bacteriophage in close association with AuNP and S1MP; (C) Temperature as a function of NIR laser exposure time of AuNP and BASP.
Figure 5
Figure 5. Time dependent degradation of S1MP and BASP in 100% FBS
(A) SEM micrographs showing the pattern of degradation of the porous silicon particles over time (Scale bar = 500nm); (B) ICP-OES quantification of the degradation profile expressed as a percentage of total silicon content released from S1MP over time.
Figure 6
Figure 6. Loading of S2NP into BASP
(A) Iron content analysis in S1MP, BASP and ESTA-S1MP following loading of SPION using the wet incipient method as quantified by ICP-OES; (B) Comparison of transverse relaxivity, r2 and (C) relaxation times, T2, of SPION loaded particles; (D) Fluorescence microscopic images of QD (green) loaded S1MP and BASP (red) showing S1MP colocalization with QD (yellow). In a control experiment, free QD nonspecifically bound to AuNP-bacteriophage networks (arrow heads) enable the visualization of the bacteriophage fibers (green) while the AuNP appear as red dots.
Figure 7
Figure 7. In vivo integrity of BASP
Mice bearing EF43.fgf4 mammary xenografts were injected intravenously with BASP. After a 4h circulation time, the animals were sacrificed and the tumor and liver were harvested and processed for histological analysis. (A) Fluorescence microscopy and (B) Immunohistochemistry analyses for bacteriophage (brown) show that the (i) bacteriophage remains associated with S1MP and the assembly is not impaired in the circulation (ii) Negative staining control; (C) Hyperspectral images of the liver show superimposed spectral mapping of silicon and AuNP also confirming the close association of the AuNP and S1MP in the BASP.
Figure 8
Figure 8. In vitro targeting in Kaposi sarcoma cells
Kaposi sarcoma cells incubated with integrin targeted systems (104 TU/μL bacteriophage concentration) for 6h. Enhanced association of bacteriophage (red) with cells incubated with integrin targeted BASP can be seen when compared to bacteriophage only. Nuclei stained with DAPI (blue).
Figure 9
Figure 9. Biodistribution of targeted BASP
Silicon content in different organs as measured by ICP-OES. Balb/C mice bearing orthotopic EF43.fgf4 tumors were injected intravenously with either S1MP or integrin mimicking BASP. After a 4h circulation time, the animals were sacrificed and the organs were harvested and processed for silicon content analysis.
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