Polyethylene glycol modified ORMOSIL theranostic nanoparticles for triggered doxorubicin release and deep drug delivery into ovarian cancer spheroids

https://doi.org/10.1016/j.jphotobiol.2017.07.020Get rights and content

Highlights

  • PEGylated Ormosil theranostic nanoparticles for ovarian cancer applications

  • Ormosil nanoparticles generate heat & release drug to near infrared laser exposure.

  • Laser exposure markedly increased cytotoxicity in ovarian cancer cells.

  • Exposure to laser improved drug distribution in 3-D ovarian cancer spheroids.

  • Encapsulation of IR820 led to an increase in its in-vivo circulation time.

Abstract

A novel pegylated multifunctional probe of Ormosil nanoparticles (PEGCDSIR820) loaded with Near Infrared dye (NIR; IR820) and a chemotherapeutic drug, Doxorubicin (DOX) was developed for cancer theranostic applications. PEGCDSIR820 nanoparticles had an average diameter of 58.2 ± 3.1 nm, zeta potential of − 6.9 ± 0.1 mV in cell culture media and stability against aggregation in physiological buffers. The encapsulation efficiency of DOX was 65.0 ± 3.0%, and that of IR820 was 76.0 ± 2.1%. PEGCDSIR820 showed no cytotoxicity in ovarian cancer cells (Skov-3). The cytotoxicity markedly increased when Skov-3 cells incubated with PEGCDSIR820 particles were exposed to 808 nm laser due to the combination of adjuvant hyperthermia (43 °C) and enhanced DOX release. Exposure to laser enhanced the release of DOX, 45% of DOX release was observed in 3 h compared to 23% without laser exposure. Confocal imaging in Skov-3 cells showed that the combination of hyperthermia due to NIR exposure and release of DOX caused cell necrosis. Furthermore, in spheroids exposed to NIR laser penetration of DOX was deeper compared to the absence of laser exposure. Skov-3 spheroids incubated with pegylated nanoparticles for 24 h and exposed to laser showed 94% reduction in cell viability. Encapsulation of IR820 in PEGCDSIR820 increased the in-vivo elimination half-life to 41.0 ± 7.2 h from 30.5 ± 0.5 h of free IR820.

Section snippets

Background

Theranostic nanomedicine has the potential to simultaneously treat (therapy) and image (diagnostics) cancer. Multifunctional nanoparticles encapsulated with imaging probes and chemotherapeutic agents can be delivered to tumors in-vivo passively via the enhanced permeation and retention (EPR) effect and to cancer cells through actively targeting cell specific receptors. For theranostic nanomedicine to be effective, the imaging agent and drug must be retained effectively by the carrier (against

Nanoparticle Synthesis

DOX-Silane (DOX-ICPTES) conjugate was prepared by reacting 5 mg DOX-HCL with 20 μl 3-(Triethoxysilyl)propylisocyanate (ICPTES)) in the presence of 2 M excess Triethylamine (TEA). Organically modified silica nanoparticles were formulated by a modification of the ternary microemulsion system reported by Paras et al. [11]. Briefly, 0.44 mg of Dioctyl sulfosuccinate sodium salt (AOT) was dissolved in 20 ml of deionized water followed by the addition of 800 μl 1-butanol resulting in a clear solution. To

Size and Zeta-potential

The physical characteristics of CDSIR820 and PEGCDSIR820 are shown in Table 1. In aqueous media, physical processes such as aggregation and swelling of organic groups on the nanoparticle surface determine the effective nanoparticle size measured by dynamic light scattering (hydrodynamic diameter). PEG layers on the nanoparticle surface swell in PBS and hence the hydrodynamic diameter of CDSIR820 increased to 58.2 ± 3.1 nm from 52.5 ± 2.5 (5.7 nm increase) after pegylation. Addition of PEG improved

Conclusion

We report a novel theranostic system of pegylated Ormosil nanoparticles encapsulated with NIR dye IR820 and DOX (PEGCDSIR820) that is capable of NIR imaging, chemotherapy and adjuvant NIR hyperthermia. Pegylated nanoparticles possess the physical properties, e.g., stability against aggregation in physiological media, size (50–60 nm) and surface charge (− 6.2 mV) for optimal cell uptake and passive targeting of tumors via the EPR effect. Exposure to NIR laser resulted in a rapid rise of temperature

Acknowledgements

The authors would like to acknowledge the contribution of Mr. Pedro Da Costa, Mr. Mathhew Chacko, Mr. Nour Ahlawad and Mr. Juan Pablo Olguin in assisting with the in-vivo bio distribution studies. We also thank the Chambers Lab and Dr. Jeremy W Chambers of Herbert Wertheim College of Medicine at FIU for the use of LiCor Imaging system.

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