Biocompatibility of synthetic nanomaterials and their applications in gene delivery

Nanomedicine is the use of nanoscale or nanostructured materials in medicine that due to their structure have unique medical effects. Prominent applications of nanomedicine are the use of nanomaterials for the delivery of drugs and nucleic acids (to correct gene defects). Nanomaterials offer several attractive features as delivery vehicles: First, their size in the nano-regime endows them with more desirable pharmacokinetic and biodistribution profiles in vivo. Second, they are amenable to diverse chemical engineering that enables loading of a wide range of substances. Third, they can protect therapeutic agents from premature degradation or from inducing undesired side effects.

In this thesis, two types of synthetic nanomaterials, namely silica and polythiophene, were investigated for their biocompatibility and applications in gene delivery.

In Paper I, human red blood cell hemolysis and premyelocytic leukemia HL-60 cell cytotoxicity induced by silica nanoparticles with distinct physicochemical properties were studied, suggesting that silica nanoparticles potentially induce membrane permeability through a universal mechanism of action. Moreover, plasma protected against silica nanoparticle-induced membrane damage primarily by shielding the surface of silica particles.

In Paper II, the cytotoxicity and oxidative stress induced by amorphous silica nanoparticles were compared to nanoparticles with similar size but different chemical compositions. Overexpression of the liver phase II enzyme microsomal glutathione transferase 1 (MGST1) in human breast carcinoma MCF-7 cells reversed the cytotoxicity and oxidative stress induced by some silica nanoparticles but did not protect against the cytotoxic effects induced by zinc oxide nanoparticles.

In Paper III, amino-functionalized silica nanoparticles were used to deliver plasmid DNA (pDNA) into human breast carcinoma MCF-7 cells, with the nonporous particles delivering pDNA at higher efficiency than their mesoporous counterparts (with 2.4 nm pore diameter).

In Paper IV, polythiophene nanoparticles were used as vectors to deliver small interference RNA (siRNA) into human osteosarcoma U2-OS cells and human cervical carcinoma HeLa cells. The cationic polythiophenes were considerably more efficient delivery vectors than their zwitteronic counterparts.

In conclusion, studies to improve the understanding of the biocompatibility and delivery efficiency of nanomaterials, are crucial to assist the rationale design of nanomaterials for delivery applications.

List of scientific papers

I. Shi J, Hedberg Y, Lundin M, Odnevall Wallinder I, Karlsson HL, Möller L. The hemolytic properties of synthetic nano- and porous-silica particles: the effect of surface properties and the protection by the plasma corona. Acta Biomateriala. 2012; 8: 3478-90.
https://doi.org/10.1016/j.actbio.2012.04.024

II. Shi J, Karlsson HL, Johansson K, Gogvadze V, Xiao L, Li J, Burks T, Garcia-Bennett A, Uheida A, Muhammed M, Mathur S, Morgenstern R, Kagan VE, Fadeel B. Microsomal glutathione transferase 1 protects against toxicity induced by silica nanoparticles but not by zinc oxide nanoparticles. ACS Nano. 2012; 6(3): 1925-38.
https://doi.org/10.1021/nn2021056

III. Shi J, Rhode Y, Ersson C, Geny S, Ye F, Muhammed M, Smith CIE, Möller L. Amino-modified nonporous and mesoporous silica nanoparticles as non-viral vectors for the delivery of plasmid DNA. [Manuscript]

IV. Lundin P, Viola JR, Moreno PMD, Shi J, Zaghloul EM, Möller L, Smith CIE, El-Andaloussi S. Delivery of small interfering RNA (siRNA) using an amino acid-modified polythiophene. [Submitted]