The intracellular delivery of cancer drugs can reduce the side-effects if the target cells can be distinguished from healthy cells. Folic acid targeting increased the uptake of PSi nanoparticles into HeLa human cancer cells through folate receptor mediated endocytosis. The nanoparticles were seen coalescent with lysosomes in the confocal microscopy study (Paper II, Figure 7). The endosomal compartments of target cells, with reduced pH, are the desired accumulation site for nanoparticles which express pH-dependent release of the doxorubicin cargo.
HeLa cell line with stable gene expression of luciferase enzyme with a mutation promoting aberrant splicing of pre-messenger RNA provided a convenient tool for evaluating the intracellular delivery of oligonucleotides. Splice correcting oligonucleotide (SCO) can prevent the normally occurring aberrant splicing resulting with fully functional luciferase enzyme.
However, SCO needs to enter the cytosol and the nucleus before it can exert its effect. PSi nanoparticles functionalised with CPP were used to deliver SCO into the cytosol of cancer cells.
Without the functionalisation with CPP, the SCO loaded nanoparticles were also readily internalised to the cells but no biological response from SCO was observed. (Paper V, Figure 5 and Figure 6). SCO could also be delivered into the cells using only CPP which aids the SCO to penetrate through the cell membranes into the cytosol. However, by protecting the cargo within the pores of PSi nanoparticles it could be rendered more resistant against degradation by proteases and nucleases (Paper V, Figure 7).
The present study describes the development of drug delivery vehicles based on PSi nanoparticles for nanomedical applications. The results lead to following conclusions.
1. The nanoparticle surface could be easily modified to contain targeting molecules, i.e.
antibodies or folic acid, as well as PEG polymer coating, which reduced the opsonisation of the particles. Additionally, a feasible method for conjugation of imaging tracers was developed.
2. PSi nanoparticles were found to be suitable for peptide delivery as they permitted manipulation of the pharmacokinetics of the peptide being administered within the nanoparticles. Furthermore, the peptides maintained their biological effects when delivered within the nanoparticles.
3. The nanoparticles by themselves could exert effects on the cardiovascular function of rats after a bolus injection without an inflammatory reaction. The mechanism of action for reduction of blood pressure by the THCPSi nanoparticles remained to be clarified.
4. Specific uptake into the endosomal compartments of cancer cells and following pH-dependent release of the cargo could be achieved with PSi nanoparticles. Furthermore, PSi nanoparticles were found to be suitable for the intracellular delivery of antisense oligonucleotides preserving their biologically active form.
28
Functionalised mesoporous silicon nanoparticles have shown interesting properties in drug delivery and imaging, and have demonstrated their ability to work as targeted nanomedicals.
The results here provide fundamental knowledge about the development of drug delivery devices and have examined some of the major problems that one may encounter in the nanomedicine development process. Opsonisation and the activation of the immune system are still the greatest challenges preventing efficient nanoparticle-based drug delivery systems.
Opsonisation can hinder the targeting and the efficient removal by immune system may seriously impair the delivery. Thus, gaining a deeper knowledge of the interaction between nanomedicals and the biological environment is essential for future research. The nanocarriers themselves can have unexpected effects on the patient physiology. Therefore, more resources need to be provided into developing in vitro toxicity techniques which would be cheap and have a high throughput but which would correlate with the more costly and time consuming in vivo studies.
Controlled and sustained release of the drug molecules represents the rationale behind drug delivery applications. Therefore, novel and more efficient utilities for triggered release of the cargo need to be developed. One possible direction is to utilize so-called multistage carriers which would be activated, for example, by physiological stimuli and release second stage nanocarriers which could then home onto their target site and treat the disease in question. In conclusion, the field of nanomedicine has advanced significantly and it seems likely that novel drug delivery vehicles will be approved and marketed in the near future.
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