Xenografts in Zebrafish and Dendrimers as Drug Delivery System

Introduction

While a convencial approach in cancer therapy brings many side effects, the concept of targeted drug delivery system (DDS) can open new possibilities in this filed. The approach of targeted DDS should be opened by a new nanostructures called dendrimers. Carbosilane dendrimers used in our experiments are the new type of nanoparticles with several different modifications, which should be able to fix and deliver drug to the target tissue. This property we will use in vivo after xenotransplantation of human adenocarcinoma of lungs to Zebrafish.

Material and method

In our experiments were used carbosilane dendrimers with NMe₃, PMe_3, P(Et₂)₂(CH₂)₃OH, Pbu₃, P(C₆H₄-Ome)_3, and P(Ph)₃ periphery substituents for in vivo tests. There was used a Fish Embryo Acute Toxicity (FET) Test established by OECD¹ with Danio rerio embryos. For five days were embryos in chorion incubated in 28°C in dendrimers solution of concentrations 100μM, 10μM, 1μM, 0,1μM, 0,001μM plus positive and negative control. Four lethal-end points as a cogulation, lack of somite formation, lack of tail detachment from the yolk, heart oedema or lack of heartbeat were recorded by a microscope every 24 hours.

Results and discusion

The lowest toxicity has a phosphonium dendrimer (PMe₃)_. Embryos incubated in this type have as good viability as negative control till concentration 1μM, while dendrimers P(Ph)₃ and Pbu₃ has in concentration 1μM 100% mortality. All tested dendrimers have 100% mortality in concentrations 10μM and 100μM.

Results of toxicity test help us to choose a good candidate and concentration for other experiments including the treatment of tumours caused by a transplantation a xenografts of human adenocarcinoma of lungs to Danio embryos. Xenotransplantation od CRL cells stained by a fluorescent tracker dye to embryos will be made by a mikroinjection into a yolk sac. The tumourgenesis will be analyzed by a volume measurment of each single tumour distributed to body. These results should be compared with tumour development in individual treated by a dendrimer-drug conjugate. We suggest the interaction of ligand on the dendrimer´s perifery and EGFR receptor overexpressed in tumor.

Conclusions

Dendrimers are a good candidates for targeted DDS, because of a possibility to make many modifications and commonly design it for many reactions and connections on really high specific level. These property determine their big potential for using in cancer therapy.

¹ [OECD Guidelines for the Testing of Chemicals 236], (2013)

Research was supported by project 2018-53-005-3 Internal Grand Agency UJEP.