Ispitivanje mogućnosti korišćenja nanočestica TiO2 kao nosača za ciljanu i kontrolisanu dostavu lekova na bazi kompleksa prelaznih metala

Abstract

Sinteza i primena kompleksa prelaznih metala u lečenju kancera je predmet istraživanja velikog broja naučnika. Potreba za razvojem novih citostatika proizilazi iz želje da se prevaziđu nedostaci već postojećih, kao što su rezistencija, toksičnost i uzak terapeutski opseg (aktivnost protiv malog broja tipova tumora). Tako se pored kompleksa platine, i dalje najčešće korišćenih citostatika u kliničkoj praksi, razvila čitava serija novih kompleksa redizajniranjem već postojećih izmenom liganada i/ili izmenom centralnog metalnog jona. Posebno su se izdvojili kompleksi rutenijuma zbog manje toksičnosti, aktivnosti na metastazama i tumorima na kojima su dotadašnji citostatici bili neaktivni, a neki od njih su pokazali aktivnost tek kada se ozrače svetlošću odgovarajuće talasne dužine i potencijal za primenu u fotodinamičkoj terapiji. Uprkos razvoju novih generacija citostatika s poboljšanim karakteristikama, kao problem ostaje kontrola postizanja maksimalne koncentracije leka u tumorskom tkivu. Na putu do ciljnog, tumorskog tkiva i ciljnih biomolekula, lek interaguje i s brojnim drugim biomolekulima što za posledicu može imati toksičnost, pojavu rezistencije, inaktivaciju leka i smanjenje njegove efektivne koncentracije na željenom mestu dejstva. Potreba za prevazilaženjem ovog problema dovela je do brzog razvoja nosača za lekove. Njihova uloga je da vežu ili inkapsuliraju lek, nose ga do tumorskog tkiva sprečavajući njegovu interakciju s okolnim biomolekulima i zatim ga otpuste, aktivnim ili pasivnim mehanizmom, u ciljnom tumorskom tkivu. Cilj upotrebe ovakvih sistema je smanjenje štetnog dejstva leka na zdravo tkivo, mogućnost kontrole doziranja leka tj. postizanje njegove optimalne koncentracije u tumorskom tkivu, a samim tim i postizanje veće efikasnosti terapije. Nosači koji se testiraju za mogućnost primene u kontrolisanoj i ciljanoj dostavi medikamenata su uglavnom na bazi organskih i neorganskih nanomaterijala, međutim mali broj njih je u kliničkoj upotrebi (lipozomi i polimerni nanomaterijali). U fazi ispitivanja su mnogobrojni nosači koji reaguju na stimulanse kao što su pH sredine, ultrazvuk, temperatura i svetlost. U novijim istraživanjima veliku pažnju kao nosači za lekove zauzimaju nanočestice TiO2 zbog svoje biokompatibilnosti, fotoaktivnosti, dostupnosti i mogućnosti modifikacije površine.

A significantly rising interest in the design and use of metal complexes for cancer treatment is currently observed in the area of scientific inquiry. There has been a growing demand for development and improvement of metal-based compounds used in routine clinical practice in order to overcome disadvantages and limitations such as resistance, toxicity and narrow spectrum of activity (activity against a small number of tumor types). Beside platinum complexes, the leading agents in clinical use, many more metal-based compounds have been synthesized by redesigning the existing chemical structure through ligand substitution and/or central metal ion switching. Among them ruthenium complexes have been investigated as one of the most promising candidates because they shown less toxicity, significant activity against cancer metastases, and activity on tumors that were resistant to a variety of standard chemotherapeutic agents. Moreover, some of them are light sensitive drugs i.e. their functions is triggered once they are activated by light of a specific wavelength which make them promising candidates for photodynamic therapy. Despite fast development of new generation of cytostatics with better characteristics, there are still areas where substantial improvements need to be made. One such area is achievement of a maximum concentration of the drug on tumor site. Once the drug enters the systemic circulation, it could face a number of challenges. Drug could react with nontarget biomolecules on its way to target biomolecules in tumor tissue which could cause severe side effects such as toxicity, resistance, inactivation of the drug and reduction of its effective concentration at the target tumor site. One way to solve these problems is the development of drug delivery systems which consist of drug and drug carrier. Role of drug carriers is to bind or encapsulate the drug, prevent its interaction with non-target biomolecules, to carry the drug to the target tumor tissue and then release it with active or passive mechanism. The main advantages of using drug delivery systems are reduction of side effects of drug onto the healthy tissue, dosage control, optimal concentration of drug in the tumor tissue, and more effective treatment which could improve outcome of therapy. Many organic and inorganic nanoparticles have been tested as drug carriers, but just few of them are in clinical use (liposomes and polymers). In recent years smart nanosystems for targeted drug delivery that respond to various stimuli including pH, ultrasound, temperature and light irradiation are in the center of many investigations.