The use of cyclodextrins in the development of therapeutic delivery systems for antitumor drugs

Onkološke bolesti su drugi uzrok smrtnosti u svijetu, a broj oboljelih raste. Terapija tumora uništava i zdrave, normalne stanice, osobito one koje se brzo dijele što dovodi do brojnih nuspojava. Citostatici su većinom slabo topljivi u vodi pa ih je teško formulirati, a pomoćne tvari koje se koriste u tu svrhu često uzrokuju dodatne nuspojave. Ciklodekstrini omogućuju povećanje topljivosti citostatika bez izazivanja novih nuspojava. To su biokomptibilni ciklički oligosaharidi izgrađeni iz α-1,4-D-glukopiranoznih jedinica. Strukture su šupljeg krnjeg stošca čija je unutrašnjost hidrofobna, a vanjština hidrofilna. Uklapanjem slabo topljivih lijekova u svoju šupljinu povećavaju im topljivost, maskiraju okus i miris lijeka, sprječavaju iritaciju gastrointestinalnog trakta ili sprječavaju interakcije s drugim lijekovima. CD se primjenjuju kao solubilizatori pri čemu povećavaju bioraspoloživost citostatika, a smanjuju im toksičnost. Klinička ispitivanja melfalana uklopljenog u CD pokazala su objektivnu stopu odgovora od 95%, a teške nuspojave koje se povezuju s konvecionalnom formulacijom melfalana izbjegnute su. CD polimeri s kamptotecinom stvaraju CRLX101 nanočestice koje imaju do 1000 puta veću topljivost, a zbog EPR učinka smanjena je sistemska toksičnost. Klinička ispitivanja CRLX101 pokazala su stopu kliničkog benefita od 68% za monoterapiju i čak 95% za kombinaciju s bevacizumabom. Također, CD se koriste i kako bi se spriječila inkompatibilnost alkalne otopine 5-FU s kiselim leukovorinom. Naime, CD omogućavaju topljivost 5-FU pri fiziološkoj pH vrijednosti pa se, osim reakcije neutralizacije, izbjegava i kardiotoksičnost povezana s primjenom alkalne otopine. Razvijaju se i istražuju napredni sustavi dostave citostatika u tumorske stanice pri čemu se CD modificiraju za ciljanu dostavu ili lakše uklapanje gena.Oncologycal diseases are the second leading cause of death worldwide, with a growing number of patients. Tumor therapy also destroys healthy normal cells, especially ones that divide quickly, which leads to numerous adverse effects, Cytostatics are usually poorly soluble in water which makes them hard to formulate and other excipients often cause additional adverse effects. Cyclodextrins can be used to improve drug solubility without aggravating side effects. Cyclodextrins are biocompatible cyclic oligosaccharides built from α-1,4-D-glucopyranose units. Spatially, they form an inverted hollow truncated cone, the interior of which is hydrophobic, and the exterior is hydrophilic. By fitting poorly soluble drugs into their cavity, they increase their solubility, mask the taste and smell of the drug, prevent irritation of the gastrointestinal tract or prevent interactions with other drugs. CDs are used as solubilizers, increasing the bioavailability of cytostatics and reducing their toxicity. Clinical trials of melphalan incorporated into CD have shown an objective response rate of 95%, and the severe side effects associated with conventional melphalan formulation have been avoided. CD polymers create CRLX101 nanoparticles with camptothecin that have up to 1000 times greater solubility, and due to the EPR effect, systemic toxicity is reduced. Clinical trials of CRLX101 showed a clinical benefit rate of 68% for monotherapy and even 95% for the combination with bevacizumab. Also, CDs are used to prevent the incompatibility of the alkaline solution of 5-FU with the acidic leucovorin. Namely, CDs enable the solubility of 5-FU at a physiological pH value, so, in addition to the neutralization reaction, the cardiotoxicity associated with the use of an alkaline solution is also avoided. Advanced delivery systems for cytostatics to tumor cells are being developed and investigated, whereby CDs are modified for targeted delivery or easier gene insertion