Preparation Of Isothiocyanate Conjugates And Their Applications In Drug Delivery

Paclitaxel(PTX)is one of the most effective anticancer drugs for the treatment of various solid tumors,but its clinical use is limited by its poor solubility,non-specific distribution,and severe systemic toxicity of PTX itself and of the toxic vehicle solvent Cremophor EL in its commercial formulation(Taxol).Nanomedicines such as polymer micelles and albumin-based nanoparticles represent an innovative field to overcome these problems,which can improve drug solubility,prolong circulation time,reduce adverse effects,target to tumor,and offering patients improved quality of life.However,only a few nanomedicines have entered the clinical trial stage.These drug delivery systems still need improvements in stability,pharmacokinetics,therapeutic efficacy,and safety profiles.Isothiocyanates(ITCs)are hydrophobic compounds in cruciferous vegetables which have attracted a great amout of research interests due to their anticancer effects.The click reaction of isothiocyanate(R-NCS)with the amines makes the conjugation facile and produces thiourea groups,which may form intermolecular hydrogen bonds with drug to improve the drug loading and stability.Furthermore,some thiourea derivatives exert inherent in vivo anticancer activity,which may generate a synergistic effect with the carried drugs.We proposed to develop biocompatible ITCs conjugates with inherent anticancer activity forming PTX-binding nanoparticles to improve the stability and therapeutic efficacy of PTX delivery sysytem.In the first part of this thesis,we demonstrate a facile fabrication of a stable PTX-binding micelle made from poly(ethylene glycol)-block-dendritic polylysine,whose primary amines were reacted with phenethyl isothiocyanate(PEITC),a hydrophobic anticancer agent under clinical study.The amphiphilic conjugate(PEG-Gx-PEITC;Gx,the generation of the polylysine dendron)formed well-defined micelles whose cores were composed of phenyl groups and thiourea groups binding PTX via ?-? stacking and hydrogen bonding.PTX-loaded PEG-Gx-PEITC third-generation(PEG-G3-PEITC/PTX)micelles had a very high PTX encapsulation efficiency(98.3%)at a drug content of 23.7%,whose size was about 31 nm with a polydispersity index(PDI)of 0.13.The PEG-G3-PEITC/PTX micelles showed similar in vitro cytotoxicity with free PTX.Compared with the PTX-loaded poly(ethylene glycol)-block-poly(D,L-lactide)(PEG-PDLLA/PTX)micelles in clinical use,PEG-G3-PEITC/PTX micelles showed slowed blood clearance,enhanced tumor accumulation,and thus much improved in vivo therapeutic efficacy in both subcutaneous and orthotopic human breast cancer xenografts.Therefore,PEG-G3-PEITC is a promising drug delivery system for PTX in the treatment of breast cancer.In the second part of this thesis,bovine serum albumin-isothiocyanate conjugates with varying isothiocyanate densities(BSA-ITCs)were prepared for anticancer drug delivery.BSA with 35 conjugated PEITC molecules(BSA-PEITC35),where lysine residues of proteins were reacted with PEITC to form stable thiourea derivatives,was non-cytotoxic but exerted the ability to inhibit tumor growth in vivo.Compared to the nanoparticle albumin-bound(nab)technology-based PTX nanoparticles(Abraxane)in clinical use,PTX-loaded BSA-PEITC35 nanoparticles(BSA-PEITC35/PTX)showed improved pharmacokinetics and enhanced antitumor efficacy.Therefore,BSA-ITCs conjugates are considered as a promising antitumor drug and a potent delivery platform for hydrophobic drugs.