Synthesis And Application Of The Nanoparticle-based Targeted Anticancer Drug Delivery Systems With DOX

The three multi-functional nanoparticle drug delivery systems based on bio-compatibleand water-soluble mesoporous silica nanoparticles, fullerene aggregates and block copolymermicelles (P(DEMA-co-APMA)-b-PEGMA) were designed and synthesized. This thesis ismainly focused on the preparation and application of multi-functional drug delivery systems.This study demonstrates that the multi-functional drug delivery systems have strong responseto mildly acid pH values and are capable of rapidly releasing DOX, active targeting and PDTinside the cells to yield significantly enhanced drug efficacy. We expect to provide someuseful insights for designing and improving the applicability of the multi-functional drugdelivery systems in targeted anticancer prodrug systems. The main contents and results of thisthesis are as follows:(1) A targeted anticancer prodrug system was fabricated with180nm mesoporoussilica nanoparticles (MSN) as carriers. The anticancer drug doxorubicin (DOX) wasconjugated to the particles through an acid-sensitive carboxylic hydrazone linker which iscleavable under the acidic conditions. Moreover, folic acid (FA) was covalently conjugated tothe particle surface as the targeting ligand for folate receptors (FR) over-expressed in somecancer cells. The in vitro release profiles of DOX from the MSN-based prodrug systemsshowed a strong dependence on the environmental pH values. Thus, with180nm MSN as thecarrier for the prodrug system, good drug loading, selective targeting and sustained release ofdrug molecules within targeted cancer cells can be realized.(2) A multi-functional anti-cancer prodrug delivery systems based on water-solublefullerene nanoparticles was designed and synthesized. For the synthesis of thefullerene-aggregate-based targeted prodrug, a hydrophilic oligo(ethylene glycol)(OEG) linkerwas first covalently incorporated onto fullerene through fullerenol and succinic acid conjugate.After that, DOXs were conjugated onto the fullerene through the acid-sensitive carboxylichydrazone which is cleavable under acidic conditions. Moreover, an active targeting ligand(folic acid, FA) was also linked onto the fullerene through amidation reaction for targeting theFR-positive cancer cells. The large amounts of hydrophilic OEG linkers, hydrazone groupsand amide groups on the surface of fullerene could lead to strong intermolecular interactions (such as hydrogen bonding), and accordingly the prodrug readily formed aggregates. The sizeof fullerene aggregates was controlled at ca.135nm by optimizing the amounts of theconjugated functional groups. In addition, fullerene aggregates capable of generating singletoxygen1O2can provide a new method of combination therapy (chemotherapy and PDT).(3) A multi-functional anti-cancer drug delivery system based on dual pH-responsiveblock copolymer micelles (P(DEMA-co-APMA)-b-PEGMA) was designed and synthesized.In the present work, the complementary adenine-uracil (A:U) base pair between A inhydrophobic core of micelles and cross-linker U-(CH₂)₆-U was employed to constructsupramolecular cross-linking block copolymers micelles (P (DEMA-co-APMA)-b-PEGMA).Benefiting from the reversible conversion between hydrophobicity and hydrophilicity in thecore of micelles and noncovalent cross-linking, P(DEMA-co-APMA)-b-PEGMA andU-(CH2)6-U could self-assemble into micelles with dual pH-responsive abilities in aqueoussolution. These novel stimuli-responsive micelles not only exhibited similar properties toconventional micelles from cross-linked micelles, but also rapid dual-pH response to mildacidic stimulus. Moreover, with folic acid as the targeting ligand, the cross-linked micellardrug delivery systems could be preferably internalized by FA-positive cells.In summary, the multifunctional anticancer drug delivery systems have the effect ofenhanced efficacy and reduced side effects of doxorubicin (DOX) and may provide someuseful insights and alternative approachs for future research and development of new drugdelivery systems.