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Fabrication and Nanostructural Tuning of Tumor Microenvironments-Responsive Polymeric Drug Vectors

Author: HuXiangLong
Tutor: LiuShiYong
School: University of Science and Technology of China
Course: Polymer Chemistry and Physics
Keywords: Tumor Microenvironments-Responsiveness Polyprodrug Amphiphiles Self-Assembly Nanostructures Biological Performances Magnetic ResonanceImaging Vesicular Permeability
CLC: TQ460.1
Type: PhD thesis
Year: 2013
Downloads: 48
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Abstract

The research on tumor microenvironments-responsive polymeric vectors has been increasingly regarded as an important area in biomedicine due to their long blood circulation, improved water solubility, and facile integration of functionalities. This dissertation mainly focuses on the design, complicated nanostructural fabrication, and related functional performance of tumor microenvironments-responsive polymeric vectors, especially acid-and reduction-responsive polymers. The first chapter gave a brief introduction concerning the development and challenges of stimuli-responsive polymeric carriers in recent years. In the second chapter, dual-responsive dynamic covalent shell cross-linked micelles for triggered release of chemotherapeutic drugs were explored. The third chapter demonstrated the targeting ligand folic acid-decorated dual-responsive dynamic covalent shell cross-linked micelles conjugated with photo-responsive camptothecin prodrug for photo-triggered drug release and photoactiviated cytotoxicity. The forth chapter reported a novel kind of polymeric drug vectors, termed as polyprodrug amphiphiles, affording multiple hierarchical nanostructures through facile solution self-assembly, exhibiting shape-modulated biological performances. The fifth chapter described some integrated multifunctional application of polyprodrug amphiphiles. Firstly, one type of long blood circulating branched polyprodrug amphiphiles with cell-penetrating ability for reduction-responsive enhancement of magnetic resonance imaging signals and anticancer ability. Secondly, one kind of "windows closing-doors opening" strategy was investigated to regulate the permeability of polymeric vesicles fabricated from polyprodrug amphiphiles, realizing the synergetic delivery of hydrophobic drugs and hydrophilic drugs or proteins. This dissertation can be further clarified as described below:1. Well-defined amphiphilic diblock copolymer, PCL-b-P(OEGMA-co-MAEBA), was synthesized via ring-opening polymerization (ROP) of ε-caprolactone (CL) and then atom transfer radical polymerization (ATRP) of oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA) and p-(methacryloxyethoxy) benzaldehyde (MAEBA) comonomers. In aqueous solution, the diblock copolymer self-assembles into micelles consisting of hydrophobic PCL cores and hydrophilic P(OEGMA-co-MAEBA) coronas covalently anchored with pendent aldehyde groups. The subsequent shell cross-linking reaction was conducted at pH6.2upon addition of difunctional dithiolbis(propanoicdihydrazide)(DTP). The formation of dynamic acylhydrazone cross-linking linkages was facilitated under the catalysis of aniline. The obtained SCL micelles can be de-crosslinked via two biologically relevant modes, namely, acidic pH-triggered cleavage of acylhydrazone bonds into aldehyde and hydrazide and reduction-triggered cleavage of disulfide linkages, which have been utilized for triggered release of physically encapsulated chemotherapeutic drugs. Camptothecin (CPT)-loaded SCL micelles were used to investigate reduction and pH-modulated CPT release profiles. Compared with CPT-loaded non-crosslinked (NCL) micelles, CPT-loaded SCL micelles can largely minimize drug leakage under physiological conditions, whilst exhibiting accelerated drug release under mildly acidic or reductive microenvironments, which are relevant to those of acidic organelles (endosomes and lysosomes) or cytosol within tumor cells. Cell cytotoxicity studies revealed that drug-free SCL micelles are almost nontoxic, whereas CPT-loaded SCL micelles can efficiently deliver chemotherapeutic drug (CPT) into HepG2cells, leading to considerable nucleic accumulation at extended incubation duration. The reported dynamic covalent shell crosslinking strategy can exert intricate control concerning the micellar stability and the release profile of encapsulated drugs in response to biological microenvironments, which augurs well for their potential use as novel smart nanocarriers for drug delivery in cancer chemotherapy.2. Two types of amphiphilic diblock copolymers, P(CL-g-CPT)-b-P(OEGMA-co-MAEBA)-CPT and PCL-b-P(OEGMA-co-MAEBA-co-FA), were synthesized via the combination of ring-opening copolymerization (ROP) of ε-caprolactone (CL) and2-bromo-e-caprolactone (CL-Br), atom transfer radical polymerization (ATRP) of oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA) and p-(methacryloxyethoxy) benzaldehyde (MAEBA) comonomers, and "click" post-functionalization with photocaged camptothecin (CPT) prodrug and alkynyl-functionalized folic acid (FA) moieties, respectively. Mixed micelles coassembled from PCL-b-P(OEGMA-co-MAEBA-co-FA) and P(CL-g-CPT)-b-P(OEGMA-co-MAEBA)-CPT possess hydrophobic cores conjugated with photocaged CPT prodrugs and hydrophilic outer coronas covalently attached with aldehyde groups and FA moieties for subsequent shell cross-linking and cancer cell targeting. Shell cross-linking was performed at pH6.2upon addition of difunctional crosslinker, dithiol bis(propanoic dihydrazide)(DTP), under the catalysis of aniline. The obtained FA-decorated SCL micelles contain acylhydrazone and disulfide linkages in the outer coronas, which can be de-crosslinked under mildly acidic or reductive microenvironments, that is, endosomal/lysosomal pH or high GSH level in the cytosol. The cleavage of caged CPT drug within the cores of SCL micelles can be effectively actuated under photo irradiation, whereas its diffusion out of micellar nanocarriers can be further modulated by pH and thiol levels due to the dually responsive nature of DTP cross-linker. Compared with the control, FA-decorated SCL micelles can more efficiently enter folate-receptor expressing cancer cells than folate-receptor deficient ones. Cell viability assays revealed that SCL micelles displayed at least-9.7-fold enhanced cytotoxicity upon light irradiation. The reported targeting ligand decorated and prodrug-conjugated dynamic covalent SCL micelles exert intricate control concerning micellar stability, cancer cell targeting, photo-triggered parent drug release with photoactivated cytotoxicity, and tunable drug release profiles. All of these augur well for their potential application as a novel integrated platform for targeted drug delivery in cancer chemotherapy.3. Camptothecin (CPT) prodrug monomer with a disulfide linkage, CPTM, was synthesized from2,2’-dithiodiethanol and triphosgene via fuctionalizing the20-hydroxy of CPT parent drug. We employed reversible addition-fragmentation transfer (RAFT) technique to polymerize CPTM prodrug monomer using hydrophilic PEG-based macroRAFT agent, affording PEG-b-PCPTM diblock copolymers with CPT moieties in the hydrophobic block. This kind of amphiphiles with hydrophilic chain and polymerized block of prodrug monomer were termed as polyprodrug amphiphiles. In this system, PEG-b-PCPTM, a typical representation of polyprodrug amphiphiles, possess>50wt%drug loading content, improved water solubility, drug stability and reduction-responsive parent drug release characteristics. It’s very accidental to find that the solution self-assembly of PEG-b-PCPTM can afford multiple hierarchical nanostructures. Among these, four typical nanostructures, including spheres, flower-like large compound vesicles, and in particular smooth disks and staggered lamellae with spiked periphery, with the latter being unprecedented. Amongst these, staggered lamellae exhibit the longest blood circulation duration, and smooth disks possess slightly faster blood elimination than staggered lamellae. Staggered lamellae and large compound vesicles show quite fast cellular uptake, may follow unique internalization pathways. Reductive milieu-triggered release kinetics of parent CPT drugs and nanostructure degradation, and shape-modulated in vitro cytotoxicity were also explored. The controlled hierarchical organization of polyprodrug amphiphiles and shape-tunable biological functions open up new horizons for exploring next-generation drug self-delivery and co-delivery systems with further improved efficiency.4. In terms of potential applications of polymeric assemblies from polyprodrug amphiphiles in clinical diagnosis (magnetic resonance imaging, MRI), we explored the following design. RAFT polymerization was employed to prepare branched P(CPTM-co-GMA) in the presence of RAFT chain transfer agent monomer, prodrug monomer CPTM, and glycidyl methacrylate (GMA). Then, branched P(CPTM-co-GMA) was further used as macro RAFT agent to copolymerize oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA) and3-guanidinopropyl methacrylamide (GPMA), affording branched polyprodrug amphiphiles, P(CPTM-co-GMA)-b-P(OEGMA-co-GPMA). Subsequent treatment with sodium azide to functionalize the epoxy groups in the branched core and click conjugation with alkynyl-containing MRI contrast agent, alkynyl-DOTA(Gd) afforded branched P(CPTM-co-DOTA(Gd))-b-P(OEGMA-co-GPMA). This type of branched polyprodrug amphiphiles with caged MRI contrast agent in the branched core possess good cell-penetrating ability and extended blood circulation. Upon treatment with tumor cells’reductive milieu, CPT parent drugs were released as the active form accompanied with the great enhancement of MRI signals. These observations demonstrate that our obtained multi-functional combined branched polyprodrug platforms have great potential applications in cell-penetrating, controlled parent drug release and in-situ therapeutic monitoring. In terms of the permeability regulation of vesicle nanostructures from polyprodrug amphiphiles and the demand for synergetic drug delivery, we conceived the following design to regulate vesicular permeability for biomedical application. RAFT polymerization was employed to prepare PEG-b-P(TMSPMA-co-CPTM) in the presence of PEG macroRAFT agent, prodrug monomer CPTM, and3-(trimethoxysilyl)propyl methacrylate (TMSPMA). Polymeric vesicles were fabricated via solution self-assembly of PEG-b-P(TMSPMA-co-CPTM). Upon treating under weak alkaine milieu, the bilayer of vesicles was crossliked by the sol-gel reaction of silane moieties, affording crosslinked vesicles with decreased permeability of vesicle bilayer. Thus, the permeability of bilayer was enhanced under the tumor cell’s reduction microenvirnoments, accopanied with CPT parent drug release from the vesicle bilayer. This kind of "windows closing-doors opening" strategy was further investigated to realize the synergetic delivery with hydrophilic drugs or proteins.

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