| Cellular internalization of anticancer drugs has played a crucial role in the field of chemotherapy considered as one of the most important approaches for cancer treatment. However, the utilization of most of the conventional chemotherapeutic agents, though having effective cancer therapy in vitro, has been severely limited due to its poor pharmacokinetics profiles and non-specifically distribution in the body resulting in systemic toxicity associated with adverse side effects. To address the above problems, nanoscale drug delivery system such as liposomes, polymeric micelles, polymersomes, nanogels, and nanocapsules have emerged as an indispensable platform for modern cancer therapy. Biodegradable polymer nanoparticles with stealthy surfaces made of water soluble non-fouling polymers such as poly(ethylene glycol)(PEG), dextran, and poly(acrylic acid), have been widely used in the clinical applications for anticancer drug delivery due to prolonged blood circulation time and enhanced accumulation However, this highly hrdrophiphilicsurface failed to create optimal uptake by cancer cells within the tumor. This problem which has been referred to by some as the “PEG dilemma” has been suggested to hinder efficient drug delivery in tumor as these NPs end up releasing their therapeutic payload into the tumor milieu rather than within cancer cells. Consequently, as vehicles, ideal nanoparticles are obliged to target cells with high drug loading levels without drug leakage on the way, while rapidly unload drug at the intracellular site of action. In this paper, special attention will be focused on the potential strategies that can enable drug-loaded polymeric nanoparticles to rapidly recognize cancer cells, leading to enhanced internalization.Although it has demonstrated that positively surface-chargednanoparticles shownenhanced uptake by cancercells via electrostatic interactions, their application fordrug delivery faces challenges because of their rapidbody elimination, tissue toxicity and reduced tumorpenetration. Taking these factors into consideration, it is thus necessary to develop smart drug delivery system(DDS) thatcan avoid non-specific protein adsorption duringblood circulation, yet can actively be transformed intoa more cell-interactive structure once localized andaccumulated in tumor tissues. To this end, new strategies of engineeringnano-scaled DDS with the capability of transformingsurface charges from negative to neutral/positive inresponse to tumor extracellular acidity(pHe 6.0~7.0) have emerged.On the other hand, the driving forces for the interaction between nanoparticles and cells are quite complex and include hydrophobicity of nanoparticles. So, an alternative method is using the stimuli-responsive polymers to modify the nanoparticle surface. The surface properties of the nanoparticles could be changed in response to external or internal stimuli so that the interactions between nanoparticles and cellular membranes can be improved timely.In general, at normal body temperature, the thermo-responsive polymer surfaces of the nanoparticles arehydrophilic which serve as the stealthy shells. As the temperature increases to higher thanLCST of the polymeric shells, they turn to be hydrophobic exhibiting enhanced interactionwith the cell membranes.This thesis was divided intotwo parts:1. Direct encapsulation of hydrophobic drugs into amphiphilic block copolymer micelles has been frequently subjected to low drug loading efficiency(DLE) and loading content(DLC) as well as lower micellar stability and uncontrollable drug release. In this report, we prepare the copolymer prodrugs(PPEMA-co-PCPTM) via reversible addition-fragmentation chain transfer(RAFT) polymerization of 2-(piperidin-1-yl)ethyl methacrylate(PEMA) and reduction-responsive CPT monomer(CPTM), which were quantitatively encapsulated into poly(ethylene glycol)-blockpoly(?-caprolactone)(PEG-b-PCL) micelles. The polymer prodrug-loaded micelles showed high stability for a long time in aqueous solution and even maintain similar size after a lyophilizationdissolution cycle. The tumoral pH(~ 6.8)-responsive properties of PPEMA segments endow the micellar cores with triggered transition from neutral to positively charged and swellable properties. The PEG-b-PCL micelles loading polymer prodrugs(PPEMA-b-PCPTM) eliminated burst drug release. Simultaneously, CPT drug release can be triggered by reductive agents and solution pH. At pH 6.8, efficient cellular internalization was achieved due to positively charged cores of the micelles. As compared with micelles loading PCPTM, higher cytotoxicity was observed by the micelles loading PPEMA-b-PCPTM at pH 6.8. Further multicellular tumor spheroids(MCTS) penetration and growth suppression studies demonstrated that high-efficiency penetration capability and significant size shrinkage of MCTs were achieved after treatment by PPEMA-b-PCPTM-loaded micelles at pH 6.8. Therefore, the responsive polymer prodrug encapsulation strategy represents an effective method to overcome the disadvantages of common hydrophobic drug encapsulation approaches by amphiphilic block copolymer micelles and simultaneously endows the micelles with responsive drug release behaviors as well as enhanced cellular internalization and tumor penetration capability.2. In this part, to address the issues of low-efficiency cellular internalization of stealthy polymeric drug delivery systems, we demonstrate photothermal effect-promoted cellular internalization of finely tuned thermo-responsive amphiphilic biodegradable block copolymer nanocar-riers via noninvasive stimuli of near-infrared(NIR) light irradiation. Amphiphilic block copolymers,PCL-b-P(NIPAM-co-DMA, are prepared with finely tuned compositions of P(NIPAM-co-DMA) for desirable lower critical solution temperature(LCST) of the block copolymer micelles in aqueous solution. The block copolymers are then used to co-encapsulate doxorubicin(DOX) and indocyanine green(ICG), which show high encapsulation efficiency and significant photothermal effect upon exposure to NIR light irradiation. The photothermal effect-induced collapse and hydrophilic-to-hydrophobic transition of P(NIPAM-co-DMA) shells significantly enhance the interactions between drug-loaded micelles and cell membranes, which dramatically promote the cellular internalization of the micelles and therapeutic efficacy of loaded anticancer drugs. |
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