Preparation Of Bio-responsive And Ultra-stable Nanodrugs With High Drug Loading Content And Their Applications In Cancer Therapy

Cancer is a leading cause of death in all countries and chemotherapy has been widely used in combination with other treatments like radiotherapy for curing the disease. However, many current anticancer drugs suffer from serious limitations such as poor water solubility, rapid blood clearance, widespread targeting, low accumulation in disease sites, and detrimental side effects for healthy tissues. In an attempt to address these limitations, during the past few decades, many nanovehicles have been developed as drug carriers such as liposomes, micelles, polymeric nanoparticles(NPs) and metal NPs. These nanovehicles are able to tremendously enhance the water solubility of drugs and increase their accumulation in tumors via an enhanced permeability and retention(EPR) effect, leading to enhanced efficacy and alleviated side effects. Although effective, in these strategies, the carriers do not have a therapeutic function and simply act as a platform to load and transport drug molecules. In this circumstance, these drug carriers are predominantly a major component in the drug system and account for a higher weight portion than actual therapeutics. It apparently leads to a rather low drug loading capacity(DLC). Even worse, many carriers may have potential systemic toxicity when used in the clinic. Recently, pure anticancer therapeutic NPs have been developed for a new generation of drug delivery systems, which generally involve the preparation of one or more pure hydrophobic drugs into the form of NPs, and then followed by surface modification with a small amount of surfactants to realize water dispersity and bioenvironmental stability for efficient drug delivery. Such a drug delivery system can substantially boost drug loading capacity and avoid the risk of any unnecessary burden to patients. Nevertheless, this type of drug NPs possess inadequate in vivo stability, since the surfactant is anchored to the surface of NPs only through weak hydrophobic interactions. The lack of stability may result in premature drug release following administration into the blood stream. Moreover, the intracellular drug release from NPs may be unmanageable, since the disaggregation of these nanoparticles could simply depend on the dissolution of cytoplasm. Meanwhile, there are some other problems in the clinic, such as the poor passive targeting effect and the multidrug resistance. All the problems seriously restrict therapeutic efficacy of drug NPs. Herein, our main studies are listed as follows:1. With the aim to enhance the stability of drug NPs, we develop GSH-responsive and crosslinkable amphiphilic polyethylene glycol(PEG) molecules to modify carrier-free drug NPs. These PEG molecules can be cross-linked on the surface of the NPs to endow them with greater stability and the cross-link is sensitive to intracellular environment for bio-responsive drug release. With this elegant design, our experimental results show that the liberation of DOX from DOX-cross-linked PEG NPs is dramatically slower than that from DOX-noncross-linked PEG NPs, and the DOX release profile can be controlled by tuning the concentration of the reducing agent to break the cross-link between PEG molecules. More importantly, in vivo studies reveal that the DOX-cross-linked PEG NPs exhibit favorable blood circulation half-life(>4 h) and intense accumulation in tumor areas, enabling effective anti-cancer therapy. We conceive the experimental findings to be of great importance to guide the preparation and application of carrier-free nanomedicines in research and future clinical settings.2. With the aim to manage the drug release at tumor sites precisely and overcome the multidrug resistance, we develop a dimeric drug molecular, CAD-PTX, with a pH-responsive bond. Then the CAD-PTX NPs are prepared by solvent exchange and coated by the GSH-responsive and crosslinkable surfactant which is based on HA segment. Thus, the CAD-PTX-CLHA NPs are prepared. The stability, in vitro drug release, cytotoxicity and cellular uptake were systematically studied for these nanoparticles. The CAD-PTX-CLHA NPs show perfect stability, manageable intracellular drug release profile, excellent active targeting effect. Moreover, due to the synergistic combination effect of DOX and PTX, the CAD-PTX-CLHA NPs show much better cytotoxicity than any single drug sample. We expect this work will provide a powerful strategy for functionalized carrier-free nanomedicines and pave the way to their successful clinical applications in the future.