Study On The Nano-drug Delivery Systems Based On Alginic Acid

Over the past few decades, there has been extensive interest in developing biocompatible and biodegradable nanoparticles (NPs) as effective drug delivery devices. Nanoparticles, which are particles of less than1μm in diameter that are prepared from natural or synthetic materials, have recently become an important area of research in the field of drug delivery for their ability to deliver a wide range of drugs to varying areas of the body for sustained periods of time. Not only the effectiveness of the loading of the drugs, the nanoparticles can also solubilize drugs for intravascular delivery, and improve the stability and the bioavailability of loaded drugs, what is more, the nanoprticles can increase the efficacy of the therapeutic agents while minimizing their side effects. Besides, nanoparticles with the diameter of several hundred nanometers can passive accumulate into tumor site owing to the enhanced permeability and retention (EPR) effect caused by the disorganized vascularization, defective vascular architecture of tumors and lack of lymphatic drainage, which can be taken advantage to effectively improve the concentration of drug in tumor tissues after systemic administration. It is important to increase the drug level and resident time in tumor tissue for developing and research of nanoparticles for drug loading and delivery.Alginic acid (ALG) is a linear polysaccharide with excellent biocompatibility and biodegradability consists of a-L-guluronic acid and (3-D-mannuronic acid, and without any toxicity. Recently, ALG has been widely used in a variety of biomedical applications, such as drug delivery and diagnosis. Unfortunately, the sizes of these nanoparticles were often too large and the size distribution of these systems was relatively wide, which severely confined their application in drug delivery. In this paper, a series of ALG nanoparticles and nanogel with suitable sizes and narrow size distributions have been prepared according to the method of macromolecular electrostatic self-assembly, counter-ion complexation, and covalent cross-linking. The synthesized nanoparticles and nanogel were further employed as the drug carrier and their drug delivery behavior was investigated in vitro and in vivo with Doxorubicin (DOX) as a model drug. The in vitro and in vivo antitumor efficacy of the nanoparticles was evaluated after the examinations of in vitro cytotoxicity, in vivo near-infrared (NIR) fluorescence imaging, in vivo antitumor activity and biodistribution.This paper is composed of5aspects as followed.(1) Alginic acid-poly(2-(diethylamino)ethyl methacrylate)(ALG-PDEA) nanoparticles have been prepared in aqueous medium by polymerizing the2-(diethylamino)ethyl methacrylate (DEA) monomer in the presence of alginic acid (ALG). It is found that the ALG-PDEA nanoparticles were size-monodispersed and the preparation is mild, feasible, and solvent and surfactant free. A series of characterizations of the ALG-PDEA nanoparticles were carried out, and the in vitro and in vivo antitumor efficacy of the doxorubicin (DOX) loaded ALG-PDEA nanoparticles was evaluated. It is found that the DOX loaded ALG-PDEA nanoparticles can increase the circulation time and also drug level in the tumor tissue compared to that of free drug, and significantly suppress the growth of the tumor.(2) In present work, we developed a new strategy to prepare ALG NPs with the diameter of about100nm. The small molecule2,2’-(ethylenedioxy)diethylamine (DA) was initially employed as a building block to electrostatically complex with ALG in aqueous solution to form ALG NPs by the assistant of Ca2+. The ALG NPs were further served as drug carrier and their drug delivery behavior with DOX as a model drug was investigated through a serial of experiments in vitro and in vivo. After evaluation of in vitro cytotoxicity, in vivo near-infrared (NIR) fluorescence imaging, and in vivo antitumor experiments of murine H22tumor bearing mice, the in vivo drug delivery behavior and antitumor efficacy of the ALG NPs, which served as drug carriers, was investigated. It is found that DOX-loaded ALG NPs exhibit significantly superior antitumor activity than free DOX while elongated the lifetime of the mice accepted treatment and lowered the cardiotoxicity of DOX combining with the results of biodistribution experiments.(3) In order to further enhance the stealth ability of the ALG-PDEA NPs and increase their circulation time, the esterification reaction between carboxyl terminated poly ethylene glycol (PEG) and hydroxyl group on the backbone of the ALG was conducted, and PEGylated ALG was resulted and employed PEGylated ALG-PDEA NPs (PEG-ALG-PDEA). The prepared PEG-ALG-PDEA NPs were served as DOX carriers and their antitumor efficacy was proved to be better than that of free DOX and can elongate the living time of the tested animals through in vitro cytotoxicity, in vivo NIR fluorescence imaging, and in vivo antitumor and biodistribution experiments.(4) The physical cross-linking of the NPs mentioned above was substituted to covalent cross-linking to reinforce the in vivo and in vitro stability of the ALG based NPs. The double bonds of carbon were involved on the moiety of the ALG backbone by esterificating with methacrylic acid, and co-polymerizated with cross-linking agent in aqueous solution to prepare novel size mono-dispersed ALG nanogel with relative high pH stability. Bio-studies were went through and it is found that the DOX loaded ALG nanogel possess better antitumor activity compared to free DOX, as well as can elongate the living time of the tested animals and decrease the cardiotoxicity of DOX.(5) Preliminary attempts were made towards dual drug loading and targeting group modification of the ALG nanogel to enhance the capacity of the nanoparticles in synergistic effect of drugs by synchronically drug loading of cisplatin and DOX, and to research active targeting of the ALG nanogel by modification of cRGD and octreotide, while efforts were endeavored to develop the versatility of the nanoparticles. The tumor accumulation effect of the targeting group modified nanoparticles was analyzed as well as the drug release and cytotoxicity of the dual drug loaded nanoparticles that simultaneously loaded cisplatin and DOX for further application in antitumor study.