Hydroxyethyl Starch Based Nanomedicine For Tumor Suppression

Chemotherapy is one of the widely used methods for tumor treatment in clinic.Traditional chemotherapeutic drugs lack the ability of specific aggregation in tumors,and thus,they commonly show limited therapeutic efficiency while having varied kinds of side effects.With the rapid development of nanotechnology,many types of nanomedicines have been developed for different cancer diagnosis and chemotherapy since last two decades.These nanomedicines exhibit a variety of capabilities to solve the existed problems of traditional chemotherapy drugs and improve the efficacy of the drugs to varying degrees.Many kinds of natural polymers have been employed as carriers for delivering chemotherapeutic drugs.Among them,hydroxyethyl starch?HES?appears to be a safe and effective one.HES has good biocompatibility and biodegradability with high in vivo tolerance.In addition,HES has the structural prunability and modifiability.In this study,HES was used as a carrier material to prepare amphiphilic copolymer self-assembled nanoparticles for delivering chemotherapeutic drugs.Considering that the delivery efficiency of nanomedicines can be affected by complex physiological barriers in vivo,a strategy based on reticuloendothelial system temporary blocking was adopted by using size-adjustable nanoparticles,in order to improve the delivery efficiency of the chemotherapeutic drugs towards tumors.It is known that the single chemotherapy strategy for tumor treatment has a lot of limitation,and hence,two new types of HES-based nanomedicines with hyperthermia chemotherapy features were also developed by using polymer-drug conjugates to improve the anticancer efficiency of the loaded drugs.The main research and obtained results were presented as follows:?1?Preparation and characterization of amphiphilic polymer HES-g-PLA.HES with molecular weight and substitution degree of 70 kDa and 0.5,and PLA with molecular weight of 5 kDa were selected as starting materials.PLA was chemically conjugated to HES by ester bonds under mild reaction conditions using dicyclohexyl carbodiimide?DCC?and dimethylaminopyridine?DMAP?as reaction assistants.The molecular structure of the resulting HES-g-PLA was characterized by FT-IR and ¹H-NMR.By adjusting the feed ratio of PLA to HES,HES-g-PLA_s with different degrees of substitution were synthesized.After a series of orthogonal tests,two kinds of HES-g-PLA_s polymers with different degrees of substitution were optimized and their PLA substitution degrees were 0.82 and 1.62,respectively.These two amphiphilic polymers with desirable structures and properties were further self-assembled into two types of nanoparticles:the empty HES-g-PLA_1.62 nanoparticles with mean size of about 700 nm and the DOX-loaded DOX@HES-g-PLA_0.86 nanoparticles with mean size of about 130 nm.?2?Anti-tumor evaluation of above-prepared two kinds of nanoparticles?nanoparticle partner?.The large empty HES-g-PLA_1.62 nanoparticles were used to block up thereticuloendothelial system in advance whereas the small-size DOX@HES-g-PLA_0.86nanoparticles were subsequently applied to suppress tumors.By administered these nanoparticles in such a sequential way,RES can be effectively blocked.Results associated with pharmacokinetics and tissue distribution of drugs showed that the RES-blockade strategy could significantly prolong plasma half-life time of drugs and reduce the clearance rate as well as enhance intratumoral accumulation of drugs when comparing to the administration of free DOX.In vivo antitumor studies demonstrated that the DOX@HES-g-PLA_0.86 nanoparticles working together with their partner exhibited remarkably enhanced antitumor efficacy in comparison to free DOX.Moreover,the HES-g-PLA_s nanoparticle partner showed negligible damage to the normal organs of the treated mice.Considering safe and efficient antitumor performance of DOX@HES-g-PLA_0.86 nanoparticles,the newly developed partner nanocarriers in combination with their administration mode have promising potential in clinical cancer chemotherapy.?3?Preparation and characterization of multifunctional HES-SS-DOX@ICG NPs.DOX-loaded HES conjugates with redox-sensitivity?HES-SS-DOX?were first synthesized and they were then combined with ICG to self-assemble into HES-SS-DOX@ICG NPs with controlled compositions and sizes via collaborative interactions.The optimal HES-SS-DOX@ICG NPs with a mean size of about 170 nm had good physical and photothermal stability in aqueous media and showed high photothermal efficiency in vivo.They were able to fast release the loaded DOX in response to the redox stimulus and the applied laser irradiation.?4?Anti-tumor effects evaluation of multifunctional HES-SS-DOX@ICG NPs.Based on the H22-tumor-bearing mouse model,these NPs were found to tendentiously accumulate inside tumors in comparison to other major organs.The HES-SS-DOX@ICG NPs together with dose-designated laser irradiation were able to fully eradicate tumors with only one injection and one single subsequent laser irradiation on the tumor site during a 14-day treatment period.In addition,they showed almost no impairment to the body.The presently developed HES-SS-DOX@ICG NPs have good in vivo safety and highly efficient anti-tumor capability.These NPs in conjugation with laser irradiation have promising potential for chemo-photothermal cancer therapy in the clinic.?5?Preparation and characterization of multifunctional GNR@HES-SS-DOX NPs.First we prepared gold nanorods?GNR?using a modified seed method.Then HES-SS-DOX was conjugated onto the surface of GNR to obtain GNR@HES-SS-DOX NPs.Particle size,Zeta potential,UV-Vis spectrum,morphology and stability of GNR@HES-SS-DOX NPs were evaluated.The results showed that GNR@HES-SS-DOX NPs had better photothermal conversion efficiency,and after multiple irradiations the GNRs@HES-SS-DOX NPs still had higher stability,which laid a foundation for the subsequent evaluation of anti-tumor effect.