Synthesis And Properties Of PH Sensitive Poly(Ester Amide)-Doxorubicin Conjugates

Cancer, cardiovascular and cerebrovascular diseases are three major threats topublic health. Chemotherapy is commonly used as one of effective clinical treatmentfor cancer. However, most of currently used anti-cancer drugs have some inherentdrawbacks, such as low solubility and poor targeting ability, which eventually lead tothe lower drug use efficiency, severe side effects and multidrug resistance. Toovercome these disadvantages, minimize the side effects and enhance the therapeuticefficacy, researchers have developed a novel nano drug delivery system. This newdelivery system may achieve the long term of targeting controlled release byphysically or chemically incorporating the low molecular anti-cancer drugs inside thenano size carriers.Aliphatic polyesters, such as polyglycolide and poly(L-lactide), have alreadybeen used in nano drug delivery system because of their good biodegradability andbiocompatibility. However, the unalterable chemical structures have determined thatthe aliphatic polyesters do not widely adjustable physicochemical properties, whichmay further limit many potential application in drug-controlled release field.Naturally occurring amino acid-based poly(ester amide)(PEA) is a new class ofbiodegradable polymers. The PEAs have not only biodegradable ester bonds but alsoamide bonds which enable polymer has excellent thermostability and mechanicalproperties. In this dissertation, two kinds of functional amphiphilic PEAs copolymershave been successfully designed and synthesized, and the anti-cancer drugdoxorubicin has been chemically conjugated onto the hydrophobic blocks ofcopolymers via hydrazine bonds. These pH-sensitive nano drug delivery system mayform micelle in water, and deliberately deliver doxorubicin inside the tumor cellwhich was triggered by the difference of microenvironment between normal tissuesand tumor tissues.1.PEA telechelic polymers with nitrophenol ester end groups were synthesized by solution polycondensation. After reacting with1,3-diamino-2-hydroxypropane, theprepolymers have been expanded to achieve functional PEA telechelic polymerwhich has many pendant hydroxyl groups along the backbone. The poly(ethyleneglycol)--poly(ethylene glycol)(PEG-COOH-PEG) amphiphilic triblock copolymerswere yield by reacting functional prepolymer with amine-terminated PEG. ThepH-sensitive doxorubicin prodrug was eventually obtained by chemically bondingdoxorubicin onto the hydrophobic blocks of PEG--PEG copolymer through theacid-labile hydrazone bond. The amphiphilic prodrug can self-assemble into micellesin water. The stability of micelles was proved by measuring the critical micelleconcentration (CMC). In vitro drug release assay under the simulated slightly acidicenvironment of the tumor tissue showed that the lower pH value may promote therelease of doxorubicin. Cell experiments proved that the nano drug delivery systemhas good biocompatibility and release efficacy inside the tumor cells.2.Based on the solution polycondensation of PEA, we synthesized PEAtelechelic polymers composed of nitrophenol ester end groups and pendantcarbo-xylic acid groups by using benzyl alcohol protected lysine as nucleophilicmon-omer and Di-p-nitrophenyl sebacate diester as electrophilic monomer. ThePEG-PEA(COOH)-PEG triblock copolymers were obtained by reacting functionalPE-A(COOH) prepolymer with amine-terminated PEG. Doxorubicin was chosen as amodel drug, and chemically boned on the copolymer via acid-labile hydrazine bond.Amphiphilic characteristic enabled the doxorubicin conjugate copolymer to formmicelles in aqueous solution. The morphology and stability of micelles were furtherexamined by dynamic light scattering (DLS) and Transmission electron microscopy(TEM). MTT results showed that the blank carrier material has good biocompatibility,and the doxorubicin conjugate triblock copolymers have excellent tumor suppressoreffect.