Study On Polyamide - Amine Dendrimers As Drug Carriers

PAMAM dendrimer is a potential drug carrier. In this paper, the synthesis, characterization, physical and chemical properties, PEG modification, properties of drug loading, cell toxicity and cell affinity of PAMAM have been studied. and Choosing doxorubicin as a model drug, the in vitro and in vivo properties of the dendrimer have been studied.In this paper, PAMAM dendrimer of 1-5 Generation were synthesized referring to the method reported in the literature, and characterized by IR, NMR, GPC. Furthermore, PAMAM dendrimer has been modified with PEG characterized as well. The modification was expected to achieve extended releasing effect and reduce the toxic effects of the dendrimer.In this paper, the maximum bubble pressure method was used in the determination of surfactancy of the 3.0-5.0G PAMAM dendrimer. According to single point method,the intrinsic viscosity of 3.0-5.0GPAMAM were investigated using Ubbelohde viscometer and the fluid dynamics of equivalent sphere radius of PAMAM dendrimers was calculated Solubility of 0.5-5.0G PAMAM molecules in polar solvents such as water, ethanol and in non-polar solvents such as chloroform were inspected, The pH of 0.5-5.0G PAMAM macromolecules in aqueous solution was investigated which can provide a basis for the application of PAMAM dendrimers as drug carriers. Results showed that semi-generation of PAMAM macromolecules have some certain degree of surfactancy, and the whole generation of PAMAM have weak surfactancy. The intrinsic viscosity of whole generation of denderimers was greater than that of the semi-generation; the pH of whole-generation of PAMAM in aqueous solution was basic in some degree, while semi-generation solution has neutral pH values; The semi-generation of PAMAM macromolecules have good solubility in both polar solvents and non-polar solvents, while the whole generation of PAMAM dissolved well in polar solvents and poor in non-polar solvents.In this paper, weak acid drugs such as curcumin and ibuprofen, amphoteric compounds sulfamethoxazole, hard ionization drug cucurbitacin, weak alkaline drug doxorubicin were used to investigate the properties of the drug loading capability of dendrimer. In addition, the in vitro release of PAMAM was studied and the mechanism of loading different types of drugs was discussed. The capacity of drug loading and drug release characteristics of PAMAM and PEG-PAMAM were compared. The experimental results showed that ibuprofen, curcumin, and Sulfamethoxazole were combined to the PAMAM dendrimers through electrostatic incorporation. This kind of combination was unstable in the PBS buffer and the release of the above drugs in PBS buffer was fast. Cucurbitacin and doxorubicin were physically embedded into the macromolecular cavity, and both showed a sustained release effect. Doxorubicin was used as a model drug to study the characteristics of drug loading and invitro drug release from PAMAM and PEG-PAMAM. The results showed that PAMAM and PEG-PAMAM have a similarly high capacity of drug loading, and PEG-PAMAM- doxorubicin has more obvious sustained-release effect.The cytotoxicity of 2.5-5.0 generations PAMAM and that of the PEG-PAMAM5.0G on hepG2 were determined by the method of MTT. The cell affinity of PAMAM and PEG-PAMAM5.0G have been studied through flow cytometry experiments. The results showed that the toxicity of PAMAM increased along with the increasing of dendrimer concentration; the toxicity of whole-generation of PAMAM was greater than that of the semi-generation. The toxicity of PEG-PAMAM is smaller than that of the PAMAM 5.0G without PEG modification. Flow cytometry results showed that both PAMAM and PEG-PAMAM preparation group showed good cell affinity, and PEG-PAMAM preparation group had better affinity than that of PAMAM.The fluorescence spectrophotometry was used in the determination of doxorubicin concentration in rat plasma, by which the study of pharmacokinetics of PAMAM and PEG-PAMAM preparation group was held. The results showed that both drug-loaded PAMAM and PEG-PAMAM could extend the elimination half-life of doxorubicin, as well as increase the AUC. DOX-PEG-PAMAM group had a more pronounced effect of long circulation, which greatly raised the AUC, and slower the distribution and elimination.The studies of tissue distribution of doxorubicin solution group and doxorubicin-PAMAM group and doxorubicin-PEG-PAMAM were held. The results showed that the doxorubicin solution was widely distributed in mice, but could not penetrate the blood-brain barrier. Doxorubicin-PAMAM solution preparation group significantly increased liver targeting, reduced the distribution in the lungs comparing to doxorubicin solution group and doxorubicin-PEG-PAMAM group, as well as had a certain ability to penetrate the blood-brain barrier. Doxorubicin-PEG-PAMAM preparation group distributed to tissues slowly, and had higher concentration of doxorubicin in lung than the doxorubicin-PAMAM preparation group.