Preliminary Study On Bone-targeted Ultradeformable Nano-liposomes

In this paper, several bone targeting ultradeformable nano-liposmomes (UL) was designed and prepared. The properties were preliminarily studied with lipophilic model drug, Pyrene.Poloxamer407 (P407), ethylene diamine tetra (methylene phosphonic acid) (EDTMPA) was selected to modify the UL surface. To further increase the target efficiency, 1,12- dodecane diamine tetra (methylene phosphonic acid) (12-DTMPA) was also synthesized though Mannich-type reaction, with phosphorous acid, 1,12-dodecane diamine and formaldehyde as raw materials, which has the same main function groups as EDTMPA. Pyrene is a representative lipophilic fluorescent compound. In this paper, the fluorescent detection of pyrene in vitro and in vivo was founded. Moreover, normal UL (N-UL), P407 UL (P-UL), 12-DTMPA UL (12-UL) and EDTMPA UL (E-UL) were prepared respectively. The single-factor analysis was applied to optimize the preparing techniques of these kinds of UL. The entrapment efficiency, the diameters and distribution of the prepared UL were examined. For future preservation, the protective reagents in freeze-drying process were also preliminary investigated. All the quantitative indexes of UL satisfied the requirement of delivery of drug to bone or marrow.The pharmacokinetic and tissue distribution characteristics in mice of pyrene in N-UL, P-UL, 12-UL and E-UL were examined respectively in a systemic way. The result showed that the pharmacokinetic characteristics of pyrene in N-UL in mice accorded with the two-compartment model, but the characteristics in P-UL, 12-UL and E-UL accorded with the three-compartment model. Different compartment models of pyrene indicated that UL with target function can remarkably alter the pharmacokinetic behavior of pyrene in vivo. Evaluated by drug targeting efficiency (DTE), drug targeting index (DTI,DTIAUC) and relative targeting efficiency (RTE), the results of tissue distribution tests showed that, P-UL, 12-UL and E-UL all possessed the ability of targeting on bone and E-UL had the strongest ability. In addition, the targeted mechanism of the three surface-modified UL was also studied preliminary, which showed that P-UL relatively concentrated in bone marrow, while 12-UL and E-UL relatively in bone matrix.