Pulsed-high intensity focused ultrasound and low temperature-sensitive liposomes for enhanced targeted drug delivery and antitumor effect.

PURPOSE: To determine if pulsed-high intensity focused ultrasound (HIFU) could effectively serve as a source of hyperthermia with thermosensitive liposomes to enhance delivery and efficacy of doxorubicin in tumors. EXPERIMENTAL DESIGN: Comparisons in vitro and in vivo were carried out between non-thermosensitive liposomes (NTSL) and low temperature-sensitive liposomes (LTSL). Liposomes were incubated in vitro over a range of temperatures and durations, and the amount of doxorubicin released was measured. For in vivo experiments, liposomes and free doxorubicin were injected i.v. in mice followed by pulsed-HIFU exposures in s.c. murine adenocarcinoma tumors at 0 and 24 h after administration. Combinations of the exposures and drug formulations were evaluated for doxorubicin concentration and growth inhibition in the tumors. RESULTS: In vitro incubations simulating the pulsed-HIFU thermal dose (42 degrees C for 2 min) triggered release of 50% of doxorubicin from the LTSLs; however, no detectable release from the NTSLs was observed. Similarly, in vivo experiments showed that pulsed-HIFU exposures combined with the LTSLs resulted in more rapid delivery of doxorubicin as well as significantly higher i.t. concentration when compared with LTSLs alone or NTSLs, with or without exposures. Combining the exposures with the LTSLs also significantly reduced tumor growth compared with all other groups. CONCLUSIONS: Combining low-temperature heat-sensitive liposomes with noninvasive and nondestructive pulsed-HIFU exposures enhanced the delivery of doxorubicin and, consequently, its antitumor effects. This combination therapy could potentially produce viable clinical strategies for improved targeting and delivery of drugs for treatment of cancer and other diseases.

A novel polymeric chlorhexidine delivery device for the treatment of periodontal disease.

An implantable, anti-microbial delivery device for the treatment of periodontal disease has been developed. In this polymer-based delivery system, the encapsulation efficiency, release characteristics, and bioactivity of anti-microbial agent were controlled by the complexation of the drug with cyclodextrins of differing lipophilicity. Microparticles of poly(dl-lactic-co-glycolic acid) (PLGA) containing chlorhexidine (Chx) free base, chlorhexidine digluconate (Chx-Dg) and their association or inclusion complex with methylated-beta-cyclodextrin (MBCD) and hydroxypropyl-beta-cyclodextrin (HPBCD) were prepared by single emulsion, solvent evaporation technique. It was observed that encapsulation efficiency and release of the chlorhexidine derivatives from the microparticles was a function of the lipophilicity of the cyclodextrin. Complexation of the poorly water soluble Chx with the more hydrophilic HPBCD resulted in 62% higher encapsulation efficiency and longer duration of sustained release over a 2-week period than complexation with the more lipophilic MBCD. In contrast, the complexation of the more water-soluble derivative of chlorhexidine, Chx-Dg, with the more lipophilic MBCD improved encapsulation efficiency by 12% and prolonged its release in comparison to both the free Chx-Dg and its complex with HPBCD. Furthermore, it was observed that the initial burst effect could be diminished by complexation with CD. Preliminary studies have shown that the chlorhexidine released from PLGA chips is biologically active against bacterial population that is relevant in periodontitis (P. gingivalis and B. forsythus) and a healthy inhibition zone is maintained in agar plate assay over a period of at least a 1-week. The PLGA/CD delivery system described in this paper may prove useful for the localized delivery of chlorhexidine salts and other anti-microbial agents in the treatment of periodontal disease where prolonged-controlled delivery is desired.