The arnphipathic anthracycline base doxorubicin (DXR) was accumulated in the aqueous phase of the liposomes where it reached a level as high as 100-fold its concentration in the remote loading medium. Most of the intraliposomal D X R was present in an aggregated state. Eflicient (>90%) and stable loading into the liposomes' and ligandoliposomes' aqueous phase was obtained by using gradients of ammonium sulfate in which the ammonium sulfate concentration in the liposomes was higher than its concentration in the extraliposomal medium [(NH,),SO,)lip. > > [(NH,),SO,)med.]. The "remote" loading is a result of the D X R exchange with ammonia from (NH,),SO,. Both the ammonium and sulfate contribute to high level and stability of the loading. The ammonium sulfate gradient method differs from most other chemical approaches used for remote loading of liposomes since it neither requircs to prepare the liposomes in ijcidic pH, nor to alkalinize the extraliposomal aqucous phase. Although most of the intraliposomal D X R is present in an aggregated gel-like state, the drug is bioavailable. This approach permits the preparation of DXRloaded liposomes of a broad spectrum of types, sizes, and composition, including sterically-stabilized liposomes, irnmunoliposomes, and sterically-stabilized immunoliposomes. Due to the long shelf stability (>6 mo), no "bedside" remote 455

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The present study aims to develop an implant coating releasing novel antimicrobial agents to prevent biomaterial-associated infections. The LL-37-derived synthetic antimicrobial and anti-biofilm peptides (SAAP)-145 and SAAP-276 exhibit potent bactericidal and anti-biofilm activities against clinical and multidrug-resistant Staphylococcus aureus strains by rapid membrane permeabilization, without inducing resistance. Injection of SAAP-145, but not SAAP-276, along subcutaneous implants in mice reduces S. aureus implant colonization by approximately 2 log, but does not reduce bacterial numbers in surrounding tissue. To improve their efficacy, SAAP-145 and SAAP-276 are incorporated in a polymer-lipid encapsulation matrix (PLEX) coating, providing a constant release of 0.6% daily up to 30 d after an initial burst release of >50%. In a murine model for biomaterial-associated infection, SAAP-145-PLEX and SAAP-276-PLEX coatings significantly reduce the number of culture positive implants and show ≥3.5 and ≥1.5 log lower S. aureus implant and tissue colonization, respectively. Interestingly, these peptide coatings are also highly effective against multidrug-resistant S. aureus, both reducing implant colonization by ≥2 log. SAAP-276-PLEX additionally reduces tissue colonization by 1 log. Together, the peptide-releasing PLEX coatings hold promise for further development as an alternative to coatings releasing conventional antibiotics to prevent biomaterial-associated infections.

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