Nevertheless,

the pharmacokinetics after administration in dogs was more similar to free doxorubicin than Doxil, which demonstrates the need to further optimize the lipid composition. Although liposomal cisplatin with 80% hydrogenated soy phosphatidylcholine (HSPC) showed increased cisplatin accumulation in preclinical tumors over free drug [21], this did not translate into therapeutic activity in patients [310, 311]. Absence of clinical activity was correlated with a lack of detectable released drug in the serum of treated patients, revealing Inhibitors,research,lifescience,medical the need for a balance between modifying the free drug pharmacokinetics for improved biodistribution to the diseased site and bioavilability [96]. PEGylation is required for enhanced blood residency and therapeutic efficacy, but postinsertion of DSPE-PEG6000 into preformulated siRNA lipoplexes was reported to induce siRNA release in vitro [312] and was nicely overcome

by the use of cholesterol grafted siRNA for increased retention in liposomes. Inhibitors,research,lifescience,medical The combination of cellular uptake and targeting using a cholesterol-siRNA conjugate and INCB018424 cost cyclic RGD peptide allowed luciferase silencing in a B16F10-luc 2 experimental Inhibitors,research,lifescience,medical lung metastasis model, validating this new system [313]. 6.2. Cell Penetrating Peptides Cell penetrating peptides (CPPs) are amphiphatic peptides, usually cationic, either derived from viruses or synthetic that are able to improve the cellular internalization of the attached cargo [314] (Figure 4). The most frequently used CPPs are the TaT peptide derived from the transcription-transactivating protein of human immunodeficiency virus type 1 and synthetic polyarginine [315, 316]. TaT peptide is a powerful internalization moiety. However its endocytosis lacks cell-specificity and TaT peptide exposure at the liposome surface Inhibitors,research,lifescience,medical can lead to MPS elimination

after opsonin binding as well [317]. For Tat-mediated internalization only in the tumor environment, Inhibitors,research,lifescience,medical masking strategies have been proposed. This concept was proved by Kale and Torchilin using masked TaT peptide surface-functionalized lipoplexes prepared with a plasmid coding for GFP (DSPE-PEG1000-TAT) by a pH-sensitive PEG corona (DSPE-hydrazone-PEG2000), too leading to higher transgene expression in tumor tissue after intratumoral injection of pH-sensitive formulations [318]. Kuai et al. masked TaT peptide at the liposome surface (TAT-PEG2000-DSPE) by a reduction-sensitive PEG corona (PEG5000-S-S-DSPE) to take advantage of the higher concentration of reductive enzymes in tumors [319]. This allowed higher tumor accumulation and less liver uptake than unmasked Tat peptide-modified liposomes after intravenous administration. More recently, UV-triggered CPPs have been proposed [306]. They added a CPP through incorporation of a TaT peptide-lipid conjugate with two lipid anchors, a TaT peptide-PEG2000-DSPE conjugate linked to a less stable single chain hydrophobic group of 12 or 16 carbons via a UV-cleavable linker.