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Title: Encapsulation, controlled release, and antitumor efficacy of cisplatin delivered in liposomes composed of sterol-modified phospholipids

Here, we employed a recently introduced class of sterol-modified lipids (SML) to produce m-PEG-DSPE containing liposome compositions with a range of cis-platinum content release rates. SML have a cholesterol succinate attached to the phosphatidylglycerol head group and a fatty acid at the 2 position. These compositions were compared to the well-studied liposome phospholipid compositions: mPEG-DSPE/Hydrogenated Soy PC/cholesterol or mPEG-DSPE/POPC/cholesterol to determine the effect of the cis-platinum release extent on C26 tumor proliferation in the BALB/c colon carcinoma mouse model. The release rates of cis-platinum from liposomes composed of SML are a function of the acyl chain length. SML-liposomes with shorter acyl chain lengths C-8 provided more rapid cisplatin release, lower in vitro IC50, and were easier to formulate compared to liposomes using traditional phospholipid compositions. Similar to other liposome cis-platinum formulations, the half-life of m-PEG-DSPE SML liposome cisplatin is substantially longer than the free drug. This resulted in a higher tumor cisplatin concentration at 48 h post-dosing compared to the free drug and higher Pt-DNA adducts in the tumor. Moreover, the maximum tolerated dose of the liposome formulations where up to four fold greater than the free drug. Using X-ray fluorescence spectroscopy on tumor sections, we compared the location ofmore » platinum, to the location of a fluorescence lipid incorporated in the liposomes. The liposome platinum co-localized with the fluorescent lipid and both were non-uniformly distributed in the tumor. Non-encapsulated Cis-platinum, albeit at a low concentration, was more uniformly distributed thorough the tumor. Three liposome formulations, including the well studied hydrogenated HSPC composition, had better antitumor activity in the murine colon 26 carcinoma model as compared to the free drug at the same dose but the SML liposome platinum formulations did not perform better than the HSPC formulation.« less
 [1] ; ORCiD logo [2] ;  [3] ;  [4] ;  [4] ;  [4] ;  [5]
  1. Univ. of California, Berkeley, CA (United States); Univ. of California, San Francisco, CA (United States); Merck Research Labs., Boston, MA (United States); Merck & Co., Inc., Kenilworth, NJ (United States)
  2. Univ. of California, San Francisco, CA (United States); Univ. at Buffalo, Buffalo, NY (United States)
  3. Univ. of California, San Francisco, CA (United States); Stanford Univ. School of Medicine, Stanford, CA (United States)
  4. Argonne National Lab. (ANL), Argonne, IL (United States)
  5. Univ. of California, San Francisco, CA (United States)
Publication Date:
Grant/Contract Number:
Accepted Manuscript
Journal Name:
European Journal of Pharmaceutical Sciences
Additional Journal Information:
Journal Volume: 103; Journal Issue: C; Journal ID: ISSN 0928-0987
Research Org:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org:
National Institutes of Health (NIH); USDOE
Country of Publication:
United States
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; C26 colon carcinoma; Cisplatin; Liposome; X-Ray Fluorescence Microscopy; sterol-modified phospholipid
OSTI Identifier: