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

Journal Article · · European Journal of Pharmaceutical Sciences
 [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)
+ Show Author Affiliations

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 of 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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
National Institutes of Health (NIH); USDOE
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1377594
Journal Information:
European Journal of Pharmaceutical Sciences, Vol. 103, Issue C; ISSN 0928-0987
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 31 works
Citation information provided by
Web of Science

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Cited By (5)

Influence of geometric isomerism on the binding of platinum anticancer agents with phospholipids journal January 2019
Structural Factors Affecting Binding of Platinum Anticancer Agents with Phospholipids: Influence of Charge and Phosphate Clamp Formation journal February 2018
Liposomal Drug Delivery Systems and Anticancer Drugs journal April 2018
Recent progress in nanotechnology-based novel drug delivery systems in designing of cisplatin for cancer therapy: an overview journal May 2019
Enhanced Efficacy of PEGylated Liposomal Cisplatin: In Vitro and In Vivo Evaluation journal January 2020

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Related Subjects

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