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

Abstract

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

Authors:
 [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:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Institutes of Health (NIH); USDOE
OSTI Identifier:
1377594
Grant/Contract Number:
AC02-06CH11357
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
European Journal of Pharmaceutical Sciences
Additional Journal Information:
Journal Volume: 103; Journal Issue: C; Journal ID: ISSN 0928-0987
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
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

Citation Formats

Kieler-Ferguson, Heidi M., Chan, Darren, Sockolosky, Jonathan, Finney, Lydia, Maxey, Evan, Vogt, Stefan, and Szoka, Jr., Francis C.. Encapsulation, controlled release, and antitumor efficacy of cisplatin delivered in liposomes composed of sterol-modified phospholipids. United States: N. p., 2017. Web. doi:10.1016/j.ejps.2017.03.003.
Kieler-Ferguson, Heidi M., Chan, Darren, Sockolosky, Jonathan, Finney, Lydia, Maxey, Evan, Vogt, Stefan, & Szoka, Jr., Francis C.. Encapsulation, controlled release, and antitumor efficacy of cisplatin delivered in liposomes composed of sterol-modified phospholipids. United States. doi:10.1016/j.ejps.2017.03.003.
Kieler-Ferguson, Heidi M., Chan, Darren, Sockolosky, Jonathan, Finney, Lydia, Maxey, Evan, Vogt, Stefan, and Szoka, Jr., Francis C.. Fri . "Encapsulation, controlled release, and antitumor efficacy of cisplatin delivered in liposomes composed of sterol-modified phospholipids". United States. doi:10.1016/j.ejps.2017.03.003. https://www.osti.gov/servlets/purl/1377594.
@article{osti_1377594,
title = {Encapsulation, controlled release, and antitumor efficacy of cisplatin delivered in liposomes composed of sterol-modified phospholipids},
author = {Kieler-Ferguson, Heidi M. and Chan, Darren and Sockolosky, Jonathan and Finney, Lydia and Maxey, Evan and Vogt, Stefan and Szoka, Jr., Francis C.},
abstractNote = {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.},
doi = {10.1016/j.ejps.2017.03.003},
journal = {European Journal of Pharmaceutical Sciences},
number = C,
volume = 103,
place = {United States},
year = {Fri Mar 03 00:00:00 EST 2017},
month = {Fri Mar 03 00:00:00 EST 2017}
}

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  • The purpose of this study was to evaluate pluronic F127 for the controlled release of cisplatin in a rabbit model. Pluronic F127 becomes liquid at temperatures <25{sup o}C and converts to a gelatinous state at temperatures between 25 and 60{sup o}C. Six Japanese white rabbits were injected with pluronic + cisplatin (n = 3, renal group A) or saline + cisplatin (n = 3, renal group B) to measure the platinum concentration in kidneys. Another 25 rabbits with VX2 liver tumors were divided into five equal groups. They were injected with saline, saline + cisplatin, iodized oil + cisplatin, pluronicmore » alone, or pluronic + cisplatin and labeled as liver groups A, B, C, D, and E, respectively. The antitumor effect of pluronic was then assessed. In the presence of pluronic, the platinum concentration in the kidneys of rabbits remained relatively high. In animals with liver tumors, the delivery of pluronic + cisplatin produced higher tumor reduction rates (P < 0.05) than in the other groups, without apparent damage to normal liver tissue. We conclude that pluronic is useful for the controlled release of cisplatin in a rabbit model.« less
  • The antitumor efficacies of vaccinia virus-modified tumor cell vaccines were examined in murine syngeneic MH134 and X5563 tumor cells. UV-inactivated vaccinia virus was inoculated i.p. into C3H/HeN mice that had received whole body X-irradiation at 150 rads. After 3 weeks, the vaccines were administered i.p. 3 times at weekly intervals. One week after the last injection, mice were challenged i.p. with various doses of syngeneic MH134 or X5563 viable tumor cells. Four methods were used for preparing tumor cell vaccines: X-ray irradiation; fixation with paraformaldehyde for 1 h or 3 months; and purification of the membrane fraction. All four vaccinesmore » were effective, but the former two vaccines were the most effective. A mixture of the membrane fraction of untreated tumor cells and UV-inactivated vaccinia virus also had an antitumor effect. These results indicate that vaccine with the complete cell structure is the most effective. The membrane fraction of UV-inactivated vaccinia virus-absorbed tumor cells was also effective. UV-inactivated vaccinia virus can react with not only intact tumor cells but also the purified membrane fraction of tumor cells and augment antitumor activity.« less
  • Purpose: To report the experience of treating selected fit patients with locally advanced head-and-neck squamous cell carcinoma with three cycles of induction TPF (docetaxel 75 mg/m{sup 2}, cisplatin 75 mg/m{sup 2}, 5-fluorouracil 750 mg/m{sup 2}, Days 2-5) followed by concurrent three-weekly bolus cisplatin 100 mg/m{sup 2} chemoradiotherapy. Methods and Materials: Between March 2006 and February 2010, 66 patients with nonmetastatic Stage IV head-and-neck squamous cell carcinoma were treated in a single institution with three cycles of induction TPF, followed by radical radiotherapy with concurrent cisplatin 100 mg/m{sup 2}. Results: Median age was 54 years (range, 33-69 years). Median follow-up wasmore » 21 months (range, 4-55 months). During TPF, Grade 3 toxicity occurred in 18 patients (27%), dose modifications in 10 (15%), delays in 3 (5%), and unplanned admissions in 6 (9%); a clinical tumor response was documented in 60 patients (91%). Median time from the final cycle of TPF to commencing radiotherapy was 22 days. Sixty-two patients (94%) received radical radiotherapy, and all completed treatment with no delays {>=}3 days. One, two, and three cycles of concurrent cisplatin were delivered to 18 patients (29%), 38 patients (61%), and 3 patients (5%), respectively. Ninety-two percent of patients received enteral feeding; median weight loss during treatment was 7%. Forty-two patients (68%) had unplanned admissions with no on-treatment deaths. Three unrelated deaths occurred after treatment. At 1 year after treatment, 21% of patients without disease progression remained gastrostomy dependent. Of 58 assessable patients, 50 (86%) achieved a complete response after treatment. One- and 2-year progression-free survival, cause-specific survival, and overall survival were 88%, 92%, and 86% and 80%, 85%, and 80%, respectively. Conclusion: The combination of induction TPF with concurrent cisplatin chemoradiotherapy in patients with locally advanced head and neck squamous cell carcinoma is tolerable, with encouraging efficacy.« less
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