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

Abstract

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.

Enhanced Efficacy of PEGylated Liposomal Cisplatin: In Vitro and In Vivo Evaluation

“…The bags were then immersed in 100 mL of PBS and stirred (200 rpm, room temperature). At different time points (0, 1,2,3,8,12,18,24,30,36,42, and 48 h), 1 mL of PBS was collected to determine Cispt concentration using AAS method and replaced with 1 mL of fresh PBS. Cumulative drug release percentage was calculated using the formula below:…”

“…The results showed that the nanoparticles caused a significant reduction in the tumor volume compared to when Cispt was used (tumor volumes of 0.68 and 0.3 cm 3 in Cispt and Cispt-loaded NDAT nanoparticles receiver animals, respectively). Liposome nanoparticles are another delivery system, which are widely used for the treatment of cancer in in vitro and in vivo environments [9,12,13].…”

Recent progress in nanotechnology-based novel drug delivery systems in designing of cisplatin for cancer therapy: an overview

“…The CDDP-loaded sialyl Lewis X-modified liposomes (CDDP-SLX-LIP) were constructed and optimized. Liposomes had extended higher drug release and were gradually accumulated inside the tumour cell [84]. Vhora et al reported that the sterol cisplatin-based liposome demonstrated the greater half-life as a match free drug.…”

Mesenchymal Stem Cells As Guideposts for Nanoparticle-Mediated Targeted Drug Delivery in Ovarian Cancer

“…Encapsulation of chemotherapeutics in nanocarriers, such as liposomes [6,7], nanoparticles [8,9], dendrimers [10,11] or micelles [12,13], which exploit the enhanced permeability and retention (EPR) effect, is the most extensively explored strategy for improving tumor bioavailability and reducing exposure to healthy tissues. However, these systems have had limited success, and only a small fraction (less than 1%) of the injected dose accumulates within the tumor, even in highly permeable tumors [14].…”