Pharmacokinetics of sterically stabilized hexadecylphosphocholine liposomes versus conventional liposomes and free hexadecylphosphocholine in tumor-free and human breast carcinoma bearing mice

Abstract

The pharmacokinetics of free and different liposomal formulations of hexadecylphosphocholine (HPC) was investigated in tumor-bearing (human mammary tumor MaTu) and tumor-free mice after intravenous and intraperitoneal administration. The levels of HPC were evaluated at different times in serum, normal tissues, and tumor. The purpose was to test the hypothesis that the enhanced therapeutic efficacy of sterically stabilized HPC liposomes in comparison to conventional vesicles and free HPC is due to its pharmacokinetics. Conventional non-compartmental pharmacokinetic analysis and an elaborate three- and four-compartmental model were used for explaining the experimental data. The serum levels of HPC obtained with sterically stabilized liposomes were only consistently higher in comparison to conventional vesicles and free HPC in the first 4 h. In the xenografted MaTu carcinoma, the differences of the HPC content between the different groups are unexpectedly low and do not reflect the high therapeutic activity [5] of sterically stabilized HPC liposomes. Detailed analysis shows that the liposomally encapsulated drug displays a modified pharmacokinetic behavior, which may also involve lymphatic absorption of the liposomal drug.

Mathematical Modeling of Vesicle Drug Delivery Systems 2: Targeted Vesicle Interactions with Cells, Tumors, and the Body

“…Often the drug is administered orally or through intraperitoneal injection, which is an injection into the body cavity. Arangoa et al 40 and Arndt et al 44 altered their compartmental models and found that the modifications improved the accuracy of their models in characterizing the pharmacokinetics of their delivery systems in vivo. Arndt et al 44 used hexadecylphosphocholine liposomes as a drug carrier that was administered first intravenously and then intraperitoneally, and they used an altered model for intraperitoneal injection.…”

Interaction of Alkylphospholipid Formulations with Breast Cancer Cells in the Context of Anticancer Drug Development

“…2). Initial preclinical tests were promising, indicating a good anti-cancer activity against several human tumour xenograft models in the mouse (Arndt et al, 1997;Fichtner et al, 1994), including different breast cancer cell lines like: MT-3 (Zeisig et al, 1998), MDA-MB 435 and MDA-MB 231 (Sobottka & Berger, 1992), MaTu (Arndt et al, 1999), MT-1 (Naundorf et al, 1992), C3H, Ca 755 (Zeisig et al, 1991) and also syngeneic models like murine P388 leukemia, and B 16 melanoma (Zeisig et al, 1991). Preclinical experiments further demonstrated that alkylphospholipids, if used in liposomal form, are able to abolish multi drug resistance in human breast cancer xenografts (Zeisig et al, 2004) and inhibit metastasis if combined with an aggregation inhibitor inside liposomes in murine syngene (Wenzel et al, 2010) and human xenograft breast cancer models (Wenzel et al, 2009).…”

Growth inhibition of human mammary carcinoma by liposomal hexadecylphosphocholine: Participation of activated macrophages in the antitumor mechanism

“…Thioglycollate broth was purchased from Baltimore Biological Laboratory (Cockeysville, MD). 3 [H] thymidine was purchased from ICN Biomedicals (Irvine, CA). All reagents were proven to be endotoxin free as determined by LAL-test from Associates of Cape Cod (Walpole, MA, detection limit 0.125 ng/ml).…”

“…The cells were activated with L-HPC and the appropriate positive and negative controls for 24 hr and washed extensively afterwards. Tumor cells were labelled with 0.25 Ci/ml 3 [H]Thymidine (specific activity of 2 Ci/mmol) in T 25 flasks in the exponential growth phase for 24 hr. The cells were washed 3 times with HBSS and trypsinized (0.25% trypsin, 0.02% EDTA).…”

“…[1][2][3] The therapeutic effect of etherlipids and alkylphosphocholines has also been shown in clinical trials, 4 -7 whereas colorectal carcinoma and soft tissue sarcomas were not effected. 8,9 HPC was demonstrated to be especially effective in estrogen and progesterone receptor-negative human mammary carcinoma models, whereas receptor-positive tumor cells were less responsive.…”