Delivery of daunorubicin to cancer cells with decreased toxicity by association with a lipidic nanoemulsion that binds to LDL receptors

Abstract

A lipidic nanoemulsion termed LDE concentrates in neoplastic cells after injection into the bloodstream and thus can be used as a drug carrier to tumour sites. The chemotherapeutic agent daunorubicin associates poorly with LDE; the aim of this study was to clarify whether the derivatization of daunorubicin by the attachment of an oleyl group increases the association with LDE, and to test the cytotoxicity and animal toxicity of the new preparation. The association of oleyl-daunorubicin (oDNR) to LDE showed high yield (93 +/- 2% and 84 +/- 4% at 1:10 and 1:5 drug:lipid mass, respectively) and was stable for at least 20 days. Association with oDNR increased the LDE particle diameter from 42 +/- 4 nm to 75 +/- 6 nm. Cytotoxicity of LDE-oDNR was reduced two-fold in HL-60 and K-562 cell lines, fourteen-fold in B16 cells and nine-fold in L1210 cells when compared with commercial daunorubicin. When tested in mice, LDE-oDNR showed remarkable reduced toxicity (maximum tolerated dose > 253 micromol kg(-1), compared with <3 micromol kg(-1) for commercial daunorubicin). At high doses, the cardiac tissue of LDE-oDNR-treated animals had much smaller structural lesions than with commercial daunorubicin. LDE-oDNR is therefore a promising new preparation that may offer superior tolerability compared with commercial daunorubicin.

Effect of neoadjuvant chemotherapy on low-density lipoprotein (LDL) receptor and LDL receptor-related protein 1 (LRP-1) receptor in locally advanced breast cancer

“…In multiple myeloma patients, the use of carmustine associated with the nanoemulsion resulted in amelioration of both clinical and laboratorial disease parameters (36). In addition, we showed that the use of nanoemulsions markedly reduced drug toxicity in animal experiments (22,32-35) and in clinical trials (16-18,23,28,30,31,36). …”

“…Nonetheless, in animals implanted with B16 melanoma or Walker tumor, we showed that different drugs carried in nanoemulsions that bind to LDL receptors, such as carmustine (32), etoposide (33), paclitaxel (34) or daunorubicin (35) were more efficient in inhibiting tumor growth than the commercial preparations of these drugs. In multiple myeloma patients, the use of carmustine associated with the nanoemulsion resulted in amelioration of both clinical and laboratorial disease parameters (36).…”

Association of daunorubicin to a lipid nanoemulsion that binds to low-density lipoprotein receptors enhances the antitumour action and decreases the toxicity of the drug in melanoma-bearing mice

“…The data obtained from these experiments support the feasibility of the novel preparation destined to upgrade the use of DNR in cancer chemotherapy. A new methodological approach based on recycling high‐pressure homogenisation was successfully tested to replace the time‐consuming and costly method based on prolonged ultrasonication and ultracentrifugation utilised in our previous studies [16]. In a short working time, the new procedure can produce large batches of LDE‐loaded drug formulations, sufficient for conducting larger preclinical studies and clinical trials.…”

“…The high‐pressure homogenisation process was effective in producing smaller size nanoemulsion particles when compared with the LDE‐oDNR formulations obtained by ultrasonication: 48 ± 1 vs 75 ± 6 nm [16]. The process improvement is advantageous because the smaller size of the particles can facilitate the binding to the LDL receptors.…”

“…However, the yield of the association to LDE of free DNR, which is a hydrophilic compound, is poor (<1%). This would preclude the use of LDE‐free DNR in the clinical practice, but subsequently we attained a high‐yield (>90%) and stable preparation by associating the DNR lipophilic derivative N‐oleyl daunorubicin (oDNR) with LDE [16]…”