Stability Influences the Biodistribution, Toxicity, and Anti-tumor Activity of Doxorubicin Encapsulated in PEG-PE Micelles in Mice

Abstract

Purpose To investigate the influences of stability of doxorubicin (DOX) retained in PEG-PE/HSPC micelles on its biodistribution, toxicity and anti-tumor activity in mice. Methods We incorporated HSPC into PEG-PE micelles at various molar ratios by a self-assembly procedure. Micelles were characterized by dynamic light scattering, transmission electron microscope, atomic force microscopy. Agarose gel electrophoresis assay was used to detect stable retention of DOX in micellar preparations. Biodistribution, toxicity and antitumor activity of doxorubicin encapsulated in PEG-PE/HSPC micelles in mice were investigated. Results HSPC incorporation not only changed the size and shape of PEG-PE micelles, but also decreased the ability of DOX stable retained in PEG-PE micelles, resulting in a great discrepancy in biodistribution, toxicity and anti-tumor activity among micellar DOX preparations. DOX encapsulated in PEG-PE micelles (M 1 -DOX), with narrower size distribution and greater stability, demonstrated better cytotoxicity in vitro and low systemic toxicity with superior anti-tumor metastasis activity in vivo. Conclusions Encapsulation of DOX into PEG-PE micelles showed the best therapeutic activity and lowest systemic toxicity compared to other HSPC-incorporated PEG-PE micellar preparations. Stable retention of drugs within micelles is important and is determined by compatibility between drugs and polymer blocks.

Small-sized polymeric micelles incorporating docetaxel suppress distant metastases in the clinically-relevant 4T1 mouse breast cancer model

“…SPM did not outperform Duopafei in terms of suppressing growth of the primary tumor [39], but dramatically suppressed metastasis, especially in mice with resected primary tumors. The enhanced anti-metastatic efficacy of SPM may be attributed to its lymphatic accumulation associated with its small size and increased delivery to the lymphatic system, which is consistent with previous observations using other kinds of anti-cancer drugs [19-22,24]. …”

“…Preventing or inhibiting lymph node metastasis is thus critical for improving the outcome of BC patients, and the role of the lymphatic system as a major conduit for the proliferation and spread of pathologies, including metastatic BC [16-18], has directed attention on suitable drug-delivery strategies. Smaller nanodrugs (10–30 nm diameter) have recently proven effective against tumor metastasis and their mechanisms can be explained by lymphatic accumulation of these small-sized nanodrugs [19-22]. …”

“…paclitaxel and docetaxel (DTX)) [19-22,24]. However, taxanes demonstrate a high level of clinical activity, represented by clinical remissions in advanced ovarian, breast and the upper aerodigestive tract cancers [25-27].…”

Anti-tumor activity of nanomicelles encapsulating CXCR4 peptide antagonist E5

“…In our previous studies, we have shown that a number of water-soluble drugs, such as Dox, vinorelbine tartrate and epirubicin hydrochloride, can be effectively incorporated into PEG-PE micelles with high drug-loading efficiency (>99.0%) using a one-step self-assembly method [20,26,27]. This method is very simple, fast and efficient for preparing the drug carriers in aqueous solution without using organic solvents.…”

“…The concentration of free Dox in filtrate was quantified by reverse-phase HPLC (RP-HPLC, Agilent 1206, USA) with a C 18 column (ZORBAX 300SB-C18, 5 μm, 4.6 × 150 mm, Agilent, USA). The detection wavelength used was 254 nm, and the mobile phase was composed of sodium dodecyl sulfate (SDS) solution (2.88 g of SDS and 1.36 mL of phosphoric acid were co-dissolved in 1000 ml of Milli-Q water)-acetonitrile-methanol (25: 25: 3, v/v/v) at a flow rate of 1.0 ml/min, as previously reported [20]. The concentration of free E5 in filtrate was quantified using spectrophotometer (SpectraMax i3, Molecular Devices, USA).…”