Methylene diphosphonate-conjugated adriamycin liposomes: preparation, characteristics, and targeted therapy for osteosarcomas in vitro and in vivo

Abstract

Methylenediphosphonate (MDP)-conjugated adriamycin liposomes (MDP-LADMs) were prepared using mild dynamic dialysis equilibrium method, and their targeted therapeutic effects against osteosarcomas and metastatic SOSP-M lung nodules were evaluated in vivo. The drug loading and encapsulation efficiency of the MDP-LADMs were measured via high-performance liquid chromatography, and their size and morphology of the MDP-LADMs were determined using transmission electron microscopy and a particle size analyzer, respectively. Cells apoptosis were evaluated by flow cytometry and caspase-3 activity. The targeted therapeutic effects of MDP-LADMs against UMR106 and SOSP-M osteosarcoma cells were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor growth and animal survival rates were evaluated after UMR106 osteosarcomas were established in Sprague-Dawley rats and SOSP-M pulmonary metastatic osteosarcoma model were established in nude mice, respectively. The results show that the average diameter of the MDP-LADMs was 152 ± 14 nm, and their ADM encapsulation efficiency was 91.7% with respect to a 250 μg/ml of loading efficiency. The conjugation efficiency between technetium-MDP and LADMs was 87.6%. Infrared spectra results of the samples dissolved in deuterated water confirmed that the methylenediphosphonate (MDP) was conjugated with LADMs through hydrogen bonding. The toxicity assay revealed a median lethal dose of 26.78 mg/kg for MDP-LADMs, which was significantly higher than doses observed for free ADM of 9.64 mg/kg (P < 0.05) and LADMs of 15.02 mg/kg(P < 0.05). Tumor growth and animal survival in the MDP-LADMs group were significantly higher than those in the ADM-only, MDP-only (P < 0.01) and LADMs groups (P < 0.05). These findings indicate that MDP-LADMs have higher therapeutic efficacy against osteosarcomas, demonstrate lower toxicity and their clearly targets osteosarcomas more clearly than the stand-alone systems, making them as a promising novel targeted therapy for the treatment of osteosarcoma.

Mulberry-like dual-drug complicated nanocarriers assembled with apogossypolone amphiphilic starch micelles and doxorubicin hyaluronic acid nanoparticles for tumor combination and targeted therapy

“…For the toxicity of DOX, various studies have reported that the LD 50 values of DOX can increase by twofold after loading DOX into nanocarriers. Our group previously reported on methylene diphosphonateconjugated adriamycin liposomes, and Liao et al prepared a targeting liposomal for DOX delivery inhibiting tumor growth without systemic toxicity [45,46] and determined the low toxicity of DOX loaded into nanocarriers. Similar results were found for ApoG2 and AASt MCs (data not shown).…”

Current Therapeutic Strategies and Novel Approaches in Osteosarcoma

“…Liposomal encapsulation of doxorubicin has been shown to be effective in vitro and in vivo [159,160]. Furthermore, the efficacy of SLIT cisplatin has been investigated, in particular in osteosarcoma patients [67].…”

Advances in Bone‐targeted Drug Delivery Systems for Neoadjuvant Chemotherapy for Osteosarcoma

“…Additionally, liposomes modified by folic acid actively targeted over‐expressed folate receptor α on the surface of osteosarcoma, indicating that curcumin–C6 ceramide liposomes have an inhibiting effect on osteosarcoma in vivo and in vitro . Wu and Wan performed a similar experiment in which doxorubicin was sealed in a lipid bilayer of liposomes and diphosphonic acid and found that this system had less systemic toxicity and stronger selectivity for osteosarcoma than a bone‐target drug delivery system with a single mechanism. Low et al .…”