Synthesis, characterization and in vitro studies of pegylated melphalan conjugates.
Melphalan, a drug used for the treatment of breast, ovaries and a certain type of cancer in the bone marrow, was conjugated to linear methoxy poly (ethylene glycol) (M-PEG) of 2000 and 5000, Da. An ester linkage between polymer and drug was used in the coupling to yield a polymeric prodrug. Purified esters were characterized by Maldi-Tof and IR spectroscopy methods. The modification allowed overcoming the known melphalan aqueous solubility problem (0.1 µg/ml) leading us to obtain a polymer-drug bioconjugate more suitable for oral and parental administration. It was found that molecular weight of M-PEG is critical for the conjugates stability, aqueous solubility (80 times and 123 times higher aqueous solubility for M-PEG 2000 and M-PEG 5000, respectively), and hemolytic activity. The melphalan caused 100% hemolysis above the concentration 3.5 µg/ml in 1 h. whereas conjugate of M-PEG 2000 and M-PEG 5000 shows 81.3 ± 0.5% and 48.8 ± 1.5% hemolysis, respectively at 32 µg/ml after1 h. Further In vitro anticancer activity of melphalan and its conjugates was performed with breast cancer MCF-7 cell lines. It shows that LD50 concentration was higher 1.14 and 2 µm for M-PEG 2000 and M-PEG 5000, respectively in comparison to pure melphalan (0.74 µm). Above studies revealed improved pharmacokinetics properties upon conjugation.
Department of Pharmaceutical Sciences, Rungta College of Pharmaceutical Sciences and Research, Bhilai, (C.G), India. write2ajaz@gmail.com
Ajazuddin
Amit
A
Alexander
Basant
B
Amarji
Parijat
P
Kanaujia
D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002855:Chromatography, Thin Layer; D004355:Drug Stability; D006801:Humans; D006868:Hydrolysis; D008558:Melphalan / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D012995:Solubility; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D017550:Spectroscopy, Fourier Transform Infrared
D018906:Antineoplastic Agents, Alkylating; D011092:Polyethylene Glycols; C028210:monomethoxypolyethylene glycol; D008558:Melphalan