Synthesis And Characterization Of Poly (Ethylene Glycol)-Lapatinib Conjugates

Objective:Lapatinib (LPT) is a tyrosine kinase inhibitor targeting epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor HER2. It is combined with capecitabine to treat HER2+ advanced metastatic breast cancer. Recent studies indicate that lapatinib can inhibit the cancer stem cells of the glioblastoma multiforme (GBM) cell line U87-MG and the ductal carcinoma in situ (DCIS) cell line SUM225. However, lapatinib has poor water solubility, low oral bioavailability and severe side effects. We aim to improve the solubility and enhance the bioavailability and efficacy significantly, and reduce the side effects by synthesizing poly (ethylene glycol)-lapatinib conjugate nano-targeting drugs.Methods:We first reacted lapatinib (LPT) with Boc-Gly (1A), removed the Boc and obtained Gly-LPT (1F), then we reacted Gly-LPT (1F) with Boc-Glu (1D), removed the Boc and obtained intermediates Asp-(Gly-LPT)2(1H). Then we coupled Asp-(Gly-LPT)2 (1H) with Boc-Asp (1D) again, removed the Boc, and obtained the intermediates Asp-[Asp-(Gly-LPT)2]2(2B); we also coupled Asp-[Asp -(Gly-LPT)2]2 (2B) with the Boc-Gly (1A), removed the Boc, reacted this product with Boc-Asp (1D) again, removed the Boc, and produced Asp-{Gly-Asp-[Asp-(Gly-LPT)2]2}2(3D). Then, we coupled the three intermediates respectively with Boc-protected 6-aminocaproic acid or its NHS ester via amidation or substitution. After removing the Boc again, we obtained three amino-ending long-chain LPT polyploids, respectively, and finally coupled them with three PEG carriers 4ARM-SCM-40K and M-SCM-40K, respectively, and synthesized PEG-LPT conjugates 1-3. All the intermediates and final products were characterized by 1H-NMR, MS and elemental analysis. All the new compounds were not reported in the literature.