Synthesis of a novel polyamidoamine dendrimer conjugating with alkali blue as a lymphatic tracer and study on the lymphatic targeting in vivo

Abstract

In this study, a novel lymphatic tracer polyamidoamin-alkali blue (PAMAM-AB) was synthesized in order to evaluate the intra-lymphatic targeting ability and lymphatic tropism of PAMAM-AB after subcutaneous administration. UV-Vis, FT-IR, NMR and HPLC characterization were performed to prove the successful synthesis of PAMAM-AB. The calculated AB payload of PAMAM-AB conjugate was seven per dendrimer molecule (27.16% by weight). Hydrolysis stability of PAMAM-AB in vitro was evaluated, which was stable in PBS and human plasma. Lymphatic tracing were studied to determine the blue-stained intensity of PAMAM-AB in right popliteral lymph nodes (PLNs), iliac lymph nodes (ILNs) and para-aortic lymph nodes (PALNs) after subcutaneous administration. The pharmacokinetics and biodistribution of PAMAM-AB in mice were investigated. PLNs, ILNs and PALNs could be obviously blue-stained within 10 min after PAMAM-AB administration, and displayed a more rapid lymphatic absorption, a higher AUC value in lymph nodes and a longer lymph nodes residence time compared with methylene blue solution (MB-S), MB water-in-oil microemulsion (MB-ME), MB multiple microemulsion (MB-MME). Enhanced lymphatic drainage from the injection site and uptake into lymph of PAMAM-AB indicated that PAMAM-AB possesses the double function of lymphatic tracing and lymphatic targeting, and suggested the potential for the development of lymphatic targeting vectors or as a lymphatic tracer in its own right.

Lymphatic changes in cancer and drug delivery to the lymphatics in solid tumors

“…Polyamidoamin dendrimers conjugated to alkali blue (PANAM-AB) have been synthesized as a lymphatic tracer [163]. When administered subcutaneously, lymph nodes were stained blue after 10 minutes.…”

Enzyme-responsive doxorubicin release from dendrimer nanoparticles for anticancer drug delivery

“…20 Further, Yang et al synthesized PAMAM conjugated with alkali blue for targeting of the lymphatics. 23 They showed that this alkali blue-conjugated PAMAM dendrimer enhanced lymphatic drainage and had a longer residence time in the lymph nodes when compared with methylene blue solution. He …”

“…[19][20][21][22][23] Various molecules, including an anticancer drug, a targeting moiety, a peptide, and PEG can be simultaneously attached in the terminal group of a dendrimer molecule. Especially, dendrimer itself having various biomolecules has nanostructural properties in aqueous solution.…”

“…This characteristic enables dendrimers to conjugate with various molecules, such as anticancer drugs and poly(ethylene glycol) (PEG), and a targeting moiety and peptide can be simultaneously conjugated to the dendrimer. 20,23,24 In a report by He et al an RGD peptide for targeting cancer cells, PEG for avoidance of the reticuloendothelial system, and an anticancer drug were simultaneously introduced to a poly(amidoamine) (PAMAM) dendrimer. 24 These authors showed that a multifunctional dendrimer efficiently targeted U87MG cells via a receptor-mediated pathway and could inhibit cell viability.…”

“…[15][16][17][18] Among the nanomaterials, dendrimers have been extensively investigated in the biomedical field. [19][20][21][22][23] Dendrimers are a class of macromolecular hyperbranched polymers having an intrinsic structure composed of a core, branches, void spaces, and terminal groups. 19 Due to their structural peculiarity, dendrimers have better physicochemical behavior than linear or branched polymers.…”