Chemistry Seminar Series: Dendrimers as carriers of anticancer drugs

Biographical Information

Prof. Barbara Klajnert-Maculewicz completed her PhD in 2002 from the University of Lodz, Poland, and postdoctoral studies at the McMaster University, Ontario, Canada. She is a full professor at the University of Lodz, Poland. From 2015 to 2020, she was an external scientific member at Leibniz IPF in Dresden, Germany. She is a co-author of 2 books and 170 articles (h-index 48). In the years 2009-2012, she was the Management Committee Chair of the COST Action TD0802 “Dendrimers in biomedical applications”. Then, she coordinated the COST Action CA17140 “Cancer nanomedicine – from the bench to bedside” (2019-2021). She has been awarded the L’Oréal-UNESCO Fellowship for Women in Science (Polish Edition). Her research interests are focused on biological properties and biomedical applications of dendrimers and other nano-systems.

Abstract

Dendrimers belong to the class of polymers. They are characterized by a specific globular structure with internal cavities and many terminal groups.

These two features make them interesting candidates for transporting small molecules, especially drugs. Due to a large number of surface groups to which drug molecules can be conjugated or noncovalently attached, one molecule of the dendrimer is capable of carrying drugs at a high density that intensifies the therapeutic effect. Encapsulating drugs inside dendrimers offers potential benefits such as prolonging blood circulation time or protecting unstable drugs from the environment. Frequently, nanocarriers are applied to enhance drug solubility and provide controlled release. In this talk, three main strategies to transport drugs by dendrimers (i.e., by encapsulation, via electrostatic interactions with the outer shell, and finally due to covalent attachment to the surface) will be analyzed. The emphasis will be put on anticancer therapy, i.e., (a) transporting nucleoside analogs used in therapy for leukemia by polypropyleneimine dendrimers, (b) transporting photosensitizers used in photodynamic therapy by phosphorus dendrimers.
(a) Polypropyleneimine dendrimers with a partially modified surface by maltose residues formed complexes with negatively charged 5’-triphosphates of nucleoside analogs (NAs). NAs are commonly used in the treatment of acute myeloid leukemia, acute lymphocytic leukemia, and lymphomas. Most nucleoside analogs are administered as inactive dephosphorylated prodrugs, then require specialized nucleoside transporters to cross plasma membranes, and finally, they are activated to a cytotoxic triphosphorylated form inside a cell. Unfortunately, the therapy has limitations due to several primary and acquired resistance mechanisms that arise during prodrug activation steps. It may lead to inefficient concentration of the therapeutics in cancer cells. Dendrimers were used to deliver active forms of NAs (1, 2).
(b) Photodynamic therapy (PDT) is an alternative to chemotherapy and radiotherapy treatment for tumors. It is based on the induction of cell death through the combination of a photosensitizer and irradiation. The main limitations of PDT are related to photosensitizers, e.g., their insufficient cellular uptake. Phosphorus, PPI, and PAMAM dendrimer complexes with a photosensitizer were characterized by improved cellular uptake and a stronger phototoxic effect (3, 4).
In all the above-mentioned studies, it has been proven that applying dendrimers increased cytotoxicity when compared with a free drug. The effect was mostly attributed to the enhanced uptake of drugs when combined with the dendrimers.