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- ItemUnusual Enhancement of Doxorubicin Activity on Co-Delivery with Polyhedral Oligomeric Silsesquioxane (POSS)(Basel : MDPI, 2017) Sobierajska, Ewelina; Konopka, Malgorzata; Janaszewska, Anna; Piorecka, Kinga; Blauz, Andrzej; Klajnert-Maculewicz, Barbara; Stanczyk, Maciej; Stanczyk, Wlodzimierz A.Polyhedral oligomeric silsesquioxane (POSS), bearing eight 3-chloroammoniumpropyl substituents, was studied as a potential nanocarrier in co-delivery systems with doxorubicin (DOX). The toxicity of doxorubicin and POSS:DOX complexes at four different molar ratios (1:1; 1:2, 1:4, 1:8) towards microvascular endothelial cells (HMEC-1), breast cancer cells (MCF-7), and human cervical cancer endothelial cells (HeLa) was determined. The rate of penetration of the components into the cells, their cellular localization and the hydrodynamic diameter of the complexes was also determined. A cytotoxicity profile of POSS:DOX complexes indicated that the POSS:DOX system at the molar ratio of 1:8 was more effective than free DOX. Confocal images showed that DOX co-delivery with POSS allowed for more effective penetration of doxorubicin through the cell membrane. Taking all the results into account, it can be claimed that the polyhedral oligomeric silsesquioxane (T8-POSS) is a promising, complex nanocarrier for doxorubicin delivery.
- ItemConjugate of PAMAM Dendrimer, Doxorubicin and Monoclonal Antibody—Trastuzumab: The New Approach of a Well-Known Strategy(Basel : MDPI, 2018) Marcinkowska, Monika; Sobierajska, Ewelina; Stanczyk, Maciej; Janaszewska, Anna; Chworos, Arkadiusz; Klajnert-Maculewicz, BarbaraThe strategy utilizing trastuzumab, a humanized monoclonal antibody against human epidermal growth receptor 2 (HER-2), as a therapeutic agent in HER-2 positive breast cancer therapy seems to have advantage over traditional chemotherapy, especially when given in combination with anticancer drugs. However, the effectiveness of single antibody or antibody conjugated with chemotherapeutics is still far from ideal. Antibody–dendrimer conjugates hold the potential to improve the targeting and release of active substance at the tumor site. In the present study, we developed and synthesized PAMAM dendrimer–trastuzumab conjugates carrying doxorubicin (dox) specifically to cells overexpressing HER-2. 1HNMR, FTIR and RP-HPLC were used to characterize the products and analyze their purity. Toxicity of PAMAM–trastuzumab and PAMAM–dox–trastuzumab conjugates compared with free trastuzumab and doxorubicin towards HER-2 positive (SKBR-3) and negative (MCF-7) human breast cancer cell lines was determined using MTT assay. Furthermore, the cellular uptake and cellular localization were studied by flow cytometry and confocal microscopy, respectively. A cytotoxicity profile of above mentioned compounds indicated that conjugate PAMAM–dox–trastuzumab was more effective when compared to free drug or the conjugate PAMAM–trastuzumab. Moreover, these results reveal that trastuzumab can be used as a targeting agent in PAMAM–dox–trastuzumab conjugate. Therefore PAMAM–dox–trastuzumab conjugate might be an interesting proposition which could lead to improvements in the effectiveness of drug delivery systems for tumors that overexpress HER-2.
- ItemMolecular mechanisms of antitumor activity of PAMAM dendrimer conjugates with anticancer drugs and a monoclonal antibody(Basel : MDPI, 2019) Marcinkowska, Monika; Stanczyk, Maciej; Janaszewska, Anna; Gajek, Arkadiusz; Ksiezak, Malgorzata; Dzialak, Paula; Klajnert-Maculewicz, BarbaraTaxanes are considered fundamental drugs in the treatment of breast cancer, but despite the similarities, docetaxel (doc) and paclitaxel (ptx) work differently. For this reason, it is interesting to identify mechanisms of antitumor activity of PAMAM dendrimer conjugates that carry docetaxel or paclitaxel and monoclonal antibody trastuzumab, specifically targeted to cells which overexpressed HER-2. For this purpose, the impact on the level of reactive oxygen species, the mitochondrial membrane potential, cell cycle distribution and the activity of caspases-3/7, -8 and -9 of PAMAM-doc-trastuzumab and PAMAM-ptx-trastuzumab conjugates was determined and compared with free docetaxel and paclitaxel toward HER-2-positive (SKBR-3) and negative (MCF-7) human breast cancer cell lines. Moreover, apoptosis and necrosis were studied using flow cytometry and confocal microscopy, respectively. Our studies show the complexity of the potential mechanism of cytotoxic action of PAMAM-drug-trastuzumab conjugates that should be sought as a resultant of oxidative stress, mitochondrial activation of the caspase cascade and the HER-2 receptor blockade.