Unusual Enhancement of Doxorubicin Activity on Co-Delivery with Polyhedral Oligomeric Silsesquioxane (POSS)

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

In vitro studies of polyhedral oligo silsesquioxanes: Evidence for their low cytotoxicity

As scientific literature considers polyhedral oligosilsesquioxanes (POSS) as potential drug delivery systems, it is necessary to check their impact on mammalian cells. Toxicity of octaammonium chloride salt of octaaminopropyl polyhedral oligomeric silsesquioxane (oap-POSS) towards two cell lines: mouse neuroblastoma (N2a) and embryonic mouse hippocampal cells (mHippoE-18) was studied. Experiments consisted of analysis of a cell cycle, cell viability, amount of apoptotic and necrotic cells, and generation of reactive oxygen species (ROS). POSS caused a shift in the cell population from the S and M/G2 phases to the G0/G1 phase. However, the changes affected less than 10% of the cell population and were not accompanied by increased cytotoxicity. POSS did not induce either apoptosis or necrosis and did not generate reactive oxygen species. A cytotoxicity profile of POSS makes it a promising starting material as drug carrier

Novel Polyhedral Silsesquioxanes [POSS(OH)32] as Anthracycline Nanocarriers—Potential Anticancer Prodrugs

Anthracyclines belong to the anticancer drugs that are widely used in chemotherapy. However, due to their systemic toxicity they also exert dangerous side effects associated mainly with cardiovascular risks. The pathway that is currently often developed is their chemical and physical modification via formation of conjugated or complexed prodrug systems with a variety of nanocarriers that can selectively release the active species in cancer cells. In this study, six new nanoconjugates were synthesized with the use of polyhedral oligosilsesquioxanes [POSS(OH)32] as nanocarriers of the anticancer drugs anthracyclines—doxorubicin (DOX) and daunorubicin (DAU). These prodrug conjugates are also equipped with poly(ethylene glycol) (PEG) moieties of different structure and molecular weight. Water-soluble POSS, succinic anhydride modified (SAMDOX and SAMDAU) with carboxylic function, and PEGs (PEG1, PEG2 and PEGB3) were used for the synthesis. New nanoconjugates were formed via ester bonds and their structure was confirmed by NMR spectroscopy (1H-NMR, 13C-NMR, 1H-13C HSQC, DOSY and 1H-1H COSY), FTIR and DLS. Drug release rate was evaluated using UV-Vis spectroscopy at pH of 5.5. Release profiles of anthracyclines from conjugates 4–9 point to a range of 10 to 75% (after 42 h). Additionally, model NMR tests as well as diffusion ordered spectroscopy (DOSY) confirmed formation of the relevant prodrugs. The POSS-anthracycline conjugates exhibited prolonged active drug release time that can lead to the possibility of lowering administered doses and thus giving them high potential in chemotherapy. Drug release from conjugate 7 after 42 h was approx. 10%, 33% for conjugate 4, 47% for conjugate 5, 6, 8 and 75% for conjugate 9

Star-Shaped and Linear POSS-Polylactide Hybrid Copolymers

Novel octakis-2[(6-hydroxyhexyl)thio]ethyl-octasilsesquioxane (POSS-S-OH) as well as heptaisobutyl-2[(6-hydroxyhexyl)thio]ethyl-octasilsesquioxane (iBu-POSS-S-OH) were synthesized. POSS structures, bearing both types of groups i.e., 2[(6-hydroxyhexyl)thio]ethyl and the vinyl ones, pendant from the octahedral cage are also described. The synthetic pathway involved thiol-ene click reaction of 6-mercapto-1-hexanol (MCH) to octavinyloctasilsesquioxane (POSS-Vi), and heptaisobutylvinyloctasilsesquioxane (iBu-POSS-Vi), in the presence of 2,2′-azobisisobutyronitrile. The functionalized silsesquioxane cages of regular octahedral structure were used further as initiators for ring opening polymerization of L,L-dilactide, catalyzed by tin (II) 2-ethylhexanoate. The polymerization afforded biodegradable hybrid star shape and linear systems with an octasilsesquioxane cage as a core, bearing polylactide arm(s)

In Vitro Studies of Polyhedral Oligo Silsesquioxanes: Evidence for Their Low Cytotoxicity

As scientific literature considers polyhedral oligosilsesquioxanes (POSS) as potential drug delivery systems, it is necessary to check their impact on mammalian cells. Toxicity of octaammonium chloride salt of octaaminopropyl polyhedral oligomeric silsesquioxane (oap-POSS) towards two cell lines: mouse neuroblastoma (N2a) and embryonic mouse hippocampal cells (mHippoE-18) was studied. Experiments consisted of analysis of a cell cycle, cell viability, amount of apoptotic and necrotic cells, and generation of reactive oxygen species (ROS). POSS caused a shift in the cell population from the S and M/G2 phases to the G0/G1 phase. However, the changes affected less than 10% of the cell population and were not accompanied by increased cytotoxicity. POSS did not induce either apoptosis or necrosis and did not generate reactive oxygen species. A cytotoxicity profile of POSS makes it a promising starting material as drug carrier

Hydrophilic Polyhedral Oligomeric Silsesquioxane, POSS(OH)32, as a Complexing Nanocarrier for Doxorubicin and Daunorubicin

A novel strategy, recently developed by us, to use polyhedral oligomeric silsesquioxanes (POSS) as an anti-cancer drug carrier is presented. Anthracycline:POSS complexes were prepared by simple co-addition of doxorubicin (DOX) or daunorubicin (DAU) with hydrophilic POSS(OH)32. Co-delivery of POSS and anthracyclines led to higher anti-cancer activity towards HeLa (cervical cancer endothelial) and MCF-7 (human breast adenocarcinoma) cell lines. The obtained supramolecular hybrid complexes were characterised by nuclear magnetic resonance (NMR) spectroscopy (nuclear Overhauser effect spectroscopy [NOESY] and homonuclear correlation spectroscopy [COSY]), Fourier transform infrared spectroscopy (FTIR), and dynamic light scattering (DLS). The two-dimensional (2D) NOESY spectra of the complexes showed the cross-correlation peaks for hydroxyl groups of POSS (~4.3–4.8 ppm) with OH groups of DOX and DAU. FTIR showed that hydroxyl group of POSS can interact with amine and hydroxyl groups of DOX and DAU. The viability of HeLa and MCF-7 was analysed with the MTT assay to evaluate the cytotoxicity of free DOX and DAU and the relevant complexes with POSS at different molar ratios. At a low DOX concentration (2.5 µM), for molar ratios 1:1, 1:4, and 1:8 (POSS:DOX), the complexes showed two and three times higher cytotoxicity towards HeLa and MCF-7 cells, respectively, than DOX itself after both 24- and 48-h incubation. The 1 µM concentration for a 1:4 POSS:DOX molecular ratio and the 2.5 µM concentration for all complexes were more toxic towards MCF-7 cells than free DOX after 48-h incubation. In the case of POSS:DAU complexes, there was higher toxicity than that of free drug after 48-h incubation. It can be concluded that the formation of non-covalent complexes increases toxicity of anthracycline drugs towards Hela and MCF-7 cells. The novel complexes are inexpensive to prepare and more effective than free drugs at low systemic toxicity