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Biotin Transport-Targeting Polysaccharide-Modified PAMAM G3 Dendrimer as System Delivering α-Mangostin into Cancer Cells and C. elegans Worms.

ABSTRACT: The natural xanthone α-mangostin (αM) exhibits a wide range of pharmacological activities, including antineoplastic and anti-nematode properties, but low water solubility and poor selectivity of the drug prevent its potential clinical use. Therefore, the targeted third-generation poly(amidoamine) dendrimer (PAMAM G3) delivery system was proposed, based on hyperbranched polymer showing good solubility, high biocompatibility and low immunogenicity. A multifunctional nanocarrier was prepared by attaching αM to the surface amine groups of dendrimer via amide bond in the ratio 5 (G3^2B12gh5M) or 17 (G3^2B10gh17M) residues per one dendrimer molecule. Twelve or ten remaining amine groups were modified by conjugation with D-glucoheptono-1,4-lactone (gh) to block the amine groups, and two biotin (B) residues as targeting moieties. The biological activity of the obtained conjugates was studied in vitro on glioma U-118 MG and squamous cell carcinoma SCC-15 cancer cells compared to normal fibroblasts (BJ), and in vivo on a model organism Caenorhabditis elegans. Dendrimer vehicle G3^2B12gh at concentrations up to 20 µM showed no anti-proliferative effect against tested cell lines, with a feeble cytotoxicity of the highest concentration seen only with SCC-15 cells. The attachment of αM to the vehicle significantly increased cytotoxic effect of the drug, even by 4- and 25-fold for G3^2B12gh5M and G3^2B10gh17M, respectively. A stronger inhibition of cells viability and influence on other metabolic parameters (proliferation, adhesion, ATP level and Caspase-3/7 activity) was observed for G3^2B10gh17M than for G3^2B12gh5M. Both bioconjugates were internalized efficiently into the cells. Similarly, the attachment of αM to the dendrimer vehicle increased its toxicity for C. elegans. Thus, the proposed α-mangostin delivery system allowed the drug to be more effective in the dendrimer-bound as compared to free state against both cultured the cancer cells and model organism, suggesting that this treatment is promising for anticancer as well as anti-nematode chemotherapy.

SUBMITTER: Markowicz J

PROVIDER: S-EPMC8657743 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:One of the intensively developed tools for cancer therapy is drug-releasing matrices. Polyamidoamine dendrimers (PAMAM) are commonly used as nanoparticles to increase the solubility, stability and retention of drugs in the human body. Most often, drugs are encapsulated in PAMAM cavities or covalently attached to their surface. However, there are no data on the use of PAMAM dendrimers as a component of porous matrices based on polyurethane foams for the controlled release of drugs and biologically active substances. Therefore, in this work, porous materials based on polyurethane foam with incorporated third-generation poly(amidoamine) dendrimers (PAMAM G3) were synthesized and characterized. Density, water uptake and morphology of foams were examined with SEM and XPS. The PAMAM was liquefied with polyether polyol (G441) and reacted with polymeric 4,4'-diphenylmethane diisocyanate (pMDI) in the presence of silicone, water and a catalyst to obtain foam (PF1). In selected compositions, the castor oil was added (PF2). Analogs without PAMAM G3 were also synthesized (F1 and F2, respectively). An SEM analysis of foams showed that they are composed of thin ribs/walls forming an interconnected network containing hollow bubbles/pores and showing some irregularities in the structure. Foam from a G3:G441:CO (PF2) composition is characterized by a more regular structure than the foam from the composition without castor oil. The encapsulation efficiency of drugs determined by the XPS method shows that it varies depending on the matrix and the drug and ranges from several to a dozen mass percent. In vitro biological studies with direct contact and extract assays indicated that the F2 matrix was highly biocompatible. Significant toxicity of dendrimeric matrices PF1 and PF2 containing 50% of PAMAM G3 was higher against human squamous carcinoma cells than human immortalized keratinocytes. The ability of the matrices to immobilize drugs was demonstrated in the example of perspective (Nimesulide, 8-Methoxypsolarene) or approved anticancer drugs (Doxorubicin-DOX, 5-Aminolevulinic acid). Release into the culture medium and penetration of DOX into the tested SCC-15 and HaCaT cells were also proved. The results show that further modification of the obtained matrices may lead to their use as drug delivery systems, e.g., for anticancer therapy.

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Biotin Transport-Targeting Polysaccharide-Modified PAMAM G3 Dendrimer as System Delivering α-Mangostin into Cancer Cells and C. elegans Worms.

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