PPI‐G4 Glycodendrimers Upregulate TRAIL‐Induced Apoptosis in Chronic Lymphocytic Leukemia Cells

Abstract

Although chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western world, it remains incurable with conventional chemotherapeutic agents. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is an antitumor candidate in cancer therapy. This study examines the proapoptotic effects of poly(propylene imine) (PPI) glycodendrimers modified with the maltotriose residues (PPI-G4-OS-Mal-III and PPI-G4-DS-Mal-III) on the TNF family in CLL cells. The combination of an understanding of the signaling pathways associated with CLL and the development of a molecular profiling is a key issue for the design of personalized approaches to therapy. Gene expression is determined with two-color microarray 8 × 60K. The findings indicate that PPI-G4-OS/DS-Mal-III affect gene expression from the TRAIL apoptotic pathway and exert a strong effect on CLL cells comparable with fludarabine. Dendrimer-targeted technology may well prove to bridge the gap between the ineffective treatment of today and the effective personalized therapy of the future.

Dendrimers as Non-Viral Vectors in Gene-Directed Enzyme Prodrug Therapy

“…PAMAM dendrimers [ 177 , 178 , 179 ], phosphoric dendrimers [ 180 , 181 ], PPI dendrimers [ 182 , 183 ] are among the most-used dendrimers in GDEPT. Figure 8 presents the most-used dendrimers for the delivery of therapeutic genes [ 182 ].…”

Dendrimer-based strategies for cancer therapy: Recent advances and future perspectives

“…The results show that PPI modified with PEG (M w =7,500) has lowest drug release rate and all the PEGylated PPI dendrimers have better blood compatibility than PPI dendrimers without PEGylation. Due Phosphorylcholine [44] CBAA [45,46] Acetyl [42,[46][47][48] CBAA [45,46] RGD [49][50][51][52][53] pAb antibody [54] Lactobionic acid [55] Fluorescein isothiocyanate Fluorescence imaging [55] Fluorochrome Cy5.5 [50] PPI PEG Reducing cytotoxicity [43,56] Maltotriose [57][58][59] Anti-EGFRvlll scFV Targeting property [60] FA [61] Histidine, pyridine, piperazine Buffering capacity property [62] PLL PEG Reducing cytotoxicity [63] FA Targeting property [64] Phosphorous dendrimers Azabisphosphonate Targeting property [65] 8-Anilino-1-naphthalenesulfonate Fluorescence imaging [66] to the optimized steric hindrances of PEGs with M w of 4,000, the designed multifunctional PPI device enables the highest cellular uptake, which is desired for drug delivery applications.…”

“…The glycosylated dendrimers are widely applied as drug delivery systems, therapeutics and diagnostics for neurodegenerative diseases. Ida et al [57] studied the maltotriose residue-modified PPI dendrimers with DNAdamaging agent fludarabine for chronic lymphocytic leukemia therapy. The addition of PPI-G4-OS-Mal-III and PPI-G4-DS-Mal-III dendrimers to B-CLL cells significantly induced the cell apoptosis within these lymphocytes.…”

“…Therefore, the nucleic acid can be well protected and efficiently released to the cytoplasm and expressed [128]. Among these dendrimers, PAMAM dendrimer [88,129,130], phosphorus dendrimer [108] and PPI dendrimer [109,57] have been mostly used. A range of modification strategies have been adopted to reduce the cytotoxicity of dendrimers such as dodecylation [103,131], arginine-modification [132], or PEGylation.…”

Dendrimers as Drug Nanocarriers: The Future of Gene Therapy and Targeted Therapies in Cancer

“…Moreover, sugar-modified PPI dendrimers tested by our research team at University of Lodz, Poland, are very attractive and specific for leukemia and lymphoma cells derived from lymphocytes B. Depending on the sugar on the surface and the number of molecules, we can observe the different extend of triggering apoptosis in those cells due to the diversity in affecting particular gene pathways [48][49][50][51]. Lysine dendrimers, PAMAM, PPI, and phosphorus have been reported to be able to modulate amyloid peptide aggregation in solution [52][53][54].…”