Polyplex Nanogel formulations for drug delivery of cytotoxic nucleoside analogs.
Hydrophilic nanosized particles consisting of the cross-linked cationic polymer network (Nanogels) are suggested as a drug delivery system for nucleoside analog 5'-triphosphates, an active form of cytotoxic anticancer drugs. Preparation, properties, and cellular effects of several polyplex Nanogel formulations with the 5'-triphosphate of cytotoxic 5-fluoroadenine arabinoside (fludarabine) (FATP) were examined and discussed here. The polyplexes have formed spontaneously by mixing solutions of FATP and Nanogels because of ionic interactions between protonated polyethylenimine (PEI) chains in Nanogel network with polyphosphate groups of the drug. Subsequent compaction of the flexible Nanogel network has resulted in an encapsulation of the FATP/PEI complex in a dense core surrounded by hydrophilic poly(ethylene glycol) (PEG) envelope. This structure has provided a sustained release of the drug, as well as an efficient protection of FATP against enzymatic degradation. The drug loading could reach up to 33% by weight of the drug-Nanogel formulation. In vitro 35% of loaded drug has released from Nanogel formulations during the first 24 h, and a slower additional release was observed during the next 2 days. Nanogels have protected 90% of the encapsulated FATP from enzymatic dephosphorylation during the first 60 min of incubation in vitro. The drug-Nanogel formulation compared to the drug has demonstrated a significantly enhanced cytotoxicity in cultured cancer cells. Cancer cell-targeting molecules, such as folate, could be easily attached to Nanogels and this modification has resulted in a strong 10-fold increase of the carrier's internalization in human breast carcinoma MCF-7 cells. Moreover, transcellular transport of the folate-Nanogel polyplexes was found to be 4 times more effective compared to the drug alone using Caco-2 cell monolayers as an in vitro intestinal model. The data demonstrate that this carrier-based approach to delivery of cytotoxic drugs may enhance tumor specificity and significantly reduce side effects related to systemic toxicity usually observed during cancer chemotherapy.
Vinogradov
Serguei V
SV
Center for Drug Delivery and Nanomedicine and College of Pharmacy, Department of Pharmaceutical Sciences, 985830 Nebraska Medical Center, Omaha, NE 68198-5830, United States. inograd@unmc.edu
Zeman
Arin D
AD
Batrakova
Elena V
EV
Kabanov
Alexander V
AV
D001943:Breast Neoplasms / Q000473:pathology; D018938:Caco-2 Cells; D002277:Carcinoma / Q000473:pathology; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D016503:Drug Delivery Systems; D017097:Electric Impedance; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008854:Microscopy, Electron; D000080385:Nanogels; D049329:Nanostructures / Q000648:ultrastructure; D009705:Nucleosides / Q000008:administration & dosage* / Q000633:toxicity*; D004364:Pharmaceutical Preparations; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry; D011094:Polyethyleneimine / Q000138:chemical synthesis / Q000737:chemistry; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry
D000080385:Nanogels; D009705:Nucleosides; D004364:Pharmaceutical Preparations; D011108:Polymers; C413692:polyethylene glycol polyethyleneimine nanogel; D011092:Polyethylene Glycols; D011094:Polyethyleneimine