PEGylated G4 dendrimers as a promising nanocarrier for piperlongumine delivery: Synthesis, characterization, and anticancer activity

PAMAM dendrimers are well-known delivery vehicles for various therapeutic agents like synthetic drugs, natural phytoconstituents, and genetic materials. The tunable physicochemical properties and variety of surface interactions make them attractive nano delivery system. However, plain dendrimers particularly higher generation dendrimers are reported to cause dose-dependent toxicities. Therefore, in this study, PEGylated G4 PAMAM dendrimers were synthesized via a click chemistry approach and used for the delivery piperlongumine (PL) for the treatment of colon cancer. PL is an amide alkaloid and potential anticancer agent, but it has poor aqueous solubility. PL was loaded into the dendrimer cavity through both physical loading and electrostatic chemical interactions. The prepared PL-loaded PEGylated G4 PAMAM dendrimers (PL@PEGylated G4) possessed a nanoscale size about 20 nm, monodispersity with a PDI value of 0.098 ± 0.002 and high drug solubility 226 ± 9.4 μg/mL. The drug release profile of PL@PEGylated G4 indicated a sustained release of encapsulated PL. After 24 h, about 43.2 ± 4.2 % and 64.9 ± 4.5 % of PL was released in PBS and SAB, respectively. The PEGylated dendrimers showed good biocompatibility during hemolytic toxicity study. In cytotoxicity studies, PL@PEGylated G4 showed potential cytotoxicity (IC₅₀ = 5.8 μg/mL, p < 0.05) and greater induction of apoptosis in HCT 116 human colon cancer cells in comparison to pure PL, as demonstrated by the MTT and AO/EB assay, respectively. Overall, this biocompatible PEGylated G4 dendrimer-based formulation of PL could be a potential nanomedicine for cancer therapy.