Dendrimers: Precision-Engineered Nanocarriers for Targeted Drug Delivery Systems

Dendrimers (highly branched, monodispersive macromolecules of a core-shell structure) have incomparable benefits in drug delivery because of their tunable size (1-10 nm), their multivalency, and their inner cavities. The PAMAM and PPI families were pioneered in the 1970s-1980s by such pioneers as Tomalia and Vogtel, and allow different drug loading through either encapsulation, electrostatic complexation or covalent conjugation, with hydrophobic drug cargos, including doxorubicin and paclitaxel, improving their solubility, stability, and pharmacokinetics. The essential properties of controlled release through linker chemistry, precise structure (confirmed by NMR, DLS, TEM), and ligand conjugation through targeting (e.g., folic acid to CD44) are necessary to allow EPR-mediated tumor accumulation, gene/siRNA delivery, and usages in cancer, antivirals (VivaGel SPL7013, FDA-approved to prevent HIV/HSV), ocular/topical therapeutics and vaccines. Nevertheless, cationic variants are cytotoxic through membrane disruption and coagulation, which can be reduced by PEGylation, acetylation or biodegradable backbones (polyester/peptide) to achieve biocompatibility. Synthesis can be done by divergent synthesis (Tomalia), convergent synthesis (Fréchet), or advanced synthesis (click chemistry, double exponential growth), to scale and produce defect-free. Clinical translation is underway, the DEP platform of Starpharma and dozens of trials are evidence of maturity. The synthetic structure, synthesis, mechanism, properties, applications, products, and toxicity strategies of dendrimers are synthesized in this review, and it is affirmed that dendrimers will be more effective than linear polymers and nanoparticles. Innovations around surface engineering in the future will bring safer and targeted therapeutics to various diseases.