Molecular Engineering of Surface Functional Groups Enabling Clinical Translation of Nanoparticle–Drug Conjugates

Antibody–drug conjugates (ADCs) have recently demonstrated impressive successes in targeted drug delivery. Ultrasmall (<10 nm) nanoparticle–drug conjugates (NDCs) share many similarities with ADCs, while their unique physicochemical properties can be further molecularly engineered to overcome the limitations of ADCs presented by tumor heterogeneity. Key challenges in NDC development include linkage chemistry design between nanoparticle carriers and cytotoxic drugs, as well as meeting the stringent criteria for manufacturing controls, stability, and drug release to enable successful clinical translation. Here, we report a robust chemical approach to covalently link both chemotherapeutic drugs and targeting moieties to a poly(ethylene glycol) (PEG)-coated (PEGylated) ultrasmall silica nanoparticle platform via precisely tailoring the particle surface chemistry. This approach employs the interstitial space between PEG chains on the particle surface to load drugs, enabling the significantly enhanced drug loading capacity as compared to ADCs while the favorable biodistribution and pharmacokinetics profiles are maintained. To achieve both high plasma stability and effective drug release in cancer, cyclopentadiene silane molecules are first inserted into the PEG layer of the particles and condensed with silanol groups on the silica core surface. Via the Diels–Alder reaction, the cyclopentadiene groups are then functionalized with groups enabling click chemistry, and cytotoxic payloads are finally clicked onto the particles via cleavable linkers for drug release within the cancer tissue. The targeted NDC resulting from the systematic screening strategy described here has recently advanced to a phase 1/2 human clinical trial.