I work in IT, not chemistry. I've been reading papers on antibody-drug conjugates and peptide-drug conjugates for a while because I find the problem interesting, and I ended up sketching out an idea that I can't tell is obvious, already-done, or nonsense. I'd really appreciate honest feedback from people who actually do this work.

The problem as I understand it:

A lot of interesting drug payloads are weak bases with pKa around 8-10 (think ulotaront, baricitinib, many kinase inhibitors). When you deliver them via an ADC or PDC that gets internalized into the endolysosome, the payload gets protonated at lysosomal pH (~5.0), becomes membrane-impermeable, and stays trapped in the lysosome.…