# Receptor-Mediated Drug Delivery: Redefining Targeted Drug Conjugates in Oncology

## TL;DR

This paper reviews how receptor-mediated drug delivery can improve cancer treatment by selectively targeting cancer cells with drug conjugates.

## Contribution

The paper provides a comprehensive overview of clinically validated and emerging cell surface receptors for targeted drug delivery in oncology.

## Key findings

- Four clinically validated cell surface receptors (HER2, Trop-2, Nectin-4, and SSTR2) are highlighted with FDA-approved drug conjugates.
- Emerging receptors like EGFR, DLL3, and keratin 1 may support next-generation targeted drug delivery platforms.
- Factors like receptor type, ligand design, and endocytosis mechanisms influence drug accumulation and efficacy.

## Abstract

Targeted drug delivery (TDD), specifically through targeting ligand–drug conjugates, has reshaped oncology by enabling selective delivery of cytotoxic payloads to cancer cells while minimizing uptake by normal tissues. A key approach relies on exploiting overexpressed cell surface receptors (CSRs) to enable selective uptake of drug conjugates via receptor-mediated endocytosis. This review delineates four clinically validated CSRs (HER2, Trop-2, Nectin-4, and SSTR2) with several FDA-approved drug conjugates. Furthermore, emerging CSRs (EGFR, DLL3, and keratin 1) that may support next-generation TDD platforms for cancer treatment are also highlighted. We discuss how CSR type, density on cancer cells, and its mechanism of endocytosis, as well as the conjugate design for cellular uptake, tissue distribution, ligand size, and linker stability, collectively determine tumor drug accumulation and therapeutic efficacy. From representative examples, we elucidate the rationale for judicious refinement of these parameters, guiding the development of more potent ligands and drug conjugates to enhance the therapeutic efficacy of cytotoxic agents.