Peptide-drug conjugates as effective prodrug strategies for targeted delivery

Abstract

Peptide-drug conjugates (PDCs) represent an important class of therapeutic agents that combine one or more drug molecules with a short peptide through a biodegradable linker. This prodrug strategy uniquely and specifically exploits the biological activities and self-assembling potential of small-molecule peptides to improve the treatment efficacy of medicinal compounds. We review here the recent progress in the design and synthesis of peptide-drug conjugates in the context of targeted drug delivery and cancer chemotherapy. We analyze carefully the key design features in choosing the peptide sequence and linker chemistry for the drug of interest, as well as the strategies to optimize the conjugate design. We highlight the recent progress in the design and synthesis of self-assembling peptide-drug amphiphiles to construct supramolecular nanomedicine and nanofiber hydrogels for both systemic and topical delivery of active pharmaceutical ingredients.

Keywords: Cancer; Conjugated chemistry; Drug amphiphiles; Drug delivery; Peptide–drug conjugates.

Fig. 1

Scheme of peptide–drug conjugates bearing one drug (A) or two different types of drugs (B). All PDCs contain three essential components: the therapeutic compound, the rationally designed/chosen peptide, and the linker that bridges the two. An emerging class of PDCs are designed to spontaneously associate in aqueous solutions into a variety of well-definite nanostructures, such as nanofibers (C).

Fig. 2

Wender’s cell penetrating peptide conjugation strategy to circumvent multidrug resistance. Lipophilic drugs that are substrates for Pgp export become highly water-soluble upon conjugation to molecular transporters, and are able to rapidly enter cells without recognition by the Pgp pumps that would otherwise expel them [50].

Fig. 3

Schematic illustration of the targeted theranostic platinum(IV) prodrug with a built-in aggregation-induced emission (AIE) light-up apoptosis sensor for non-invasive in situ early evaluation of its therapeutic response [80].

Fig. 4

Conceptual illustration of controlled release of therapeutics using the peptide amphiphile (PA) platform developed by the Stupp Lab. (A) Chemical structure of the studied PA. (B) The different PA regions are highlighted in a space-filling model. (C) Schematic illustration of a self-assembled PA nanofiber. (D) Proposed structural models of PA packing arrangements. The alkyl tail is shown in gray, with β-sheet region in blue, charged residues in red, and lysine-hydrazone-Prodan group in green.

Fig. 5

Example of a supramolecular hydrogel-forming peptide–drug conjugate bearing an enzyme-cleavable solubilizing group, developed by the Xu Lab. In the absence of enzyme (alkaline phosphatase, ALP), the progelator solution exhibits no defined nanostructure (A and D). Upon addition of ALP, cleavage of the phosphate group triggers self-assembly (B and E), resulting in hydrogel formation (C and F).

Fig. 6

Schematic illustration of a representative camptothecin drug amphiphile (DA). (A) The self-assembled nanostructures contain the same drug content as that of the individual DA. (B) Illustration of the three key components: the hydrophobic drug CPT, Tau β-sheet-forming peptide, and the buSS biodegradable linker (or using a non-degradable maleimide linker). RP-HPLC chromatogram (C) and MALDI-Tof mass spectrum (D) of the mCPT-buSS-Tau DA reveals the high purity and monodispersity of the conjugate.

Fig. 7

(A) Synthesis of CPT-PTX-Sup35, and homo-dual DAs, dCPT-Sup35 and dPTX-Sup35, from the reaction of dCys-Sup35 with a 1:1 mixture of activated disulfide drugs, CPT-buSS-Pyr and PTX-buSS-Pyr. Representative TEM images of dCPT-Sup35 (B), CPT-PTX-Sup35 (C) and dPTX-Sup35 (D) in water.

Fig. 8

(A) Chemical structures and schematic representations of qCPT-Sup35-K2 and qCPT-Sup35-E2. (B) Schematic representations and TEM micrograph of the supramolecular structures formed by qCPT-Sup35-K2, qCPT-Sup35-E2, and the CAM of the two DAs. The CAM of qCPT-Sup35 (mixing ratio 1:3) results in the almost exclusive formation of tubular structures in 1:1 MeCN/H₂O. Total concentration for the sample = 400 μM.

Fig. 9

(A) Principle of imaging enzyme-triggered supramolecular self-assembly inside cells. ER, endoplasmic reticulum; G, Golgi apparatus; L, lysosome; M, mitochondria; N, nucleus. (B) The scheme for the generation of the fluorescent hydrogelator via an enzyme-catalysed dephosphorylation from precursor. (C) Enzyme-trigged self-assembly inside live cells. Fluorescent confocal microscope images show the time course of fluorescence emission inside the HeLa cells incubated with 500 or 50 μM of precursor in PBS buffer, which shows the different distribution of fluorophores inside living cells. Scale bar, 50 μm for time course panels and 10 μm for the enlarged panels.