Two-step polymer- and liposome-enzyme prodrug therapies for cancer: PDEPT and PELT concepts and future perspectives

Abstract

Polymer-directed enzyme prodrug therapy (PDEPT) and polymer enzyme liposome therapy (PELT) are two-step therapies developed to provide anticancer drugs site-selective intratumoral accumulation and release. Nanomedicines, such as polymer-drug conjugates and liposomal drugs, accumulate in the tumor site due to extravasation-dependent mechanism (enhanced permeability and retention - EPR - effect), and further need to cross the cellular membrane and release their payload in the intracellular compartment. The subsequent administration of a polymer-enzyme conjugate able to accumulate in the tumor tissue and to trigger the extracellular release of the active drug showed promising preclinical results. The development of polymer-enzyme, polymer-drug conjugates and liposomal drugs had undergone a vast advancement over the past decades. Several examples of enzyme mimics for in vivo therapy can be found in the literature. Moreover, polymer therapeutics often present an enzyme-sensitive mechanism of drug release. These nanomedicines can thus be optimal substrates for PDEPT and this review aims to provide new insights and stimuli toward the future perspectives of this promising combination.

Clip Chemistry: Diverse (Bio)(macro)molecular and Material Function through Breaking Covalent Bonds

“…394,395 This approach combines the orthogonality of an exogenously administered enzyme with the potential for significantly amplified signal through enzymatic catalysis. Beyond antibody targeting, enzyme prodrug therapy has been applied in alternative targeting modalities, 396 implanted materials, 397,398 and cell therapies. 399,400 Enzymatic uncaging also enables the tracking, activation, and deactivation of cell therapies.…”

HAase-sensitive dual-targeting irinotecan liposomes enhance the therapeutic efficacy of lung cancer in animals

“…Different strategies have been developed for liposomal agents release by utilizing the stimuli of enzymes. Enzyme-sensitive liposomes, which respond to stimuli of enzyme for “triggered” release to achieve temporal and spatial control over the release of therapeutic payloads, take advantage of the over-expression of certain enzymes in cancer to cause structural changes of liposomes by the enzymatic reaction 29 , 30 . Liposomes of light activation and heat activation have also been used to enhance the delivery of irinotecan 31 , 32 .…”

Tumor microenvironment responsive drug delivery systems

“…Legumain is an asparaginyl endopeptidase upregulated in the lysomes of several cancer cells [165] . It has highly strict specificity to cleave linkers presenting asparagine or aspartic acid residues [166] .…”