Targeting the tumour microenvironment with an enzyme-responsive drug delivery system for the efficient therapy of breast and pancreatic cancers

Abstract

A drug delivery system targeting the tumour microenvironment produces outstanding therapeutic efficacy on triple-negative mammary and pancreatic models.

Fast Cyclization of a Proline‐Derived Self‐Immolative Spacer Improves the Efficacy of Carbamate Prodrugs

“…After incubation for 1hour,c ells were washed and then incubated for 72 hours in fresh medium, followed by quantitative analysis of cell growth. This limited cell exposure to the prodrug mimics the typical conditions of extracellular drug delivery in vivo, [25] in which CPT is released from acarrier in the tumor microenvironment and then the fundamental steps for its cytotoxic activity (i.e.d iffusion through the cell membrane and inhibition of the intracellular target, that is, DNAt opoisomerase I) occur in competition with the drug clearance from the tumor tissue.A sc an be seen in the histogram in Figure 2E,t he anticancer activity of the Sp4-CPT prodrug under these experimental conditions was comparable to that of free CPT (i.e.c ell growth reduced to ca. 50 %compared to untreated cells), whereas prodrug Sp1-CPT showed lower anticancer activity,s imilar to that displayed by the slow-cyclizing prodrug Sp3-CPT.The experiment was repeated with ac ell-growth-inhibition assay with long-term drug exposure,and cells were exposed to the tested compounds for 72 hours ( Figure 2F).…”

“…[28] These in vitro data hold promise for the installation of the Sp4 spacer in alarge subset of platforms that can be activated for in vivo therapy and diagnosis.The rate of self-immolative cleavage is expected to be particularly relevant in the context of non-internalizing conjugates. [25] In fact, in this case the therapeutic outcome is ac omposite result of efficient targeting, rate of linker cleavage (SI spacer activation), and rate of SI spacer degradation, which may regulate the competition between drug entry into the cells and drug escape back into the bloodstream. Table 1: Cell-growth-inhibition assays of IGROV-1 cells upon incubation with prodrugs 1-3 and free payloads CPT and PTX.…”

Innovative Linker Strategies for Tumor‐Targeted Drug Conjugates

“…While linkers cleaved by lysosomal enzymes have been mostly investigated for drug delivery purposes, it has recently become clear that cathepsin B and other primarily intracellular enzymes can be expressed also in extracellular compartments, shed by apoptotic or dead cells. Indeed, lysosomally cleavable linkers (Val‐Cit, Val‐Ala, glucuronide fragments) were found to efficiently release cytotoxic payloads at the tumor site also when installed onto non‐internalizing carriers, such as albumin, certain monoclonal antibodies and small ligands . Moreover, extracellular enzymes have also been considered for the release of cytotoxic payloads from different carriers.…”

“…[44] The cleavage site of all linkers is indicated:w hile doxorubicin is released from conjugate 6 with the PABC spacer elimination showni nS cheme 1, drug release mechanism of conjugate 8 is described in Scheme 5. enzymesc an be expressed also in extracellular compartments, shed by apoptotic or dead cells. Indeed, lysosomally cleavable linkers (Val-Cit, Val-Ala, glucuronidef ragments) weref ound to efficiently release cytotoxicp ayloads at the tumors ite also when installed onto non-internalizing carriers, such as albumin, [36] certain monoclonal antibodies [37] and small ligands. [38] Moreover,e xtracellulare nzymes have also been considered for the releaseo fc ytotoxic payloads from different carriers.…”

Volatile Organic Compound Based Probe for Induced Volatolomics of Cancers

“…Since extracellular b-glucuronidase activity increases with tumour growth (Figure 2a), we also hypothesised that the VOC-based probe could be useful for monitoring the efficacy of cancer chemotherapy.Recent studies have shown that the targeting of the tumour microenvironment by means of bglucuronidase-responsive albumin-binding prodrugs is an efficient and versatile therapeutic strategy. [27,28] However, the efficacyo fs uch drug delivery systems depends on the concentration of the activating enzyme in the tumour.Inthis context, EtGlu could be used as apredictive probe to estimate the anticancer efficiency of glucuronide prodrugs as well as for optimising the administration schedule.…”