Folate Receptor-Mediated Enhanced and Specific Delivery of Far-Red Light-Activatable Prodrugs of Combretastatin A-4 to FR-Positive Tumor

Abstract

We examined the concept of a novel prodrug strategy in which anticancer drug can be locally released by visible/near IR light, taking advantage of the photodynamic process and photo-unclick chemistry. Our most recently formulated prodrug of combretastatin A-4, Pc-(L-CA4)2, showed multifunctionality for fluorescence imaging, light-activated drug release, and the combined effects of PDT and local chemotherapy. In this formulation, L is a singlet oxygen cleavable linker. Here, we advanced this multifunctional prodrug by adding a tumor-targeting group, folic acid (FA). We designed and prepared four FA-conjugated prodrugs 1–4 (CA4-L-Pc-PEGn-FA: n = 0, 2, 18, ∼45) and one non-FA-conjugated prodrug 5 (CA4-L-Pc-PEG18-boc). Prodrugs 3 and 4 had a longer PEG spacer and showed higher hydrophilicity, enhanced uptake to colon 26 cells via FR-mediated mechanisms, and more specific localization to SC colon 26 tumors in Balb/c mice than prodrugs 1 and 2. Prodrug 4 also showed higher and more specific uptake to tumors, resulting in selective tumor damage and more effective antitumor efficacy than non-FA-conjugated prodrug 5. FR-mediated targeting seemed to be an effective strategy to spare normal tissues surrounding tumors in the illuminated area during treatment with this prodrug.

Fluorescent chemical probes for accurate tumor diagnosis and targeting therapy

“…You et al expanded their NIR light activatable strategy by integrating a tumor-targeting folic acid group into the prodrug systems (89a-e). 235 The photosensitizer and fluorophore was phthalocyanine. The light switch was aminoacrylate with variable polyethylene glycol chains.…”

Quantitative modeling of the dynamics and intracellular trafficking of far-red light-activatable prodrugs: implications in stimuli-responsive drug delivery system

“…While we have used a non-specific uptake process in this study, we recently developed light-activatable prodrugs targeted with folate-receptor that may overcome some limitations of the non-targeted prodrugs used here [58]. In addition, we did not consider the effect of light on SO production because the light dose was kept constant in the current experimental settings.…”

Blocking Blood Flow to Solid Tumors by Destabilizing Tubulin: An Approach to Targeting Tumor Growth

“…The results obtained indicate that after prodrug administration to mice inoculated with folate-receptor colon 26 tumors and only after laser irradiation, a significant and selective antitumor effect was observed. 127 Another way to improve the poor aqueous solubility and pharmacokinetic properties of CA-4 has been through alternative delivery systems such as polymeric micelles, 128 liposomes, 129 dendrimers, 130 or pH-sensitive nanocarriers. 131 These systems do not only improve the solubility and pharmacokinetics but may allow the delivery of CA-4 to a particular cell population, using targeted drug delivery systems.…”