A Paclitaxel Prodrug Activatable by Irradiation in a Hypoxic Microenvironment

Abstract

The innate hypoxic microenvironment of most solid tumors has am ajor influence on tumor growth, invasiveness, and distant metastasis.Here,ahypoxia-activated self-immolative prodrug of paclitaxel (PTX 2-Azo) was synthesized and encapsulated by ap eptide copolymer decorated with the photosensitizer chlorin e6 (Ce6) to prepare light-boosted PTX nanoparticle (Ce6/PTX 2-Azo NP). In this nanoparticle, PTX 2-Azo prevents premature drug leakage and realizes specific release in hypoxic tumor microenvironment and the photosensitizer Ce6 not only efficiently generates singlet oxygen under light irradiation but also acts as ap ositive amplifier to promote the release of PTX. The combination of photodynamic therapy(PDT) and chemotherapyr esults in excellent antitumor efficacy,d emonstrating the great potential for synergistic cancer therapy.

Most recent advances on enzyme‐activatable optical probes for bioimaging

“…Reproduced with permission. [ 53 ] Copyright 2020, Wiley‐VCH. (D) The response mechanism of azo/ β ‐CDP, the BHQ2 ( 16 ) response to hypoxia, and the imaging of hypoxia linked with IBD by a cascade amplifier based on cytoplasmic protein‐powered FL cascade amplification.…”

“…With the self‐assembly of the hypoxia‐activatable dimeric prodrug PTX 2 ‐Azo and the peptide copolymer furnished with the photosensitizer chlorin e6 (Ce6), the light‐boosted nanoprobe 15 was formed, realizing the combination of PDT, chemotherapy, and FL imaging (Figure 7C). [ 53 ] The nanoprobe 15 exhibited as ∼100 nm‐sized well‐defined spheres and shows effective tumor accumulation due to the EPR effect. The encapsulated paclitaxel prodrug PTX 2 ‐Azo could be cleaved into free and potent PTX via the bioreduction by the overexpressed azoreductase and NTRs, the sequential 1,6‐elimination, and decarboxylation reactions in hypoxia.…”

“…[36,50] A few of azoreductase-activatable optical probes varying from molecular probe to self-assembled nanoprobes to assembly system formed via host-guest interactions have recently been reported. [51][52][53][54][55][56] The representatives are exhibited in Figure 7. Their common working mechanism is based on the efficient reduction of the azo bond (N = N) in azobenzene compounds by azoreductase treatment in the hypoxia.…”

Recent Advances in Bio‐Compatible Oxygen Singlet Generation and Its Tumor Treatment

“…Compared with the traditional PDT, this new synthetic drug can trigger chemotherapy by using the TME hypoxia induced by PDT, which greatly improves the curative effect. In another study, Zhou et al [322] developed a kind of lightpromoted nanoparticles by encapsulating paclitaxel precursor drug with polypeptide copolymer modified by Ce6. PSs Ce6 can not only effectively generate 1 O 2 to kill cancer cells under light, but also promote the release of paclitaxel due to hypoxia.…”

Singlet Oxygen Generation in Dark‐Hypoxia by Catalytic Microenvironment‐Tailored Nanoreactors for NIR‐II Fluorescence‐Monitored Chemodynamic Therapy

“…[4] However,a pplying PDT technique for tumor inhibition presents significant obstacles,s uch as limited light penetration depth and hypoxia-caused resistance. [5] As an emerging cancer therapeutic strategy,chemodynamic therapy (CDT) employs catalytic reactions to yield highly reactive ROSf rom endogenous hydrogen peroxide (H 2 O 2 ). [6] Although there is apaucity of research regarding 1 O 2 -mediated CDT,i ti sc onceivable that CDT has the potential to overcome the limitations encountered in conventional 1 O 2generating PDT antitumor process through exploration of chemodynamic agents able to produce 1 O 2 in cancer cells without the need of light irradiation and O 2 .…”