Synthesis, Spectroscopic and Fibroblast Activation Protein (FAP)‐Responsive Properties of Phthalocyanine‐Doxorubicin Conjugates

Abstract

A series of novel phthalocyanine‐doxorubicin (Pc‐DOX) conjugates have been prepared with a fibroblast activation protein (FAP)‐sensitive linker of glycine‐proline (Gly‐Pro) dipeptide. Meanwhile, two Pc‐DOX conjugates (1 c and 3 c) without FAP‐sensitive linker have also been prepared for comparison. For Pc‐DOX conjugates, the photosensitizing properties of the phthalocyanines are partly quenched after being conjugated with DOX. The aggregation behavior of these conjugates is less affected by the surfactant of Cremophor EL compared with that of corresponding precursors in aqueous media. The FAP‐responsive properties have been demonstrated by HPLC analysis and fluorescence spectroscopy in phosphate buffered saline. The Pc‐Gly‐Pro‐DOX conjugate 2 b with longer linker is more sensitive to FAP than the other two Pc‐Gly‐Pro‐DOX conjugates (1 b and 3 b). The results suggest that the longer linker and smaller steric hindrance between phthalocyanine and Dox units are beneficial for the cleavage of Gly‐Pro linker induced by FAP, while the axial or peripheral substituted positions hardly allow the enzymolysis of FAP. This work can thus provide a valuable reference for the targeted chemo‐photodynamic therapy of cancer.

Targeted cancer phototherapy using phthalocyanine–anticancer drug conjugates

“…Huang expanded on this work by comparing both the prodrug and the traditional conjugates whilst also investigating the effects of chain length between the two components and the location of DOX on the Pc macrocycle (axial vs. peripheral) (A3-A6). [61] FAP responsiveness experiments showed that the prodrugs undergo facile enzymolysis of the linker to release the DOX unit. [61] In the absence of in vitro or in vivo testing it is difficult to accurately state which linker length or difference between axial or peripheral location of the DOX moiety provided the best overall synergistic effect.…”

“…[61] FAP responsiveness experiments showed that the prodrugs undergo facile enzymolysis of the linker to release the DOX unit. [61] In the absence of in vitro or in vivo testing it is difficult to accurately state which linker length or difference between axial or peripheral location of the DOX moiety provided the best overall synergistic effect. The photophysical data indicated that the presence of the DOX moiety did reduce Φ Δ values of both the prodrug and traditional conjugates, with the free Pc displaying higher Φ Δ values on all occasions (Table 3).…”

“…The photophysical data indicated that the presence of the DOX moiety did reduce Φ Δ values of both the prodrug and traditional conjugates, with the free Pc displaying higher Φ Δ values on all occasions (Table 3). [61] The traditional conjugates with shorter chain lengths and peripheral conjugation sites displayed greater Φ Δ and Φ F values, [61] although it is not known if this translates to better PDT performance. The development of highly effective Pc-DOX conjugates displaying limited dark toxicity in conjunction with a strong PDT response still requires additional exploration.…”

Targeted Cancer Phototherapy Using Phthalocyanine–Anticancer Drug Conjugates

“…[61] FAP responsiveness experiments showed that the prodrugs undergo facile enzymolysis of the linker to release the DOX unit. [61] In the absence of in vitro or in vivo testing it is difficult to accurately state which linker length or difference between axial or peripheral location of the DOX moiety provided the best overall synergistic effect. The photophysical data indicated that the presence of the DOX moiety did reduce ΦΔ of both the prodrug and traditional conjugates, with the free Pc displaying higher ΦΔ on all occasions (Table 3).…”

“…The photophysical data indicated that the presence of the DOX moiety did reduce ΦΔ of both the prodrug and traditional conjugates, with the free Pc displaying higher ΦΔ on all occasions (Table 3). [61] The traditional conjugates with shorter chain lengths and peripheral conjugation sites displayed greater ΦΔ and Φfl, [61] although it is not known if this translates to better PDT performance. The development of highly effective Pc-DOX conjugates displaying limited dark toxicity in conjunction with a strong PDT response still requires additional exploration.…”