ma400691j_si_001.pdf (373.23 kB)
Photo-Triggered Release of Caged Camptothecin Prodrugs from Dually Responsive Shell Cross-Linked Micelles
journal contribution
posted on 2016-02-19, 01:25 authored by Xianglong Hu, Jie Tian, Tao Liu, Guoying Zhang, Shiyong LiuWe
report on the fabrication of dynamic covalent shell cross-linked (SCL)
micelles with hydrophobic cores conjugated with photocaged chemotherapeutic
drugs and coronas functionalized with ligands for tumor cell targeting.
Two types of amphiphilic diblock copolymers, P(CL-g-CPT)-b-P(OEGMA-co-MAEBA)-CPT and
PCL-b-P(OEGMA-co-MAEBA-co-FA), were synthesized via the combination of ring-opening copolymerization
(ROP) of ε-caprolactone (CL) and 2-bromo-ε-caprolactone
(CL-Br), atom transfer radical polymerization (ATRP) of oligo(ethylene
glycol) monomethyl ether methacrylate (OEGMA) and p-(methacryloxyethoxy) benzaldehyde (MAEBA) comonomers, and “click”
post-functionalization with photocaged camptothecin (CPT) prodrug
and alkynyl-functionalized folic acid (FA) moieties, respectively.
Mixed micelles coassembled from PCL-b-P(OEGMA-co-MAEBA-co-FA) and P(CL-g-CPT)-b-P(OEGMA-co-MAEBA)-CPT possess
hydrophobic cores conjugated with photocaged CPT prodrugs and hydrophilic
outer coronas covalently attached with aldehyde groups and FA moieties
for subsequent shell cross-linking and cancer cell targeting. Shell
cross-linking was performed at pH 6.2 upon addition of difunctional
cross-linker, dithiol bis(propanoic dihydrazide) (DTP), under the
catalysis of aniline. The obtained FA-decorated SCL micelles contain
acylhydrazone and disulfide linkages in the outer coronas, which can
be de-cross-linked under two biologically relevant conditions, mildly
acidic or reductive microenvironments, that is, endosomal/lysosomal
pH or high GSH level in the cytosol. The cleavage of caged CPT drug
within the cores of SCL micelles can be effectively actuated under
photo irradiation, whereas its diffusion out of micellar nanocarriers
can be further modulated by pH and thiol levels due to the dually
responsive nature of DTP cross-linker. Compared with the control,
FA-decorated SCL micelles can more efficiently enter folate-receptor
expressing cancer cells than folate-receptor deficient ones. Cell
viability assays revealed that SCL micelles displayed at least ∼9.7-fold
enhanced cytotoxicity upon light irradiation. The reported targeting
ligand decorated and prodrug-conjugated dynamic covalent SCL micelles
exert intricate control concerning micellar stability, cancer cell
targeting, photo-triggered parent drug release with photoactivated
cytotoxicity, and tunable drug release profiles. All of these augur
well for their potential application as a novel integrated platform
for targeted drug delivery in cancer chemotherapy.