Folate-decorated polymeric Pt(ii) prodrug micelles for targeted intracellular delivery and cytosolic glutathione-triggered release of platinum anticancer drugs

Abstract

Bioreducible FA-PEG-b-P(α-Pt(ii)-SS-CL/CL) conjugates have been successfully developed in order to build redox-responsive micelles with targeting and site-specific drug releasing abilities.

Folate-decorated redox/pH dual-responsive degradable prodrug micelles for tumor triggered targeted drug delivery

“…Poly(ethylene glycol) (PEG, M n = 2000 g/mol) were purchased from Fluka and dried by azeotropic distillation using anhydrous toluene. Folate-poly(ethylene glycol)-NH 2 (FA-PEG-NH 2 ) 41 and α-tert-butyl acetate-ɛ-100 caprolactone (TBACL) 35 dimethyl sulfoxide (DMSO) and epidermal growth factor (EGF) were purchased from Sigma. 5 Scheme 1 Self-assembly and activated intracellular drug delivery and release from redox and pH dual-responsive degradable FA-PEG-b-P((PTX-SS-CL)-co-CL) micelles.…”

“…Statistical analysis was carried out by means of one-way analysis of variance (ANOVA) followed by the Tukey post-test. p < 0.05 was considered to be statistically significant, and p < 0.01 was 35 considered to be highly significant.…”

“…[25][26][27][28][29][30][31][32][33][34] Inside the body, glutathione (GSH), a natural reducing agent for disulfide bonds, was found in the blood plasma at µM levels (approximately ~2 µM), due to rapid enzymatic degradation, whereas a substantially high 45 concentration at mM levels (2-10 mM) was found in the cytoplasm of cancer cells. 35 Beside, the pH at both primary and metastasized tumors is lower (6.5-7.2) than the pH of normal tissues (7.4) and intracellular pH of their endosomes (5.5-6.0) and lysosomes (4.5-5.0) are even more acidic. 36 The large GSH and 50 pH gradient between intracellular and extracellular compartments renders GSH and pH as effective intracellular triggers that can effectively cleave disulfide and pH-sensitive linkages (such as βthiopropionate, hydrazone, ortho ester and acetal) in polymeric prodrugs, respectively.…”

“…So, compared to physical encapsulation of drug by an amphiphilic block copolymer, conjugation of a drug to an amphiphilic polymer (polymeric prodrug), directly or through a bio-cleavable linker, will be much better. 2, 5, 14-16 35 Intrinsic stimuli in tumor cells, such as acidic pH, the presence of specific enzymes and redox potential, can be used to ensure successful release of therapeutic agents on the tumor site in a spatially controlled manner. [17][18][19][20][21][22][23][24] In particular, redox and pH dual-responsive DDSs were paid more attention because of the 40 existence of redox potential and pH gradient between the extraand intracellular space.…”

“…37, 38 To the best of our knowledge, up to now, amphiphilic and redox and pH dual-responsive polymer-PTX conjugates based on PEG and PCL have not been utilized to construct DDSs possessing synergistic therapeutic and active targeting functions. 75 Aiming at fulfilling the above requirements and also as a continued study to develop functional amphiphilic copolymers for preparing stimuli-responsive drug nanocarriers, 35,36,[39][40][41][42] in the present work, novel folic acid functionalized redox and pH dual-responsive degradable micellar nanoparticles were designed 80 from amphiphilic polymer-PTX conjugates with thiol and acidlabile linkages, FA-PEG-b-P((PTX-SS-CL)-co-CL). The inoculation of β-thiopropionate and disulfide linkers between PTX and polyester block was supposed to release the active PTX into tumor cells in response to an intracellular pH and glutathione 85 level (Scheme 1).…”