Reduction Responsive Self-Assembled Nanoparticles Based on Disulfide-Linked Drug–Drug Conjugate with High Drug Loading and Antitumor Efficacy

Abstract

Most anticancer drugs are poorly soluble and nonspecific, which restricts their clinical application. Drug conjugates, as a prodrug strategy, provide the possibility to overcome these shortcomings, especially combined with nanotechnology. Drug conjugate nanoparticles possess the advantages of high drug loading capacity and passive tumor targeting ability. Here, we prepared doxorubicin drug-drug conjugate nanoparticles (DOX-SS-DOX NPs) based on disulfide-linked doxorubicin drug-drug conjugate (DOX-SS-DOX). Dynamic light scattering (DLS) and transmission electron microscope (TEM) characterization indicated that DOX-SS-DOX NPs were spherical with a uniform size distribution around 89 nm. DLS and in vitro release experiment revealed that DOX-SS-DOX NPs possessed reduction responsive activity. In vitro cellular uptake studies reflected that DOX-SS-DOX NPs could increase the uptake level substantially compared with DOX liposomes. Endocytosis mechanism assay demonstrated that DOX-SS-DOX NPs internalized into cells through a clathrin-mediated endocytosis pathway in an energy-dependent manner. In this manner, the amidase in lysosomes could break the amide bond to release free DOX, which would be helpful to antitumor activity. The in vitro cytotoxicity of DOX-SS-DOX NPs was a bit weaker than that of DOX liposomes, which might be the result of the slow cleavage of the disulfide bridge; but the antitumor efficacy of DOX-SS-DOX NPs evaluated in MCF-7 bearing mice was demonstrated to be higher than that of DOX liposomes. This might be because of the long lasting effect resulting from the slow cleavage of the disulfide bond. In summary, DOX-SS-DOX NPs, prepared nearly totally with drug, provide a good strategy for cancer therapy.

pH/Reduction Dual‐Triggered Degradable Poly(doxorubicin) Prodrug Nanoparticles for Leakage‐Free Tumor‐Specific Self‐Delivery

“…As a kind of broad‐spectrum chemotherapeutics, doxorubicin (DOX) is widely used in clinical therapy. Besides the DOX delivery via the DDSs abovementioned, its dimers, namely DOX−DOX conjugates, have also been designed as self‐delivery systems to overcome drug resistance, or improve the drug loading and antitumor efficacy in DDS . Most recently, Duan et al.…”

“…In its 1 H NMR spectrum, the chemical shifts at δ = 1.41–1.52 and δ = 2.62–2.85 revealed the successful formation of the hydrazone and disulfide bonds (Figure S2, Supporting Information). Based on the integral area ratio of the two signals, the Mn of the PDOX was estimated to be 1.66 × 10 4 , meaning an average DOX units of 24 in one PDOX macromolecules with a DOX content of 78%.…”

Amphiphilic Endomorphin-1 Derivative Functions as Self-assembling Nanomedicine for Effective Brain Delivery

“…The disulfide bond can be rapidly cleaved in the presence of reducing agents such as GSH and has been extensively used as a reduction-responsive linker. 27,33,34) Here, the only structural difference between the C 18 -SS-EM1 and C 18 -CONH-EM1 is the internal chemical bond, but their nanomorphology differed significantly. We hypothesize that the disulfide bond plays a wider role in the selfassembly.…”

Self-assembly drug conjugates for anticancer treatment

“…SK-3rd, a cancer stem cell line, was chosen to evaluate the efficacy of doxorubicin NPs and it was demonstrated that NPs enhanced the cellular internalization, subsequently released the free drug in the cells in response to the endo/lysosomal pH and thus inhibited the progression of cancer stem cells. Moreover Song et al described the synthesis of a disulfide-linked doxorubicin drug-drug conjugate [45]. The in vitro cytotoxicity of doxorubicin NPs was weaker than that of the free drug but the antitumor efficacy of NPs evaluated in MCF-7-bearing mice was demonstrated to be higher than that of free doxorubicin.…”