Self‐Assembling Doxorubicin Prodrug Forming Nanoparticles and Effectively Reversing Drug Resistance In Vitro and In Vivo

Abstract

Doxorubicin (DOX) is a widely used chemotherapeutic drug to treat a range of cancers. However, its unfavorable effects, particularly the cardiotoxicity and the induction of multidrug resistance (MDR), significantly limit its clinical applications. Herein, a novel doxorubicin prodrug, PEG -DOX, is synthesized by conjugating a deprotonated doxorubicin molecule with the polyethylene glycol (PEG, MW: 2K) chain via pH-responsive hydrazone bond, and its potential as a better alternative than doxorubicin is evaluated. The data show that the amphiphilic PEG -DOX can self-assemble into stable nanoparticles with a high and fixed doxorubicin loading content (≈20 wt%), a favorable size of 91.5 nm with a narrow polydispersity (PDI = 0.14), good stability, and pH-dependent release behavior due to the acid-cleavable linkage between PEG and doxorubicin. Although doxorubicin hardly accumulates in MDR cells, PEG -DOX nanoparticles significantly increase the cellular uptake and cell-killing activity of doxorubicin in two MDR cancer cell lines MCF-7/ADR and KBv200, with the IC values dropped to 1.130% and 42.467% of doxorubicin, respectively. More impressively, PEG -DOX nanoparticles exhibit significantly improved plasma pharmacokinetics, increased in vivo therapeutic efficacy against MDR xenograft tumors, and better in vivo safety compared with doxorubicin. PEG -DOX nanoparticles hold the promise to become a better alternative than doxorubicin for cancer treatment, especially for MDR tumors.

Multifunctional Dendrimer-Entrapped Gold Nanoparticles Conjugated with Doxorubicin for pH-Responsive Drug Delivery and Targeted Computed Tomography Imaging

“…In particular, various acid-sensitive linkers, hydrazone bond, , benzoic imine bond, , and cis-aconityl linkage , have been introduced for the design of pH-responsive drug delivery systems, mainly because these linker systems are able to break under slightly acidic pH environment. For instance, as a widely used anticancer drug for tumor chemotherapy, , doxorubicin (DOX) has been attached onto the dendrimer surface through a cis-aconityl linkage to effectively improve the drug accumulation in the tumor site. , …”

Simultaneous delivery of anti-miR21 with doxorubicin prodrug by mimetic lipoprotein nanoparticles for synergistic effect against drug resistance in cancer cells

“…To address the drug-resistance issue, researchers have synthesized a large number of Dox prodrugs, which have demonstrated great potential in anticancer treatment. [13][14][15] One of these attempts is to escape the recognition of the Pgp transporter and efficiently deliver Dox into nuclei inside cancer cells. Recently, the nuclear localization signal (NLS) peptides have demonstrated the inspiring ability to facilitate active transportation toward nuclei, potentially bypassing the export of drugs by Pgp proteins.…”

Functionalized Nanoparticles Efficiently Enhancing the Targeted Delivery, Tumor Penetration, and Anticancer Activity of 7‐Ethyl‐10‐Hydroxycamptothecin

“…In Vitro Anticancer Activity : The tumor cell‐killing activity of CPT‐11, SN38, B‐SN38, and C‐SN38 nanoparticles was evaluated using MTT assays in MDA‐MB‐231, HT‐29, and MCF‐7 cell lines. All procedures were conducted according to our previous report …”