Co-delivery of doxorubicin and curcumin by pH-sensitive prodrug nanoparticle for combination therapy of cancer

Abstract

Ample attention has focused on cancer drug delivery via prodrug nanoparticles due to their high drug loading property and comparatively lower side effects. In this study, we designed a PEG-DOX-Cur prodrug nanoparticle for simultaneous delivery of doxorubicin (DOX) and curcumin (Cur) as a combination therapy to treat cancer. DOX was conjugated to PEG by Schiff’s base reaction. The obtained prodrug conjugate could self-assemble in water at pH 7.4 into nanoparticles (PEG-DOX NPs) and encapsulate Cur into the core through hydrophobic interaction (PEG-DOX-Cur NPs). When the PEG-DOX-Cur NPs are internalized by tumor cells, the Schiff’s base linker between PEG and DOX would break in the acidic environment that is often observed in tumors, causing disassembling of the PEG-DOX-Cur NPs and releasing both DOX and Cur into the nuclei and cytoplasma of the tumor cells, respectively. Compared with free DOX, free Cur, free DOX-Cur combination, or PEG-DOX NPs, PEG-DOX-Cur NPs exhibited higher anti-tumor activity in vitro. In addition, the PEG-DOX-Cur NPs also showed prolonged blood circulation time, elevated local drug accumulation and increased tumor penetration. Enhanced anti-tumor activity was also observed from the PEG-DOX-Cur-treated animals, demonstrating better tumor inhibitory property of the NPs. Thus, the PEG-DOX-Cur prodrug nanoparticle system provides a simple yet efficient approach of drug delivery for chemotherapy.

Nanoformulations for combination or cascade anticancer therapy

“…The nanoformulation of curcumin is versatile. Free curcumin, polymeric, liposomal and other types of formulations of curcumin can be co/concurrently-delivered with chemotherapy, such as camptothecin (CPT) [86], etoposide [45, 87], platinum [88], PTX [48, 89] and DOX [90, 91] to induce synergy. One study utilized flaxseed oil nanoemulsion to effectively encapsulate PTX and curcumin to enhance the cytotoxicity against both wild-type and resistant ovarian tumor cell line SKOV3[48].…”

“…Single or multiple drug-conjugated polymers exhibiting amphiphilic properties were also used to encapsulate small-molecule drugs for combination therapy based on the supramolecular interaction between drug-conjugated polymer carriers and the other drugs [90, 107–110]. For example, the platinum (IV) prodrug is conjugated to a PLA backbone via an ester bond to form the PLA-Pt(IV) conjugate [108, 109].…”

Co-delivery nanoparticles with characteristics of intracellular precision release drugs for overcoming multidrug resistance

“…13 Zhang et al reported that co-delivery NPs of DOX and curcumin could simultaneously release the drugs in the acidic microenvironment of cancer cells. 23 However, even if these drugs are transported to the cytoplasm, they still face the difficulty of escaping the fate of efflux associated with P-gp. Therefore, the intracellular precision release of NDDS-loaded P-gp substrates is still a demanding issue.…”

pH-responsive Virus-like Nanoparticles with Enhanced Tumour-targeting Ligands for Cancer Drug Delivery

“…When an intracellular pH-triggered drug release carrier is incorporated with a tumour-targeting ligand, this multifunctional nanocarrier can recognize tumour cells and release the encapsulated drug at tumour sites in a controlled manner12. A variety of nanomaterials responding to pH stimuli, such as liposomes, micelles, polymeric and prodrug nanoparticles, have been synthesised and developed as effective drug delivery systems3456. However, not much effort has gone toward developing a pH-responsive drug delivery system based on virus-like nanoparticles (VLNPs).…”