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Mitochondria-acting carrier-free nanoplatform self-assembled by α-tocopheryl succinate carrying cisplatin for combinational tumor therapy.

ABSTRACT: Unsatisfactory drug loading capability, potential toxicity of the inert carrier and the limited therapeutic effect of a single chemotherapy drug are all vital inhibitory factors of carrier-assisted drug delivery systems for chemotherapy. To address the above obstacles, a series of carrier-free nanoplatforms self-assembled by dual-drug conjugates was constructed to reinforce chemotherapy against tumors by simultaneously disrupting intratumoral DNA activity and inhibiting mitochondria function. In this nanoplatform, the mitochondria-targeting small-molecular drug, α-tocopheryl succinate (TOS), firstly self-assembled into nanoparticles, which then were used as the carrier to conjugate cisplatin (CDDP). Systematic characterization results showed that this nanoplatform exhibited suitable particle size and a negative surface charge with good stability in physicochemical environments, as well as pH-sensitive drug release and efficient cellular uptake. Due to the combined effects of reactive oxygen species (ROS) generation by TOS and DNA damage by CDDP, the developed nanoplatform could induce mitochondrial dysfunction and elevated cell apoptosis, resulting in highly efficient anti-tumor outcomes in vitro. Collectively, the combined design principles adopted for carrier-free nanodrugs construction in this study aimed at targeting different intracellular organelles for facilitating ROS production and DNA disruption can be extended to other carrier-free nanodrugs-dependent therapeutic systems.

SUBMITTER: Mei H

PROVIDER: S-EPMC8242230 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Dual functional drug carrier has been a modern strategy in cancer therapy because it is a platform to elicit additive and synergistic effects through combination therapy. Photo-activated external stimuli such as reactive oxygen species (ROS) also ensure adequate drug delivery in a precise temporal and spatial manner. However, current ROS-responsive drug delivery systems usually require tedious synthetic procedures. A facile one-pot approach has been reported herein, to obtain self-assembled polymeric nanocarriers (NCs) for simultaneous paclitaxel (PTX)- and Rose Bengal (RB)-loading to achieve combined chemo-photodynamic therapy and controlled drug release in responsive to a light-induced ROS stimulus. To encapsulate these hydrophobic and hydrophilic drugs, chitosan (CTS), branched polyethylenimine (bPEI) and polyvinyl alcohol (PVA) were selected and fabricated into nanoblended matrices through an oil-in-water emulsion method. The amphiphilic properties of CTS permit simultaneous entrapment of PTX and RB, while the encapsulation efficiency of RB was further improved by increasing the amount of short-chain bPEI. During the one-step assembly process, bovine serum albumin (BSA) was also added to condense the cationic tripolymer mixtures into more stable nanocarriers (BNCs). Hyaluronic acid (HA) was subsequently grafted onto the surface of BNCs through electrostatic interaction, leading to the formation of HA-BSA/CTS/PVA/bPEI-blended nanocarriers (HBNCs) to achieve an efficient prostate-cancer-cell uptake. Importantly, in response to external light irradiation, HBNCs become destabilized owing to the RB-mediated photodynamic action. It allows an on-demand dual-payload release to evoke a simultaneous photodynamic and chemo treatment for cancer cell eradication. Thus, HBNCs present a new promising approach that exhibits a specific vulnerability to RB-induced photosensitization. The consequent dual-cargo release is also expected to successfully combat cancer through a synergistic anti-tumor effect.

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Mitochondria-acting carrier-free nanoplatform self-assembled by α-tocopheryl succinate carrying cisplatin for combinational tumor therapy.

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