Programmable Codelivery of Doxorubicin and Apatinib Using an Implantable Hierarchical‐Structured Fiber Device for Overcoming Cancer Multidrug Resistance

Abstract

The MDR can be roughly divided into intrinsic resistance and acquired resistance. [2] The intrinsic drug resistance is related to the altered expression or mutation of BCL-2-related apoptotic proteins and is independent of drug efflux pumps. Notably, the members of BCL-2 protein family (e.g., BAX (a proapoptotic p53 transcriptional target) and BCL-2 (an antiapoptotic factor)) can primarily regulate the mitochondrial apoptotic pathway and the relative ratio of BAX to BCL-2 determines a threshold for the induction of apoptosis. [3] While, the acquired resistance, usually arising during the chemotherapy of relapsing leukemia and ovarian and breast cancers, [3b] results from the overexpression of cell membrane-bound adenosine triphosphate (ATP)-binding cassette (ABC) transporters that can recognize and catalyze the efflux of diverse hydrophobic anticancer drugs from cells, lowering the intracellular accumulation of anticancer drugs and reducing their therapeutic effect. [1a] One of the transporters, P-glycoprotein (P-gp), can pump out many drugs such as doxorubicin, paclitaxel, vinblastine, and so on. The other transporter is breast cancer resistance protein (BCRP), an ABC half-transporter, which is derived from a doxorubicin-resistant MCF-7 breast cancer cell line and resists doxorubicin and camptothecins. [4] Both P-gp and BCRP contribute to form a unique defense against chemotherapeutics and reduce the intracellular drug accumulation.To reverse or evade the mechanism of MDR and improve the efficacy of chemotherapy, many efforts have been made for the last decades. Diverse nanocarrier-based drug delivery strategies with combinations of multiple drugs, which can bypass the drug efflux pumps through endocytic pathways and lysosomal delivery, have been successfully developed to evade MDR in cancer therapy. [5] These nanocarriers include several main modalities. One is to directly suppress the function of P-gp using surfactants (e.g., pluronic P123 and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS)) which deplete ATP production, or to directly inactivate P-gp with a relevant inhibitor (e.g., apatinib (AP) and disulfiram). [6] Another one is based on RNA interference technology. This strategy is mainly by loading small interfering RNA (siRNA), which can specifically knock down the expression of drug resistance-related genes, to restore the chemosensitivity of cancer cells. [7] The third one is to design a Multiple drug resistance (MDR) of cancer cells is a major cause of chemotherapy failure. It is currently a great challenge to develop a direct and effective strategy for continuously inhibiting the P-glycoprotein (P-gp) drug pump of MDR tumor cells, thus enhancing the intracellular concentration of the therapeutic agent for effectively killing MDR tumor cells. Here, a new implantable hierarchical-structured ultrafine fiber device is developed via a microfluidic-electrospinning technology for localized codelivery of doxorubicin (DOX) and apatinib (AP). An extremely high encapsulation efficiency of ≈99% fo...

A Time‐Programmed Release of Dual Drugs from an Implantable Trilayer Structured Fiber Device for Synergistic Treatment of Breast Cancer

“…Recently, a novel microfluidic‐electrospinning technology based on single emulsion has been developed by our group to fabricate ultrafine polymeric fiber with the bamboo‐like structure . Meanwhile, considering that the sequential exposure of the tumor to cytotoxic agents and vascular inhibitors may be the best strategy of combination therapy,3a we further developed an implantable trilayer structured fiber device to achieve a time‐programmed release of combined drugs via a modified microfluidic‐electrospinning technology for enhanced localized therapy effect.…”

“…PLA and Apa‐loaded PCL also formed other parts of the trilayer structured fiber (Scheme b, B‐B). Different from our previous report, in this work we improved the structure of the fiber, in which the PLA inner wall was ingeniously introduced into the periodic cavities. By adjusting the thickness of the wall, the release rate of the cargos loaded in the cavities can be readily controlled.…”

Two Sides of Electrospun Fiber in Promoting and Inhibiting Biomedical Processes

“…A series of seminal studies conducted by Yang He et al proposed that suppression of the P-glycoprotein (P-gp) drug pump of tumor cells with multiple drug resistance could be a key factor for the prevention of chemotherapy failure. [190] To inhibit the P-gp drug pump, they applied electrospinning to engineer a particular fiber device to achieve localized co-delivery of AP and Dox. They found the continuous release of AP promoted the accumulation of Dox in the cells, which guaranteed sustained drug supply to tumor cell and revealed the superb anti-tumor efficacy of this fiber device.…”

<p>A pH-Sensitive Prodrug Nanocarrier Based on Diosgenin for Doxorubicin Delivery to Efficiently Inhibit Tumor Metastasis</p>

“…In addition, since Bcl-2 and the caspase family were involved in mitochondria-associated apoptosis, 45,46 we researched their change after B16F10 cells were treated with DOX or DOX/NPs. Western blot protein expression of Bax (proapoptotic protein), Bcl-2 (antiapoptotic protein) and cleaved caspase-3 in the cells were performed and quantified.…”