RESUMO
Chemotherapy still accounts for a large proportion of the treatments of tumors, but the drug resistance and side effects caused by long-term chemotherapy should not be underestimated. In this work, the drug combination strategy has been widely developed to overcome the side effects brought by the use of single drugs and improve the therapeutic effect. However, in clinical applications, the co-delivery of drugs is very difficult, and different in vivo kinetics due to different drug properties will lead to a decrease in efficacy. Thus, the design of novel antitumor therapeutic agents, including new platinum agents, represents an area in need of urgent attention. Our investigation implies a promising strategy for the design of a platinum prodrug to enhance the treatment of breast cancer. A dual-drug delivery nanoparticle was developed for enhanced treatment of breast cancer based on a two-into-one co-delivery strategy. Through the synergistic effect of released cisplatin hydrate and tolfenamic acid (COX-2 inhibitor) from the coordination prodrug, the tumor growth is significantly suppressed, and the survival time is greatly extended in breast tumor-bearing mice.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Nanopartículas/química , Platina/farmacologia , Pró-Fármacos/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Feminino , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Non-small cell lung cancer (NSCLC) shows high drug resistance and leads to low survival due to the high level of mutated Tumor Protein p53 (TP53). Cisplatin is a first-line treatment option for NSCLC, and the p53 mutation is a major factor in chemoresistance. We demonstrate that cisplatin chemotherapy increases the risk of TP53 mutations, further contributing to cisplatin resistance. Encouragingly, we find that the combination of cisplatin and fluvastatin can alleviate this problem. Therefore, we synthesize Fluplatin, a prodrug consisting of cisplatin and fluvastatin. Then, Fluplatin self-assembles and is further encapsulated with poly-(ethylene glycol)-phosphoethanolamine (PEG-PE), we obtain Fluplatin@PEG-PE nanoparticles (FP NPs). FP NPs can degrade mutant p53 (mutp53) and efficiently trigger endoplasmic reticulum stress (ERS). In this study, we show that FP NPs relieve the inhibition of cisplatin chemotherapy caused by mutp53, exhibiting highly effective tumor suppression and improving the poor NSCLC prognosis.
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Nanopartículas , Fosfatidiletanolaminas , Polietilenoglicóis , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Fluvastatina/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , MutaçãoRESUMO
Idiopathic pulmonary fibrosis (IPF) is a fibrotic interstitial lung disease in which collagen progressively deposits in the supporting framework of the lungs. The pathological collagen creates a recalcitrant barrier in mesenchyme for drug penetration, thus greatly restricting the therapeutical efficacy. On the other hand, this overloaded collagen is gradually exposed to the bloodstream at fibrotic sites because of the vascular hyperpermeability, thus serving as a potential target. Herein, pathological collagen targeting and penetrating liposomes (DP-CC) were constructed to deliver anti-fibrotic dual drugs including pirfenidone (PFD) and dexamethasone (DEX) deep into injured alveoli. The liposomes were co-decorated with collagen binding peptide (CBP) and collagenase (COL). CBP could help vehicle recognize the pathological collagen and target the fibrotic lungs efficiently because of its high affinity to collagen, and COL assisted in breaking through the collagen barrier and delivering vehicle to the center of injured sites. Then, the released dual drugs developed a synergistic anti-fibrotic effect to repair the damaged epithelium and remodel the extracellular matrix (ECM), thus rebuilding the lung architecture. This study provides a promising strategy to deliver drugs deep into pathological collagen accumulated sites for the enhanced treatment of IPF.
Assuntos
Fibrose Pulmonar Idiopática , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Lipossomos/metabolismo , Colágeno/metabolismo , Pulmão/metabolismo , Matriz Extracelular/metabolismo , Fibrose , Fibroblastos/metabolismoRESUMO
Cisplatin is one of the most used first-line anticancer drugs for various solid tumor therapies. However, cisplatin-based chemotherapy can induce tumor cells to secrete excessive prostaglandin E2 (PGE2) catalyzed by cyclooxygenase-2 (COX-2), which, in turn, counteracts its chemotherapeutic effect and further accelerates tumor metastasis. Here, we report a carrier-free self-delivered nanoprodrug based on platinum (II) coordination bonding coupled with tolfenamic acid (Tolf) (named Tolfplatin). Tolfplatin can spontaneously assemble into uniformly sized nanoparticles (NPs) with a high drug-loading capacity. Compared with cisplatin, Tolfplatin NPs can facilitate cellular uptake, significantly decrease PGE2 secretion by COX-2 inhibition, which further downregulate tumorous anti-apoptotic and metastasis-associated proteins, thereby efficiently inducing apoptotic cell death and significantly inhibit tumor metastasis in vitro and in vivo. Therefore, as the carrier-free nanoprodrug, Tolfplatin NPs are promising anti-tumoral agents to inhibit tumor proliferation and metastasis by enriching the function and promoting the anti-tumor activity of cisplatin.