Tumor- and mitochondria-targeted nanoparticles eradicate drug resistant lung cancer through mitochondrial pathway of apoptosis

Abstract

Chemotherapeutic drugs frequently encounter multidrug resistance. ATP from mitochondria helps overexpression of drug efflux pumps to induce multidrug resistance, so mitochondrial delivery as a means of "repurposing'' chemotherapeutic drugs currently used in the clinic appears to be a worthwhile strategy to pursue for the development of new anti-drug-resistant cancer agents. TPP-Pluronic F127-hyaluronic acid (HA) (TPH), with a mitochondria-targeting triphenylphosphine (TPP) head group, was first synthesized through ester bond formation. Paclitaxel (PTX)-loaded TPH (TPH/PTX) nanomicelles exhibited excellent physical properties and significantly inhibited A549/ADR cells. After TPH/ PTX nanomicelles entered acidic lysosomes through macropinocytosis, the positively charged TP/PTX nanomicelles that resulted from degradation of HA by hyaluronidase (HAase) in acidic lysosomes were exposed and completed lysosomal escape at 12 h, finally localizing to mitochondria over a period of 24 h in A549/ADR cells. Subsequently, TPH/PTX caused mitochondrial outer membrane permeabilization (MOMP) by inhibiting antiapoptotic Bcl-2, leading to cytochrome C release and activation of caspase-3 and caspase-9. In an A549/ADR xenograft tumor model and a drug-resistant breast cancer-bearing mouse model with lung metastasis, TPH/PTX nanomicelles exhibited obvious tumor targeting and significant antitumor efficacy. This work presents the potential of a single, nontoxic nanoparticle (NP) platform for mitochondria-targeted delivery of therapeutics for diverse drug-resistant cancers.

Nanoparticle-Based Drug Delivery in Cancer Therapy and Its Role in Overcoming Drug Resistance

“…Mitochondria-targeted NPs (Wang et al, 2020) Hypoxia Silence the HIF-1α gene HIF-1α siRNA (Zhao et al, 2015;Luan et al, 2018;Hajizadeh et al, 2020) Inhibit the function of HIF-1α HIF-1α inhibitors (Reddy et al, 2011) Indirectly downregulate HIF-1α expression Inhibitors of the PI3K/Akt/mtor pathway (Zhang et al, 2018) HSP90 inhibitors (Long et al, 2018) Abbreviations: Bcl-2 = B cell lymphoma-2; COX-2 = cyclooxygenase 2; HIF-1α = hypoxia-inducible factor 1α; HSP90 = heat shock protein 90; NF-κB = nuclear factor kappa B; NPs = nanoparticles; P-gp = P-glycoprotein; PI3K = phosphoinositol-3-kinase; siRNA = small interfering RNA.…”

“…Targeting to mitochondria led to a reduction in ATP production, which is required by ABC transporters. Additionally, paclitaxel-loaded TPP-Pluronic F127-hyaluronic acid nanomicelles caused mitochondrial outer membrane permeabilization (MOMP), which resulted in the release of cytochrome C and activation of caspase-3 and caspase-9, leading to apoptosis of drug-resistant lung cancer cells ( Wang et al, 2020 ).…”

The Dual Role of Macropinocytosis in Cancers: Promoting Growth and Inducing Methuosis to Participate in Anticancer Therapies as Targets

“…TPH/PTX nano-micelles, consist of TPP-Pluronic F127-hyaluronic acid (TPH) and paclitaxel, revealed notable cancer targeting and powerful anticancer effect by entering acidic lysosomes through macropinocytosis in breast cancers ( 178 ). PLGA-lysoGM1/DOX nano-micelles, a new nano-carrier, exhibited efficient cell absorbing through macropinocytosis, autophagy/lysosomal approach, and immense potential to treat neurologic diseases such as glioma ( 179 ).…”

Mitochondrial nanotargeting in malignancies (Review)

“…Wang et al (50) developed nanomicelles loaded with paclitaxel and functionalized with a mitochondria-targeting group (triphenyl phosphine, TPP). As in the previous study, they also used A549 cells which were exposed to their nanomaterial, showing that the positively charged nanomicelles could be localized at the mitochondrial level at 24 h after exposure.…”

“…In cancerous cells this phenomenon does not occur, therefore cellular death appears late. Wang et al (50) studied the mitochondrial pathways of apoptosis, demonstrating that releasing cytochrome c represents an important event in a cancer cell exposed to nanomaterials. In their study, as mentioned above, nanomicelles functionalized with TPP for mitochondrial targeting, causing cytochrome C release which led to apoptosis of malignant cells.…”