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Article Winner: Mitochondria Targeting Strategies for Anticancer Therapy

VANASHREE CHAUDHARI
INSTITUTE OF CHEMICAL TECHNOLOGY
pht20vh.chaudhari@pg.ictmumbai.edu.in

Cancer treatment, including chemotherapy with cytotoxic drugs, has several drawbacks, such as drug toxicity, nonselective distribution, and unexpected side effects to healthy tissues. Since the late 1990s, cancer-related mortality showed a steady decline due to the introduction of targeted therapies. Intracellular drug delivery is an important therapeutic area for cancer therapy. Intracellular drug delivery increases intracellular drug concentration, improves efficacy, and reduces toxicity. The abnormal growth of blood vessels in tumors called uncontrolled angiogenesis leaves avascular spaces with a pore diameter of around several hundred nanometres. So, nanocarriers can pass through these pores to reach the cancerous tissues and cannot pass through the healthy blood vessel wall. Following are a few of the strategies for anticancer therapy:

1.CD44, i.e., a cluster differentiation 44, is a multi-structural and multifunctional cell surface molecule. It is involved in cell differentiation, cell proliferation, cell migration, and angiogenesis. CD44 exhibits a tremendous expression level in many cancerous cells compared to healthy cells, and hence it is considered a potential therapeutic target for cancer therapy. Hyaluronic acid can specifically target CD44 receptors. Hyaluronic acid‑coated chitosan nanoparticles were used to encapsulate 5-fluorouracil. The nanoparticles enhanced drug accumulation in cancer cells and improved the drug’s anticancer efficiency by achieving targeted drug delivery via CD44. Also, due to the generation of reactive oxygen species (ROS), mitochondrial damage was induced, which activated the apoptotic pathway, thus enhancing the drug’s synergistic anticancer effects.

2.Janus mesoporous silica nanoparticles (JMSNP) were used for experimentation of targeting mitochondria in prostate cancer cells. JMSNP carries two different targeting moieties, each located in one hemisphere of the particle. Here, one-half of the nanoparticle’s surface is anchored with folic acid (FA) for cellular targeting as folate receptors are overexpressed in the human prostate cancer cells, and the second half of the nanoparticle’s surface is anchored with TPP for mitochondrial targeting. Finally, these carriers are loaded with topotecan which causes damage to nuclear and mitochondrial DNA by inhibiting DNA topoisomerase I. Consequently, topotecan-loaded JMSNP showed selective uptake and improved the efficacy in anticancer therapy.

3.TPP-poly (ethylene glycol)-poly(ε-caprolactone) (TPP-PEG-PCL) micelles were synthesized for the delivery of gallic acid (GA) into mitochondria of cancer cells. The mitochondria targeting and pro-apoptotic effects of GA-loaded TPP-PEG-PCL micelles were evaluated in lung cancer cells. Micelles showed considerable drug loading, stability, well-defined spherical structure, and improved cellular uptake. GA-TPP-PEG-PCL micelles exhibited an enhanced cytotoxic effect against A549 cells and induced apoptosis at a higher rate by inhibiting the expression of apoptosis-related proteins. Therefore, inducing apoptosis via the mitochondrial signaling pathway GA-TPP micelle system would be a promising strategy to treat lung cancers.

4.Mitochondria pH value is around 8.0 in a cancerous cell. A lipophilic cation (4-carboxybutyl) TPP bromide (CTPP) were conjugated with glucolipid-like conjugates (CSOSA) for mitochondrial-targeted conjugates (CTPP-CSOSA). CTPP-CSOSA/Celastrol micelles selectively accumulated in mitochondria of cancer cells and mitochondrial alkaline pH environment is responsible for fast drug release, further resulting in apoptosis of cancerous cells. Hence, CTPP-CSOSA/Celastrol micelles improve the tumor treating efficiency by responding to the mitochondrial alkaline pH environment, representing a potential therapy for cancer treatment.

5.DOX was packaged into a liposome for mitochondrial delivery. These liposomes contained 1,2-dioleoylsn-glycero-3-phosphatidylethanolamine, sphingomyelin, and cholesterol in the ratio 9:2:1, 1,2-distearoyl sn-glycero-3-phosphoethanolamine and stearylated octarginine localized in the mitochondria. After the mitochondrial delivery of DOX, mitochondrial functions were suppressed by mitochondrial injury, and ATP production activity in both mitochondria and the cytosol was reduced at an early stage, finally resulting in ATP deficiency and then leading to cell death. Thus, using this liposome system for DOX leads to an innovative anticancer activity strategy via mitochondrial targeting.

6.Targeting ligand triphenylphosphonium (TPP) was conjugated on the outer surface of the mesoporous silica nanoparticles (MSNP) loaded with DOX for mitochondria targeting. MSNP-TPP-DOX exhibited a quick and successful escape from lysosomes based on the endocytosis study. The decrease in cellular ATP production and mitochondrial membrane potential demonstrate the direct impairment of the bio-energetic function of mitochondria caused by MSNP-TPP-DOX. As a result, enhanced cancer cell killing efficiency was observed when using MSNP-TPP-DOX.

Reference (Jul-21-A3)

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