Treatment of non-small cell lung cancer using chem-bioinformatics-driven engineering of exosomal cargo-vehicle for telmisartan and pioglitazone targeted-delivery

Abstract

The activation of the PPARG transcription factor is linked to reduced non-small cell lung cancer (NSCLC) growth. Bioinformatics, cheminformatics, and molecular docking/dynamics studies assessing pioglitazone and telmisartan as repurposed PPARG agonists for treating NSCLC with a targeted delivery system was done. Bioinformatics confirmed that the expression of the PPARG gene can predict outcomes in lung adenocarcinoma and is related to immune cells present in the tumor. Cheminformatics data showed that pioglitazone and telmisartan have a strong attraction to the PPARG receptor, with good efficiency as ligands. Both drugs were found to be lipophilic, suggesting compatibility with a targeted delivery formulation that may include albumin. Further cheminformatics predictions highlighted systemic toxicity values and the need for targeted delivery to minimize toxic side effects. Molecular docking and dynamics simulations showed that the telmisartan-MyoVc cargo domain complex was strong and stable during an 18 ns simulation period. Bioinformatics and cheminformatics data support pioglitazone and telmisartan as promising repurposed drugs for LUAC, highlighting their lipophilicity and compatibility with exosomal components like albumin. Cheminformatics also pointed out potential off-target effects and hepatotoxicity, emphasizing the importance of exosomal targeted delivery. Molecular docking and MD simulations confirmed the affinity and stability of drug-exosomal vehicle complexes. The proposed engineering of exosomal cargo for targeted delivery of these drugs to lung cells could enhance NSCLC treatment and address drug resistance while minimizing systemic toxicity.

Keywords: Bioinformatics; Cheminformatics; Exosomes; In Silico drug repurposing; Lung adenocarcinoma; Molecular Docking; PPARG; Pioglitazone; Targeted delivery; Telmisartan.

Fig. 1

Lung genetic alterations and related pathways retrieved from KEGG, where Ras or ErbB, MAPK, calcium, and PI3K-AKT signaling pathways comprising either oncogenic or tumor suppressor genetic alteration signaling pathways give rise to atypical hyperplasia, then primary and metastatic adenocarcinoma.

Fig. 2

PPARG gene expression based on sample type, from TCGA samples, comparing primary lung tumor (n = 515) to 59 normal samples, by UALCAN, showing statistical significance (A) median gene-level TPM is 19.5 for the lung (green line pointing to 8 o’clock) for 578 samples. (B) violin plot and (C) box plot showing the higher expression of the PPARG gene in lung-normal tissue for 59 cases compared to tumor tissue for 515 cases.

Fig. 3

PPARG gene Expression in transcript/million in LUAD based on histological subtypes (A), individual cancer stages (B), nodal metastasis (C), and TP53 mutation status (D), from TCGA samples. [NOS: Lung Adenocarcinoma-Not Otherwise Specified, Mixed: Lung Adenocarcinoma Mixed subtype, Clear Cell: Lung Clear Cell Adenocarcinoma, LBC-Non mucinous: Lung Bronchioloalveolar Carcinoma Non-mucinous, Solid Pattern Predominant: Lung Solid Pattern Predominant Adenocarcinoma, Acinar: Lung Acinar Adenocarcinoma, LBC-Mucinous: Lung Bronchioloalveolar Carcinoma Mucinous, Mucinous: Mucinous (Colloid) Carcinoma, Papillary: Lung Papillary Adenocarcinoma, Mucinous: Lung Mucinous Adenocarcinoma, Micropapillary: Lung Micropapillary Adenocarcinoma, Signet Ring: Lung Signet Ring Adenocarcinoma. N0: No regional lymph node metastasis, N1: Metastases in 1 to 3 axillary lymph nodes, N2: Metastases in 4 to 9 axillary lymph nodes, N3: Metastases in 10 or more axillary lymph nodes, nodal metastasis is not available for 1 sample, NX: cancer in nearby LN cannot be measured in 11 samples.].

Fig. 4

Heatmap of the expression pattern of PPARG and other input genes in LUAD is positively correlated to the PPARG gene.

Fig. 5

Different immune infiltrating cell expression levels in LUAD samples retrieved from ImmuneCellAI. (A) Pairwise correlation values matrix for exploring the immune infiltration cells abundance in 576 samples, and (B) Heatmap presentation of the immune infiltrating cell expression levels in LUAC.

Fig. 6

Correlation values of PPARG gene expression level (expressed as log2 TPM) with the tumor immune infiltration cells level in LUAD.

Fig. 7

(A) The GeneMANIA presentation of PPARG’s protein-protein interaction (PPI) network shows networks for physical interactions between genes as pink lines, co-expression as violet lines, predictions as yellow lines, common route pathways as light blue lines, and genetic interactions as green lines. Additionally, shared protein domains were considered when examining these protein relationships. (B) The STITCH presentation of PPARG predicted functional partners’ networks.

Fig. 8

Affinity in complex with Cargo domain of MyoVc (pdb entry 4L8T) vesicles (exosomes) (upper panel) and in complex with albumin (pdb entry 1HK1) (middle panel) compared to albumin carrying T4 (the original ligand) (lower figure). Blue and green dotted arrows and green dots present hydrophobic interactions and hydrogen bonding forces.

Fig. 8

Affinity in complex with Cargo domain of MyoVc (pdb entry 4L8T) vesicles (exosomes) (upper panel) and in complex with albumin (pdb entry 1HK1) (middle panel) compared to albumin carrying T4 (the original ligand) (lower figure). Blue and green dotted arrows and green dots present hydrophobic interactions and hydrogen bonding forces.

Fig. 9

Human MyoVc Cargo Binding Domain and Telmisartan Solvated (upper panel) complex top and side views and equilibrated complex (lower panel) shown in a carton view or with a white surface view with Telmisartan in blue within the pink binding pocket.

Fig. 10

The RMSD graph for the human (A) MyoVc Cargo Binding Domain and Telmisartan complex, (B) MyoVc Cargo Binding Domain protein only, and (C) Telmisartan.

Fig. 11

The average atomic fluctuations (Beta Factor) of the Human MyoVc Cargo Binding Domain protein during the molecular dynamic simulations.