Tertiary amine mediated targeted therapy against metastatic lung cancer

J Control Release. 2016 Nov 10:241:81-93. doi: 10.1016/j.jconrel.2016.09.013. Epub 2016 Sep 14.

Abstract

In this work, two tertiary amine-derived 4'-demethylepipodophyllotoxin (DMEP) conjugates (DC and DP) have been designed and synthesized using N,N,N'-trimethyl-N'-(4-carboxyl benzyl)-1,3-propanediamine (CPDM) and 4-(4-methylpiperazinomethyl)benzoic acid (PBA) as the targeting ligands. Both DC and DP exhibited strong in vitro cytotoxicity against small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) cell lines. Cellular uptake efficiencies of DC and DP in human alveolar type II epithelial cells were significantly enhanced compared to DMEP and etoposide (VP-16), which were demonstrated to be concentration-, time- and energy-dependent. The active transport process of DC and DP might be mediated by organic cation transporters (OCTs). After systemic administration in mice, both DC and DP selectively accumulated in the lung, displaying the highest Cmax and AUC0-t values of all tested tissues. Compared with DMEP and VP-16, DC and DP remarkably reduced the lung weight and the number of lung metastases of B16 melanoma in mice, and further prolonged the survival of tumor-bearing mice. Also, DC and DP exhibited comparable levels of cell cycle arrest and cell apoptosis. Furthermore, DC and DP demonstrated minimum toxicity towards vital organs and reduced gastrointestinal injury compared to DMEP and VP-16. Taken together, tertiary amine-derived moieties such as CPDM and PBA represent an efficient yet safe strategy to achieve lung-targeted drug delivery.

Keywords: 4-(4-Methylpiperazinomethyl)benzoic acid (PubChem CID: 736532); 4′-Demethylepipodophyllotoxin (PubChem CID: 122797); Etoposide; Etoposide (PubChem CID: 36462); Imipramine (PubChem CID: 3696); Lung cancer; Lung-targeting; Metastatic lung cancer; N,N,N′-trimethyl-1,3-propanediamine (PubChem CID: 78302); Podophyllotoxin; Podophyllotoxin (PubChem CID: 10607); Tert-butyl 4-(chloromethyl) benzoate (PubChem CID: 18959012); Tertiary amine; Tetraethylammonium chloride (PubChem CID: 5946).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects*
  • Benzoates / chemistry*
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mice, Inbred Strains
  • Molecular Structure
  • Molecular Targeted Therapy
  • Piperazines / chemistry
  • Podophyllotoxin / analogs & derivatives*
  • Podophyllotoxin / chemical synthesis
  • Podophyllotoxin / chemistry
  • Podophyllotoxin / therapeutic use
  • Propylamines / chemistry*
  • Structure-Activity Relationship
  • Tissue Distribution
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Benzoates
  • Piperazines
  • Propylamines
  • Podophyllotoxin
  • 4'-demethylepipodophyllotoxin