Tumor-penetrating acetalated dextran nanoparticles capable of tandem delivery of agents for the treatment of lung cancer

Abstract

The overall survival rate for patients with lung cancer is still low and many affected patients are not eligible for the first-line treatments (surgery, chemotherapy, and radiation) for non-small cell lung cancer (NSCLC) due to severe side effects. Paclitaxel (PTX) and cisplatin (CDDP) are two of the most commonly utilized drugs in the treatment of NSCLC. These drugs will be encapsulated in tumor-penetrating polymeric nanoparticles (NP) for application in the treatment of lung cancer. Due to the limitations in the NP system itself where particles are often unable to penetrate into the tumor parenchyma to deliver its dose of drug, little has been seen in terms of an increase in clinical outcome for cancer patients treated with nanoparticles although the significant effort that has gone into the study of chemotherapeutic-loaded nanoparticles. Therefore, there is an imperative need for the development of system capable of tumor penetration. Our aim is to develop and optimize peptide-conjugated polymer nanoparticles which can deliver tandem anticancer agents capable of enhancing the targeting and treatment of NSCLC. Acetalated dextran (Ac-Dex) will be used to encapsulate both PTX and CDDP in NPs which in turn will be conjugated with the tumor-penetrating peptide iRGD. This multifunctional particle will not only release PTX and CDDP in tandem, but will be capable of tumor penetration through a mechanism imparted by the peptide. The parameters of the emulsion-based NP system (size, shape, drug loading, peptide-conjugation, cytotoxicity, penetration into NSCLC tumor spheroids, etc.) have been optimized to ensure effective targeting and delivery.