Tumor Stromal Disrupting Agent Enhances the Anticancer Efficacy of Docetaxel Loaded PEGylated Liposomes in Lung Cancer

Abstract

Aim: Therapeutic efficacy of anticancer nanomedicine is compromised by tumor stromal barriers. The present study deals with the development of docetaxel loaded PEGylated liposomes (DTXPL) and to investigate the effect of tumor stroma disrupting agent, telmisartan, on anticancer efficacy of DTXPL. Methods: DTXPL was prepared using proprietary modified hydration method. Effect of oral telmisartan treatment on tumor uptake of coumarin-6 liposomes and anticancer efficacy of DTXPL was evaluated in orthotopic xenograft lung tumor bearing mice. Results: DTXPL (105.7 ± 3.8 nm) showed very high physical stability, negligible hemolysis, 428% enhancement in bioavailability with significantly higher intratumoral uptake. Marked reduction in collagen-I, MMP2/9 and lung tumor weight were observed in DTXPL+telmisartan group. Conclusion: Combination of DTXPL with telmisartan could significantly enhance clinical outcome in lung cancer. Lung cancer is by far the most common cause of cancer related mortality in both men and women. Non-small-cell lung cancer (NSCLC) accounts for 87% of total cases of lung cancer with overall 5-year survival rate less than 18.2% [1,2]. Depending on the stage of lung cancer and condition of patients, the chemotherapeutic regimen for lung cancer includes following drugs: Cisplatin/carboplatin or paclitaxel/docetaxel, etoposide, vinorelbine, erlotinib or other tyrosine kinase inhibitors, gemcitabine and pemetrexed. Despite recent advances in diagnosis and treatment, the clinical outcome amongst NSCLC patients is still not impressive. Docetaxel (DTX) is one the most widely used for drug for the treatment of various types of solid tumor including ovarian, breast, lung and head/neck cancers. Docetaxel has extremely poor water solubility and rapid precipitation tendency, which necessitates very high concentration of ethanol and surfactant for its intravenous injection. Tween 80 in Taxotere ® formulation is responsible for severe life threatening hypersensitivity and peripheral neuropathy [3,4]. A safer formulation to enhance patient compliance and therapeutic efficacy of DTX is always in demand. As a result, current research is mainly focused on developing nanomedicinal formulation such as liposomes, polymeric micelles, albumin nanoparticles, polymer drug conjugates, etc. Liposomes are the most versatile nanocarrier with superior biocompatibility and large scale manufacturing feasibility compared to other types of nanocarrier. Abraxane ® ,

Reversal of drug-resistance by noscapine chemo-sensitization in docetaxel resistant triple negative breast cancer

“…Nos chemo-sensitizing effect can be critically important for enhancing the tumor specific toxicity of DTX liposomes and will help in reducing the dose of DTX and its dose dependent side effects. Docetaxel loaded PEGylated liposomes (DTXPL) were prepared and characterized by our group in non-small cell lung tumor bearing mice 27 .…”

“…Poor availability of anticancer drug and nanocarrier in solid tumor is one of the major limitations in their therapeutic outcome 27 – 29 . In such scenario, stromal disruption could be important for harnessing the potential of anticancer therapy.…”

Honokiol nanomicellar formulation produced increased oral bioavailability and anticancer effects in triple negative breast cancer (TNBC)

“…On the other hand, natural product based anticancer drugs exhibit better safety profile compared to standard anticancer drugs [24,47–50]. Our in vitro studies demonstrated the potential anticancer effects of HNK on different TNBC cells lines.…”

Cholecalciferol-PEG Conjugate Based Nanomicelles of Doxorubicin for Treatment of Triple-Negative Breast Cancer

“…Cellular uptake studies were conducted for DOX and P-gp substrate rhodamine 123 as mentioned in an earlier report with slight modifications (35). Briefly, MDA-MB-231DR cells were seeded in six-well plates at a density of 50,000 cells/well, washed with PBS after 24 h, and treated with DOX (5 μM), free rhodamine 123 (1 μM), and PEGCCF micelles corresponding to an equivalent amount of free DOX and an equivalent amount of rhodamine 123.…”