Abstract
In numerous studies, liposomes have been used to deliver anticancer drugs such as doxorubicin to local heat-triggered tumor. Here, we investigate: (i) the ability of thermosensitive liposomal nanoparticle (TSLnp) as a delivery system to deliver poorly membrane-permeable anticancer drug, gemcitabine (Gem) to solid pancreatic tumor with the aid of local mild hyperthermia and, (ii) the possibility of using gadolinium (Magnevist®) loaded-TSLnps (Gd-TSLnps) to increase magnetic resonance imaging (MRI) contrast in solid tumor. In this study, we developed and tested gemcitabine-loaded thermosensitive liposomal nanoparticles (Gem-TSLnps) and gadolinium-loaded thermosensitive liposomal nanoparticles (Gd-TSLnps) both in in-vitro and in-vivo. The TSLnps exhibited temperature-dependent release of Gem, at 40–42°C, 65% of Gem was released within 10 min, whereas < 23% Gem leakage occurred at 37°C after a period of 2 h. The pharmacokinetic parameters and tissue distribution of both Gem-TSLnps and Gd-TSLnps were significantly greater compared with free Gem and Gd, while Gem-TSLnps plasma clearance was reduced by 17-fold and that of Gd-TSLpns was decreased by 2-fold. Area under the plasma concentration time curve (AUC) of Gem-TSLnps (35.17± 0.04 μghr/mL) was significantly higher than that of free Gem (2.09 ± 0.01 μghr/mL) whereas, AUC of Gd-TSLnps was higher than free Gd by 3.9 fold high. TSLnps showed significant Gem accumulation in heated tumor relative to free Gem. Similar trend of increased Gd-TSLnps accumulation was observed in non-heated tumor compared to that of free Gd; however, no significant difference in MRI contrast enhancement between free Gd and Gd-TSLnps ex-vivo tumor images was observed. Despite Gem-TSLnps dose being half of free Gem dose, antitumor efficacy of Gem-TSLnps was comparable to that of free Gem(Gem-TSLnps 10 mg Gem/kg compared with free Gem 20 mg/kg). Overall, the findings suggest that TSLnps may be used to improve Gem delivery and enhance its antitumor activity. However, the formulation of Gd-TSLnp needs to be fully optimized to significantly enhance MRI contrast in tumor.
Highlights
Pancreatic cancer (PCa) remains the fourth leading cause of cancer-associated deaths in the United States due to its high malignancy, poor prognosis and profound resistance to chemotherapeutic agents [1,2,3,4]
Our results showed no significant difference in CL and volume of distribution compartment (Vd) between gadolinium chelates (Gd) and Gd-thermosensitive liposomal nanoparticle (TSLnp) CL of Gd appeared to be higher than the CL of Gd-TSLnps
Biodistribution of Gem-TSLnps and Gd-TSLnps showed increased accumulation of Gem in the heated tumor (3.5-fold higher than free Gem, despite a significantly lower drug dose: free Gem 20 mg/kg compared with Gem-TSLnps 10 mg Gem/kg) and this increased in Gem uptake might have led to significant tumor growth inhibition of a MiaPaCa-2 tumor model
Summary
Pancreatic cancer (PCa) remains the fourth leading cause of cancer-associated deaths in the United States due to its high malignancy, poor prognosis and profound resistance to chemotherapeutic agents [1,2,3,4]. The difficulty in detecting tumors early has necessitated the development of highly sensitive agents for noninvasive diagnoses of PDAC at its earliest stages [5]. Conventional low molecular weight paramagnetic agents such as gadolinium chelates (Gd) have over the years found immense applications in tumor visualization and vascular imaging [8]; this approach suffers from rapid extravasation into the extracellular compartment. This translates into a very narrow window for image acquisition that is unachievable in most situations. Contrast enhancement is limited and blurred images are the result of the short in vivo half-lives [9, 10]
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