5-Fluorouracil (5-FU) is a standard treatment option for colorectal cancer (CRC) but its rapid metabolism and systemic instability (short half-life) has hindered its therapeutic efficacy. The objective of this study was to develop a novel drug delivery system, solid lipid nanoparticle (SLN), capable of delivering high payload of 5-FU to treat CRC. The rational was to improve 5FU-nanocarrier compatibility and therapeutic efficacy. The SLN-loaded 5-FU was developed by utilizing a Strategic and unique Method to Advance and Refine the Treatment (SMART) of CRC through hot and cold homogenization approach. The SLN was made of unique PEGylated lipids and combination of the surfactants. Cytotoxicity studies, clonogenic assay, flow cytometry and confocal imaging were conducted to evaluate the effectiveness and cellular uptake of 5FU-SLN₄ in HCT-116 cancer cells. Pharmacokinetic (PK) parameters and receptor expressions were determined while tumor efficacy studies were conducted on mouse bearing subcutaneous HCT-116 cancer. Among the all the formulations, 5FU-SLN₄ was the most effective with particle size of was 263 ± 3 nm, zeta potential was 0.1 ± 0.02 and entrapment efficiency of 81 ± 10%. The IC₅₀ value of 5FU-SLN₄ (7.4 ± 0.02 µM) was 2.3 fold low compared with 5-FU (17.7 ± 0.03 µM). For tumor efficacy studies, 5FU-SLN₄ significantly inhibited tumor growth in comparison to 5-FU while area-under plasma concentration-time curve (AUC) of 5FU-SLN₄ was 3.6 fold high compared with 5-FU. HER2 receptors expression were markedly reduced in 5-FU-SLN₄ treated mice compared with 5FU and liver and kidney tissues showed no toxicity at dose of 20 mg/kg. 5FU-SLN₄ was highly cytotoxic against HCT-116 cells and significantly inhibited subcutaneous tumor growth in mice compared with 5-FU. This emphasizes the significance of developing a smart nano-delivery system to optimize the delivery efficiency of anticancer drugs to tumors.

This study investigated the cytotoxic effects of gemcitabine-loaded solid lipid nanoparticle (Gem-SLN) on the patient-derived primary pancreatic cancer cell lines (PPCL-46) and MiaPaCa-2. Different SLN formulations were prepared from glyceryl monostearate (GMS), polysorbate 80 (Tween® 80) and poloxamer 188 (Pol 188) as surfactants using a cold homogenization method. Gem-SLN was characterized for particle size and charge distribution, entrapment efficiency and loading capacity. Fourier Transform Infra-Red (FTIR) spectroscopy was used to verify Gem and SLN interaction while differential scanning calorimetry (DSC) was used to acquire thermodynamic information on Gem-SLN. Cytotoxicity studies was conducted on PPCL-46 cells and Mia-PaCa-2 cells. Among the different Gem-SLN formulations prepared, Gem-SLN₁₅ was selected based on entrapment efficiency (EE) of Gem, loading efficiency of Gem, cytotoxicity and rate of Gem release. Growth inhibition of Gem-SLN₁₅-treated PPCL-46 culture (IC₅₀ (2D) =27± 5 μM; IC₅₀ (3D) = 66 ± 2 μM) was remarkably higher than gemcitabine hydrochloride (GemHCl)-treated PPCL-46 culture (IC₅₀ (2D) =126±3 μM; IC₅₀ (3D) =241±3 μM). Similar trend of higher Gem-SLN₁₅ inhibition in MiaPaCa-2 culture was found (IC₅₀ (2D) =56±16 μM; IC₅₀ (3D) =127±4 μM) compared with GemHCl-treated Mia-PaCa-2 culture (IC₅₀ (2D) =188±46 μM; IC₅₀ (3D) =254±52 μM). The anticancer activity of Gem-SLN₁₅ was significantly more effective than GemHCl in PPCL-46 compared to Mia-PaCa-2 cancer cells.

We summarize the risk factors that may significantly contribute to racial disparities in pancreatic cancer, which is now the third leading cause of cancer deaths and projected to be second around 2030 in 12 years. For decades, the incidence rate of pancreatic cancer among Blacks has been 30% to 70% higher than other racial groups in the United States and the 5-year survival rate is approximately 5%. Diabetes and obesity have been identified as potentially predisposing factors to pancreatic cancer and both are more common among Blacks. Smoking continues to be one of the most important risk factors for pancreatic cancer and smoking rates are higher among Blacks compared to other racial groups. The overall risk of pancreatic cancer due to changes in DNA is thought to be the same for most racial groups; however, DNA methylation levels have been observed to be significantly different between Blacks and Whites. This finding may underlie the racial disparities in pancreatic cancer. Identification and prevention of these factors may be effective strategies to reduce the high incidence and mortality rates for pancreatic cancer among Blacks.

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Drug delivery into the brain has for long been a huge challenge as the blood–brain barrier (BBB) offers great resistance to entry of foreign substances (with drugs inclusive) into the brain. This barrier in healthy individuals is protective to the brain, disallowing noxious substances present in the blood to get to the brain while allowing for the exchange of small molecules into the brain by diffusion. However, BBB is disrupted under certain disease conditions, such as cerebrovascular diseases including acute ischemic stroke and intracerebral hemorrhage, and neurodegenerative disorders including multiple sclerosis (MS), Alzheimer’s disease (AD), Parkinson’s disease (PD), and cancers. This review aims to provide a broad overview of present-day strategies for brain drug delivery, emphasizing novel delivery systems. Hopefully, this review would inspire scientists and researchers in the field of drug delivery across BBB to uncover new techniques and strategies to optimize drug delivery to the brain. Considering the anatomy, physiology, and pathophysiological functioning of the BBB in health and disease conditions, this review is focused on the controversies drawn from conclusions of recently published studies on issues such as the penetrability of nanoparticles into the brain, and whether active targeted drug delivery into the brain could be achieved with the use of nanoparticles. We also extended the review to cover novel non-nanoparticle strategies such as using viral and peptide vectors and other non-invasive techniques to enhance brain uptake of drugs. Graphical 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.