Loratadine self-microemulsifying drug delivery systems (SMEDDS) in combination with sulforaphane for the synergistic chemoprevention of pancreatic cancer

Abstract

Pancreatic cancer (PC), currently the third leading cause of cancer-related deaths in the USA, is projected to become the second leading cause, behind lung cancer, by 2020. The increasing incidence, low survival rate, and limited treatment opportunities necessitate the use of alternative approaches such as chemoprevention, to tackle PC. In this study, we report significant synergistic chemoprevention efficacy for the first time from a low-dose combination of a classical antihistaminic drug, Loratadine (LOR) and a neutraceutical compound, Sulforaphane (SFN) using a self-microemulsifying drug delivery system (SMEDDS) formulation. The formulation was developed using Quality by Design approach (globule size, 95.13 ± 7.9 nm; PDI, 0.17 ± 0.04) and revealed significant (p < 0.05) enhancement in the in vitro dissolution profile confirming the enhanced solubility of BCS class II drug LOR with SMEDDS formulation. The LOR-SFN combination revealed ~ 40-fold reduction in IC50 concentration compared to LOR alone in MIA PaCa-2 and Panc-1 cell lines respectively, confirming the synergistic enhancement in chemoprevention. Further, the nanoformulation resulted in ~ 7-fold and ~ 11-fold reduction in IC50 values compared to LOR-SFN combination. Hence, our studies successfully demonstrate that a unique low-dose combination of LOR encapsulated within SMEDDs with SFN shows significantly enhanced chemopreventive efficacy of PC.

Cancer Chemoprevention Using Nanotechnology-Based Approaches

“…Further, an in vivo chemoprevention study using LSL-Kras G12D/+ ; Pdx-1 Cre/+ transgenic mice indicated significant reduction in tumor incidence with the combination nanoformulation compared to control (Sutaria et al, 2012;Thakkar et al, 2013). In another study, self micro-emulsifying drug delivery system (SMEDDS) of classical antihistaminic drug loratadine and sulforaphane was reported with enhanced oral bioavailability and chemoprevention potential in Panc-1 and Mia PaCa-2 PC cell lines (Desai et al, 2019b). Based on similar rational liposomes, dendrimers, micelles of potent chemopreventive phytochemical like curcumin, ellagic acid, etc.…”

“…Pancreatic cancer is the third leading cause of all cancer-related deaths in the United States (American Cancer Society, 2019a). Late diagnosis, faster progression, low 5-year survival rate (merely 9%), and high risk of relapse make pancreatic cancer treatment and management challenging despite available firstline drug treatment involving use of gemcitabine combinations and Folfirinox ® (a drug cocktail of fluorouracil, leucovorin, irinotecan, and oxaliplatin) (Rahman et al, 2017;Malatesta et al, 2018;American Cancer Society, 2019a;Desai et al, 2019a;Desai et al, 2019b). Hence, chemoprevention has gained wide attention as an alternative strategy to control the occurrence and relapse.…”

“…Evidently, the clinical success of these actives is restricted due to drug delivery challenges. Hence, use of smart nano drug delivery systems ensuring in vivo absorption and transportation of such actives at chemoprevention sites using passive and active targeting approaches is gradually coming on the forefront (Siddiqui et al, 2012;Desai et al, 2019a;Desai et al, 2019b). Though nanochemoprevention research is in its infancy, its potential is evident from increasing research in the field and reported scientific literature.…”

MicroRNAs as novel targets of sulforaphane in cancer therapy: The beginning of a new tale?

“…One of the most important ways for reducing or even inhibiting the side effects of sulforaphane is application of nanocarriers. A low concentration of sulforaphane can be loaded on nanocarriers, while its therapeutic impacts are at the highest level (Desai, Thakkar, Ann, Wang, & Prabhu, ; Kamal & Nazzal, ). More importantly, it appears that the beneficial effects of sulforaphane overweigh on its negligible harmful effects.…”

Development of Triptolide Self-Microemulsifying Drug Delivery System and Its Anti-tumor Effect on Gastric Cancer Xenografts

“…Self-microemulsifying drug delivery systems (SMEDDS) refer to a solid or liquid formulation containing oil phases, surfactants, and cosurfactants (10, 11). The O/W microemulsion (particle size ≤ 100 nm) can spontaneously form in the gastrointestinal tract or on slight stirring at 37°C (12–15). SMEDDS represents a new oral drug delivery system that can increase the solubility of water-insoluble drugs and improve the oral absorption and bioavailability of drugs (16, 17).…”