A novel oral micellar fenretinide formulation with enhanced bioavailability and antitumour activity against multiple tumours from cancer stem cells

Abstract

Background An increasing number of anticancer agents has been proposed in recent years with the attempt to overcome treatment-resistant cancer cells and particularly cancer stem cells (CSC), the major culprits for tumour resistance and recurrence. However, a huge obstacle to treatment success is the ineffective delivery of drugs within the tumour environment due to limited solubility, short circulation time or inconsistent stability of compounds that, together with concomitant dose-limiting systemic toxicity, contribute to hamper the achievement of therapeutic drug concentrations. The synthetic retinoid Fenretinide (4-hydroxy (phenyl)retinamide; 4-HPR) formerly emerged as a promising anticancer agent based on pre-clinical and clinical studies. However, a major limitation of fenretinide is traditionally represented by its poor aqueous solubility/bioavailability due to its hydrophobic nature, that undermined the clinical success of previous clinical trials. Methods Here, we developed a novel nano-micellar fenretinide formulation called bionanofenretinide (Bio-nFeR), based on drug encapsulation in an ion-pair stabilized lipid matrix, with the aim to raise fenretinide bioavailability and antitumour efficacy. Results Bio-nFeR displayed marked antitumour activity against lung, colon and melanoma CSC both in vitro and in tumour xenografts, in absence of mice toxicity. Bio-nFeR is suitable for oral administration, reaching therapeutic concentrations within tumours and an unprecedented therapeutic activity in vivo as single agent. Conclusion Altogether, our results indicate Bio-nFeR as a novel anticancer agent with low toxicity and high activity against tumourigenic cells, potentially useful for the treatment of solid tumours of multiple origin. Electronic supplementary material The online version of this article (10.1186/s13046-019-1383-9) contains supplementary material, which is available to authorized users.

<p>A Novel Nanomicellar Combination of Fenretinide and Lenalidomide Shows Marked Antitumor Activity in a Neuroblastoma Xenograft Model</p>

“…A comparison can be made with a nanoformulation of fenretinide recently developed for oral use. 38 In this case, the fenretinide concentrations in tumor xenografts obtained 3 h after administration of 100 mg/kg fenretinide were 3.44 ug/mL (8.78 μM), 1.71 ug/mL (4.36 μM) and 4.98 ug/mL (12.71 μM) in lung cancer, melanoma and colon cancer xenografts, respectively.…”

“…This may also increase drug concentration in tumors as a result of the increased drug-plasma concentration that affords biodistribution of increased drug amounts in the different body compartments, including the tumor site. 38 However, repeated administration of oral nanoformulations is required to achieve high drug levels in tumors that would be comparable to those achieved by a single administration of a lower drug dose using intravenously injected nanoformulations. Therefore, the high fenretinide concentrations obtained in NB tumors by FLnMs and FnMs accounted for the decrease in tumor growth observed with both nanoformulations compared to controls.…”

“…[26][27][28][29] The recent approach of fenretinide nanoencapsulation in amphiphilic macromolecules, polymers or phospholipids, provided high levels of aqueous drug solubilization, bioavailability and absorption at the tumor site. [30][31][32][33][34][35][36][37][38] Preclinical studies on nanoformulations of fenretinide-cyclodextrin complex 37 and fenretinide-phospholipid salts 38 indicated high antitumour activity in cancer stem cells of various origins in vitro, and in tumour xenografts derived from cancer stem cells of lung cancer, colon cancer and melanoma origin. Moreover, higher drug concentrations in blood and tumours were obtained in the absence of toxicity.…”

Sphingolipid Metabolism in Glioblastoma and Metastatic Brain Tumors: A Review of Sphingomyelinases and Sphingosine-1-Phosphate

“…One reason they have not been investigated further in GBM is that their structures make them unlikely to cross the BBB. Lastly, fenretinide (4-HPR), a synthetic retinoid with an early FDA approval for T-cell lymphoma, has been investigated for its ability to increase ceramide production by p53-independent mechanisms in cancer cells [ 173 , 174 , 175 , 176 ]. While 4-HPR has shown promise in vitro, its poor solubility and bioavailability have limited its use clinically, with both of the glioma clinical trials showing no improvement in progression-free survival at the doses administered ( Table 2 ) [ 175 , 177 ].…”

<p>Nanomicellar Lenalidomide–Fenretinide Combination Suppresses Tumor Growth in an <em>MYCN</em> Amplified Neuroblastoma Tumor</p>

“…Fenretinide is active in NB [7][8][9][10] and many other cancer types [11][12][13][14][15][16] by multiple mechanisms, [17][18][19][20][21][22] and it has shown efficacy against cancer stem cells. [23][24][25][26][27][28] Lenalidomide is another alternative antitumor agent currently used in the post-consolidation maintenance therapy of multiple myeloma and other hematological malignances. We selected lenalidomide to combine with fenretinide for its antiangiogenic properties and its acceptable toxicity profile.…”