Abstract
BackgroundAn 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.MethodsHere, 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.ResultsBio-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.ConclusionAltogether, 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.
Highlights
An increasing number of anticancer agents has been proposed in recent years with the attempt to overcome treatment-resistant cancer cells and cancer stem cells (CSC), the major culprits for tumour resistance and recurrence
The thermodynamic stability of the fenretinide-phosphatidylcholine ion pair is the driving force for the formation of micelles characterized by a hydrophobic inner core containing fenretinide and an hydrophilic shell formed by the spontaneous assembling of the phospholipid molecules in water where the ion bridge stabilizes the core-shell interface [24]
Bio-nFeR displays broad antitumour activity in vitro and in vivo, is well tolerated and reaches elevated and pharmacologically active intra-tumour concentrations Given the marked antitumour activity of Bio-nFeR against lung cancer cells in vitro and in vivo and the enhanced systemic exposure compared to the reference fenretinide formulation, we extended the evaluation of its cytotoxic activity in a wide range of concentrations against lung, colon cancer, melanoma, sarcoma and glioblastoma CSC
Summary
An increasing number of anticancer agents has been proposed in recent years with the attempt to overcome treatment-resistant cancer cells and cancer stem cells (CSC), the major culprits for tumour resistance and recurrence. 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. In view of the plasticity of tumour cells, drugs with broad toxicity against different tumour cell populations would to be preferred to achieve long-term antitumour efficacy [40]. Another huge obstacle to treatment efficacy is the inefficient drug absorption into the tumour environment mainly due to low systemic availability which limits the drug distribution to the different body compartments, including the tumor. Designed nanoformulations may offer the possibility of increasing the drug systemic availability, improving the drug concentration at the tumour site to levels suitable at eliciting an antitumour response
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