A solid lipid nanoparticle formulation of 4-(N)-docosahexaenoyl 2′, 2′-difluorodeoxycytidine with increased solubility, stability, and antitumor activity

Valdes, Solange A.; Alzhrani, Riyad F.; Rodriguez, Andres; Lansakara-P, Dharmika S.P.; Thakkar, Sachin G.; Cui, Zhengrong

doi:10.1016/j.ijpharm.2019.118609

Cited by 29 publications

(19 citation statements)

References 39 publications

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“…These results clearly explained why previously described fatty-acid prodrugs of gemcitabine were administered only as organic solution in DMSO, [60][61][62] or mixtures with surface active agents such as Pluronic, 53 polyethylene glycol, 57,63 Cremophor EL (i.e., polyoxyethylene castor oil) 64 or Tween 80. 31,65,66 In spite of their utilization also in clinically approved formulations (e.g., Emend ® , Taxotere ® , PM101 ® , Taxol ® ) [67][68][69] these vehicles are associated to undesired toxicity, and could negatively affect the drug pharmacokinetics thus altering its efficacy. [70][71][72][73][74] In this context, a successful attempt to develop a prodrug formulation in aqueous solvent would be extremely beneficial to face these drawbacks.…”

Section: Nanoparticle Preparation and Characterizationmentioning

confidence: 99%

“…6,21,22 Yet, opportune formulation may be needed to overcome the lack of aqueous solubility of these lipid prodrugs and to allow their systemic administration in a clinically acceptable solvent. In this context, combination with nanoscale carriers has been proposed and lipid prodrugs have been successfully loaded into liposomes, [23][24][25][26][27] solid lipid nanoparticles, [28][29][30][31] micelles [32][33][34] or polymer nanoparticles (NPs). [35][36][37] On the contrary to the above-mentioned strategies, in which the prodrug was encapsulated into other nanocarriers, we have taken advantage of the dynamically folded conformation of squalene, a biocompatible triterpene, for drug conjugation and spontaneous supramolecular assembly as nanoparticles.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Gemcitabine Lipid Prodrugs: The Key Role of the Lipid Moiety on the Self-Assembly into Nanoparticles

et al. 2021

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A small library of amphiphilic prodrugs has been synthetised by conjugation of gemcitabine (Gem) (a hydrophilic nucleoside analogue) to a series of lipid moieties and investigated for their capacity to spontaneously self-assemble into nanosized objects by simple nanoprecipitation. Four of these conjugates formed stable nanoparticles (NPs) while with the others immediate aggregation occurred, whatever the tested experimental conditions. Whether such capacity could have been predicted based on the prodrug physico-chemical features was a matter of question. Among various parameters, the hydrophilic-lipophilic balance HLB value seemed to hold a predictive character. Indeed, we identified a threshold value which well correlated with the tendency (or not) of the synthetised prodrugs to form stable nanoparticles. Such hypothesis was further confirmed by broadening the analysis to gemcitabine and other nucleoside prodrugs already described in the literature. We also observed that in the case of gemcitabine prodrugs, the lipid moiety affected not only the colloidal properties but also the in vitro anticancer efficacy of the resulting nanoparticles.Overall, this study provides a useful demonstration of the predictive potential of the HLB value for lipid prodrug NP formulation and highlights the need of their opportune in vitro screening, as optimal drug loading does not always translate in an efficient biological activity.

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Section: Nanoparticle Preparation and Characterizationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gemcitabine Lipid Prodrugs: The Key Role of the Lipid Moiety on the Self-Assembly into Nanoparticles

et al. 2021

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“…In a metastatic melanoma B16F10 model, treatment with etoposide-loaded SLNs resulted in a significant reduction in lung melanoma metastasis, as well as an increased animal survival rate and reduced systemic toxicity, compared to free etoposide [195]. More recently, Valdes and coworkers [196] formulated in SLNs the lipophilic synthetic compound 4-( N )-docosahexaenoyl 2′,2′-difluorodeoxycytidine (DHA-dFdC). The use of SLNs improved the solubility of the compounds, chemical stability and cytotoxic activity towards melanoma cells.…”

Section: Nanotechnology and Cancer Treatment—tackling Melanomamentioning

confidence: 99%

“…The use of SLNs improved the solubility of the compounds, chemical stability and cytotoxic activity towards melanoma cells. In a B16F10 melanoma model, the developed nanoformulation effectively reduced tumor growth, compared to free DHA-dFdC, unloaded SLNs, control and vehicle-treated experimental groups [196].…”

Section: Nanotechnology and Cancer Treatment—tackling Melanomamentioning

confidence: 99%

Emergent Nanotechnological Strategies for Systemic Chemotherapy against Melanoma

2019

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Melanoma is an aggressive form of skin cancer, being one of the deadliest cancers in the world. The current treatment options involve surgery, radiotherapy, targeted therapy, immunotherapy and the use of chemotherapeutic agents. Although the last approach is the most used, the high toxicity and the lack of efficacy in advanced stages of the disease have demanded the search for novel bioactive molecules and/or efficient drug delivery systems. The current review aims to discuss the most recent advances on the elucidation of potential targets for melanoma treatment, such as aquaporin-3 and tyrosinase. In addition, the role of nanotechnology as a valuable strategy to effectively deliver selective drugs is emphasized, either incorporating/encapsulating synthetic molecules or natural-derived compounds in lipid-based nanosystems such as liposomes. Nanoformulated compounds have been explored for their improved anticancer activity against melanoma and promising results have been obtained. Indeed, they displayed improved physicochemical properties and higher accumulation in tumoral tissues, which potentiated the efficacy of the compounds in pre-clinical experiments. Overall, these experiments opened new doors for the discovery and development of more effective drug formulations for melanoma treatment.

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“…Stearoyl gemcitabine was first synthesized and tested by L. Cattel and coworkers [242,243] and then developed by the group led by Zhengrong Cui [244][245][246]. Cui's group also produced and tested on Panc-1 tumors, both subcutaneous and orthotopically implanted, with good results, a variant with a polyunsaturated "tail", 4-(N)-docosahexaenoyl gemcitabine (4-(N)-docosahexaenoyl 2′,2′-difluorodeoxycytidine; DHA-dFdC) [247,248]. These drugs were usually administered i.v.…”

Section: Gemcitabine (Gem) Lipid Derivativesmentioning

confidence: 99%

Targeting Pancreatic Ductal Adenocarcinoma (PDAC)

Parrasia

Zoratti

Szabó

et al. 2020

Cell Physiol Biochem

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Pancreatic cancers are among the most ominous, and among the most studied. Their complexities have provided ample material for a huge investigative effort, which is briefly surveyed in this review. Eradication by surgery has proven extremely difficult, and a successful chemotherapeutic approach is desperately needed. Treatment with "traditional" anticancer drugs, such as benchmark gemcitabine or the current standard-of-care FOLFIRINOX quaternary combination increase the mean overall survival by only a few months and often leads to chemoresistance. Much work is therefore currently devoted to potentiating our pharmacological weapons by accurate targeting and, in particular, by acting on the dense tumoral stroma, a distinctive feature of PDAC accounting for much of the therapeutic difficulty. We give an overview of recent developments, touching on the major aspects of PDAC physiology and biochemistry, currently-used and experimental drugs, and targeting technologies under development. A few papers are discussed in some detail to help provide a sense of how the field is moving.

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A solid lipid nanoparticle formulation of 4-(N)-docosahexaenoyl 2′, 2′-difluorodeoxycytidine with increased solubility, stability, and antitumor activity

Cited by 29 publications

References 39 publications

Gemcitabine Lipid Prodrugs: The Key Role of the Lipid Moiety on the Self-Assembly into Nanoparticles

Gemcitabine Lipid Prodrugs: The Key Role of the Lipid Moiety on the Self-Assembly into Nanoparticles

Emergent Nanotechnological Strategies for Systemic Chemotherapy against Melanoma

Targeting Pancreatic Ductal Adenocarcinoma (PDAC)

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