Pharmacokinetics of lipid-drug conjugates loaded into liposomes

Signorell, Rea Deborah; Luciani, Paola; Brambilla, Davide; Leroux, Jean‐Christophe

doi:10.1016/j.ejpb.2018.04.003

Cited by 47 publications

(23 citation statements)

References 98 publications

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“…The high hydrophobicity of LDCs that allows for high drug loading also significantly hinders compound dissolution into aqueous media. However, similar studies that have incorporated LDCs into liposomal membranes demonstrated that these complexes release from the particles by transferring to other lipid membranes upon direct contact . We believe that the mechanism of release of our system relies on drug transfer between the particles, the macrophage lipid membranes, and eventually the lipid membranes of the neighboring cells.…”

Section: Resultssupporting

confidence: 76%

Macrophage‐Mediated Delivery of Hypoxia‐Activated Prodrug Nanoparticles

Evans

Shields

Krishnan

et al. 2019

Advanced Therapeutics

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Hypoxia‐activated prodrugs (HAPs) have tremendous clinical potential due to their selective toxicity toward poorly oxygenated tissues, which is a hallmark of solid tumors. Despite their promising results in vitro, HAPs have failed to make a clinical impact. This is largely because tumor hypoxia is located far from blood vessels, making it difficult for HAPs to accumulate in therapeutically sufficient concentrations. Here, a generalized strategy to overcome this barrier by employing macrophages as drug carriers to enhance the penetration and accumulation of HAPs deep in solid tumors is reported. The system leverages the chemotactic and phagocytic abilities of macrophages to improve delivery of nanoparticles encapsulating a model HAP, tirapazamine (TPZ), to the hypoxic regions of solid tumors. A sequence of in vitro assays is used to refine the properties of the system by minimizing carrier cell toxicity while maximizing therapeutic efficacy. It is demonstrated in vivo that the system improves drug accumulation in hypoxic areas of 4T1 breast tumors and slows their growth by itself and in combination with irinotecan. The results provide early evidence that macrophages can significantly improve the transport and efficacy of HAPs by improving their tumor penetration, highlighting a potential strategy to advance them into the clinic.

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Section: Resultssupporting

confidence: 76%

Macrophage‐Mediated Delivery of Hypoxia‐Activated Prodrug Nanoparticles

Evans

Shields

Krishnan

et al. 2019

Advanced Therapeutics

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“…The volume of distribution (V) was calculated to reflect the theoretical volume in which SN38 is evenly distributed after injection. 28 The calculated V for SN38-PA liposomes was significantly smaller than that of CPT-11 injection, indicating that the concentration of active SN38 in plasma circulation was greater after the administration of SN38-PA liposomes. Moreover, the mean plasma area under the curve (AUC 0-24 h ) for SN38 after the administration of SN38-PA liposomes was 7.5-fold higher than that after CPT-11 administration.…”

Section: Pharmacokineticsmentioning

confidence: 89%

Novel SN38 derivative-based liposome as anticancer prodrug: an in vitro and in vivo study

Zhang

Yang

et al. 2018

IJN

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BackgroundMany novel drug delivery systems have been extensively studied to exploit the full therapeutic potential of SN38, which is one of the most potent antitumor analogs of camptothecins (CPTs), whose clinical application is seriously hindered by poor water solubility, low plasmatic stability, and severe toxicity, but results are always unsatisfactory.MethodsIn this study, combining the advantages of prodrug and nanotechnology, a lipophilic prodrug of SN38, SN38-PA, was developed by conjugating palmitic acid to SN38 via ester bond at C10 position, and then the lipophilic prodrug was encapsulated into a long-circulating liposomal carrier by film dispersion method.ResultsThe SN38-PA liposomes were characterized as follows: an average particle size of 80.13 nm, an average zeta potential of −33.53 mv, and the entrapment efficiency of 99%. Compared with CPT-11, SN38-PA liposome was more stable in close lactone form, more efficient in conversion rate to SN38, and more potent in cytotoxicity against tumor cells. Pharmacokinetic study showed that SN38-PA liposome had significantly enhanced plasma half-life (t1/2) value of SN38 and increased area under the curve (AUC) of SN38, which was 7.5-fold higher than that of CPT-11. Biodistribution study showed that SN38-PA liposome had more active metabolite SN38 in each tissue. Finally, the pharmacodynamic study showed that SN38-PA liposome had higher antitumor effect with the antitumor inhibition rate of 1.61 times than that of CPT-11.ConclusionThese encouraging data merit further investigation on this novel SN38-PA liposome.

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“…Alternatively, PS contains a negatively charged phosphate group attached to the serine group, giving it an overall negative charge, mainly due to the low (2.2-3.6) pKa of the carboxyl group within the serine [42]. More recently, there is increased research interest in formulations of lipid-drug (or photosensitizer) conjugates to improve the pharmacokinetics and therapeutic index of liposomal therapeutics [43][44][45][46][47]. Similarly, the incorporation of PEG, a polymeric steric stabilizer, is widely used to increase the blood circulation time of liposomal formulations [48,49].…”

Section: Toxicological Evaluation Of Liposomes and Their Building Blocksmentioning

confidence: 99%

Immunological and Toxicological Considerations for the Design of Liposomes

et al. 2020

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Liposomes hold great potential as gene and drug delivery vehicles due to their biocompatibility and modular properties, coupled with the major advantage of attenuating the risk of systemic toxicity from the encapsulated therapeutic agent. Decades of research have been dedicated to studying and optimizing liposomal formulations for a variety of medical applications, ranging from cancer therapeutics to analgesics. Some effort has also been made to elucidate the toxicities and immune responses that these drug formulations may elicit. Notably, intravenously injected liposomes can interact with plasma proteins, leading to opsonization, thereby altering the healthy cells they come into contact with during circulation and removal. Additionally, due to the pharmacokinetics of liposomes in circulation, drugs can end up sequestered in organs of the mononuclear phagocyte system, affecting liver and spleen function. Importantly, liposomal agents can also stimulate or suppress the immune system depending on their physiochemical properties, such as size, lipid composition, pegylation, and surface charge. Despite the surge in the clinical use of liposomal agents since 1995, there are still several drawbacks that limit their range of applications. This review presents a focused analysis of these limitations, with an emphasis on toxicity to healthy tissues and unfavorable immune responses, to shed light on key considerations that should be factored into the design and clinical use of liposomal formulations.

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Pharmacokinetics of lipid-drug conjugates loaded into liposomes

Cited by 47 publications

References 98 publications

Macrophage‐Mediated Delivery of Hypoxia‐Activated Prodrug Nanoparticles

Macrophage‐Mediated Delivery of Hypoxia‐Activated Prodrug Nanoparticles

Novel SN38 derivative-based liposome as anticancer prodrug: an in vitro and in vivo study

Immunological and Toxicological Considerations for the Design of Liposomes

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