Development and in vivo validation of phospholipid-based depots for the sustained release of bupivacaine

Aleandri, Simone; Rahnfeld, Lisa; Chatzikleanthous, Despo; Bergadano, Alessandra; Bühr, Claudia; Detotto, Carlotta; Fuochi, Sara; Weber-Wilk, Kevin; Schürch, Stefan; Hoogevest, Peter van; Luciani, Paola

doi:10.1016/j.ejpb.2022.11.019

Cited by 7 publications

(5 citation statements)

References 45 publications

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“…This was not seen in our previous study with DPPC/DSPG/chol liposomes exposed to 10 mM divalent cation, where only aggregation was observed [33]. The obvious explanation for this is that the particles in the present study have an enhanced fluid character due to the lack of chol in the bilayer and the formation of polyhedral structures is energetically favourable under the osmotic pressure imposed by external Zn 2+ .…”

Section: Fabrication and Characterisation Of Zinc Aggregated Liposome...contrasting

confidence: 77%

“…Figure 4a) shows that ZnALs could retain the drug for longer than free liposomes with 86% released after 7 days, while 90% of the cargo was released from free liposomes already after 3 days. The use of aggregated liposomes for sustained drug delivery was recently proposed by our group in a study, where bupivacaine's release was retained in vitro by calcium aggregated liposomes and the bioavailability of the drug was increased in vivo [33]. However, the previously reported aggregates needed an outside source of cations to retain the aggregated state and control the drug release.…”

Section: Rapa Release From Znals and Effect On Human Oasfsmentioning

confidence: 99%

“…For these reasons, the utility of small phospholipid-based particles, such as SUVs is in practice limited and the development of new drug delivery systems with larger particle size and ability to sustain the drug release is imperative for better treatment of OA. Our group previously reported the ability of calcium and magnesium cations to aggregate the negatively charged liposomes into larger aggregated liposomes (ALs) forming injectable depots [32] and the resulting slower release of bupivacaine in vitro [33]. In vivo results suggested that the aggregates also increased the drug's area under the curve in plasma compared to the non-depot system and modulated the particle clearance from the injection site.…”

Section: Introductionmentioning

confidence: 99%

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Liposomal aggregates sustain the release of rapamycin and protect cartilage from friction

Bordon

Ramakrishna

Edalat³

et al. 2023

Preprint

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Fibrosis, low-grade inflammation, and increased friction are together with degradation of cartilage key culprits for debilitating pain in osteoarthritis (OA), which is one of the most common chronic diseases of today's aging population. Intraarticular administration of bio-lubricants loaded with a pharmaceutically active component recently showed promise to improve therapy. Liposomes have emerged as exceptional lubricant biomaterial, but their small size leads to rapid clearance from the synovium, causing a need for more frequent administration. We recently developed a liposomal drug delivery system based on aggregation of negatively charged liposomes with physiologically present divalent cations. Here, we expanded our platform by replacing calcium with zinc, reported to exert anti-inflammatory action. The liposomal aggregates extend the release of rapamycin (RAPA) beyond the free liposomes and have a diameter of nearly 100 um, which was previously established to improve retention in synovial joints. Electron microscopy showed that RAPA alters the irregular morphology of liposomal clusters, which are irreversible upon dilution. RAPA recently showed great promise both in vitro and in vivo at protecting the joints from inflammation and cartilage from further degradation. Our study adds to this by showing that RAPA is also able to dampen the fibrotic response in human OA synovial fibroblasts. Finally, the tribological properties were assessed on nano- and macro-scales on silicon surface and ex vivo porcine cartilage, which showed an excellent protective ability of the system against friction on both scales. Taken together, our study shows that liposomal aggregates have the potential of improving local OA therapy.

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Section: Fabrication and Characterisation Of Zinc Aggregated Liposome...contrasting

confidence: 77%

Section: Rapa Release From Znals and Effect On Human Oasfsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Liposomal aggregates sustain the release of rapamycin and protect cartilage from friction

Bordon

Ramakrishna

Edalat³

et al. 2023

Preprint

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“…Liposomal formulations were prepared by the thin film hydration method [ 36 ]. Briefly, an appropriate amount of S80 (325 mM) or DPPC (200 mM) stock solutions in chloroform were transferred in amber glass vials together with aliquots of GEF stock solutions in chloroform.…”

Section: Methodsmentioning

confidence: 99%

3D printing injectable microbeads using a composite liposomal ink for local treatment of peritoneal diseases

Eugster,

Ganguin,

Seidi

et al. 2023

Drug Deliv. and Transl. Res.

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The peritoneal cavity offers an attractive administration route for challenging-to-treat diseases, such as peritoneal carcinomatosis, post-surgical adhesions, and peritoneal fibrosis. Achieving a uniform and prolonged drug distribution throughout the entire peritoneal space, though, is difficult due to high clearance rates, among others. To address such an unmet clinical need, alternative drug delivery approaches providing sustained drug release, reduced clearance rates, and a patient-centric strategy are required. Here, we describe the development of a 3D-printed composite platform for the sustained release of the tyrosine kinase inhibitor gefitinib (GEF), a small molecule drug with therapeutic applications for peritoneal metastasis and post-surgical adhesions. We present a robust method for the production of biodegradable liposome-loaded hydrogel microbeads that can overcome the pharmacokinetic limitations of small molecules with fast clearance rates, a current bottleneck for the intraperitoneal (IP) administration of these therapeutics. By means of an electromagnetic droplet printhead, we 3D printed microbeads employing an alginate-based ink loaded with GEF-containing multilamellar vesicles (MLVs). The sustained release of GEF from microbeads was demonstrated. In vitro studies on an immortalized human hepatic cancer cell line (Huh-7) proved concentration-dependent cell death. These findings demonstrate the potential of 3D-printed alginate microbeads containing liposomes for delivering small drug compounds into the peritoneum, overcoming previous limitations of IP drug delivery. Graphical abstract

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“…9,11 Further, larger liposomes might escape clearance and act as long-acting depot systems. 12,13 Liposomes mainly consist of phosphatidylcholine (PC) lipids, essential for drug delivery due to their biocompatibility and ability to form stable bilayers. 14 Traditional methods of liposome production, such as thin-film hydration and ethanol injection, present challenges in scalability, reproducibility, and control over liposome size and polydispersity (Fig.…”

Section: Introductionmentioning

confidence: 99%

Leveraging machine learning to streamline the development of liposomal drug delivery systems

Eugster,

Orsi,

Buttitta

et al. 2024

Preprint

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Drug delivery systems efficiently and safely administer therapeutic agents to specific body sites. Liposomes, spherical vesicles made of phospholipid bilayers, have become a powerful tool in this field, especially with the rise of microfluidic manufacturing during the COVID-19 pandemic. Despite its efficiency, microfluidic liposomal production poses challenges, often requiring laborious, optimization on a case-by-case basis. This is due to a lack of comprehensive understanding and robust methodologies, compounded by limited data on microfluidic production with varying lipids. Artificial intelligence offers promise in predicting lipid behaviour during microfluidic production, with the still unexploited potential of streamlining development. Herein we employ machine learning to predict critical quality attributes and process parameters for microfluidic-based liposome production. Validated models predict liposome formation, size, and production parameters, significantly advancing our understanding of lipid behaviour. Extensive model analysis enhanced interpretability and investigated underlying mechanisms, supporting the transition to microfluidic production. Unlocking the potential of machine learning in drug development can accelerate pharmaceutical innovation, making drug delivery systems more adaptable and accessible.

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Development and in vivo validation of phospholipid-based depots for the sustained release of bupivacaine

Cited by 7 publications

References 45 publications

Liposomal aggregates sustain the release of rapamycin and protect cartilage from friction

Liposomal aggregates sustain the release of rapamycin and protect cartilage from friction

3D printing injectable microbeads using a composite liposomal ink for local treatment of peritoneal diseases

Leveraging machine learning to streamline the development of liposomal drug delivery systems

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