“…In this study, we synthesized a series of CA4 prodrugs with fatty chains attached at the 3′-position of the CA4 B-ring varying in length (ie, 6, 10, 14, 16, and 18 carbons) as a model drug, and prepared the prodrugs as liposomes to study the release of the parent drug. To the best of our knowledge, this was the first study to investigate the in vitro release and conversion of CA4-prodrug lipid in plasma with regard to the length of the fatty chain 24,27–29. In addition, the in vitro experiments were designed to investigate the relationship between the release trend and in vivo pharmacokinetics, biodistribution, and antitumor effect.…”
PurposeThe objective of the present study was to develop a liposomal drug delivery system based on combretastatin A4 (CA4) prodrugs modified with varying alkyl chains and investigate the in vitro drug conversion from prodrug and in vivo antitumor effect.MethodsThe prodrug of CA4 was synthesized with stearyl chloride (18-carbon chain), palmitoyl chloride (16-carbon chain), myristoyl chloride (14-carbon chain), decanoyl chloride (10-carbon chain), and hexanoyl chloride (6-carbon chain) at the 3′-position of the CA4. Subsequently, it was encapsulated with liposomes through the thin-film evaporation method. Furthermore, the characteristics of prodrug-liposome were evaluated using in vitro drug release, conversion, and cytotoxicity assays, as well as in vivo pharmacokinetic, antitumor, and biodistribution studies.ResultsThe liposome system with loaded CA4 derivatives was successfully developed with nano-size and electronegative particles. The rate of in vitro drug release and conversion was reduced as the fatty acid carbon chain lengthened. On the contrary, in vivo antitumor effects were improved with the enlargement of the fatty acid carbon chain. The results of the in vivo pharmacokinetic and tissue distribution studies indicated that the reduced rate of CA4 release with a long carbon chain could prolong the circulation time and increase the drug concentration in the tumor tissue.ConclusionThese results suggested that the release or hydrolysis of the parent drug from the prodrug was closely related with the in vitro and in vivo properties. The slow drug release of CA4 modified with longer acyl chain could prolong the circulation time and increase the concentration of the drug in the tumor tissue. These effects play a critical role in increasing the antitumor efficacy.
“…In this study, we synthesized a series of CA4 prodrugs with fatty chains attached at the 3′-position of the CA4 B-ring varying in length (ie, 6, 10, 14, 16, and 18 carbons) as a model drug, and prepared the prodrugs as liposomes to study the release of the parent drug. To the best of our knowledge, this was the first study to investigate the in vitro release and conversion of CA4-prodrug lipid in plasma with regard to the length of the fatty chain 24,27–29. In addition, the in vitro experiments were designed to investigate the relationship between the release trend and in vivo pharmacokinetics, biodistribution, and antitumor effect.…”
PurposeThe objective of the present study was to develop a liposomal drug delivery system based on combretastatin A4 (CA4) prodrugs modified with varying alkyl chains and investigate the in vitro drug conversion from prodrug and in vivo antitumor effect.MethodsThe prodrug of CA4 was synthesized with stearyl chloride (18-carbon chain), palmitoyl chloride (16-carbon chain), myristoyl chloride (14-carbon chain), decanoyl chloride (10-carbon chain), and hexanoyl chloride (6-carbon chain) at the 3′-position of the CA4. Subsequently, it was encapsulated with liposomes through the thin-film evaporation method. Furthermore, the characteristics of prodrug-liposome were evaluated using in vitro drug release, conversion, and cytotoxicity assays, as well as in vivo pharmacokinetic, antitumor, and biodistribution studies.ResultsThe liposome system with loaded CA4 derivatives was successfully developed with nano-size and electronegative particles. The rate of in vitro drug release and conversion was reduced as the fatty acid carbon chain lengthened. On the contrary, in vivo antitumor effects were improved with the enlargement of the fatty acid carbon chain. The results of the in vivo pharmacokinetic and tissue distribution studies indicated that the reduced rate of CA4 release with a long carbon chain could prolong the circulation time and increase the drug concentration in the tumor tissue.ConclusionThese results suggested that the release or hydrolysis of the parent drug from the prodrug was closely related with the in vitro and in vivo properties. The slow drug release of CA4 modified with longer acyl chain could prolong the circulation time and increase the concentration of the drug in the tumor tissue. These effects play a critical role in increasing the antitumor efficacy.
Increasing understanding of the pathogenesis of rheumatoid arthritis (RA) has remarkably promoted the development of effective therapeutic regimens of RA. Nevertheless, the inadequate response to current therapies in a proportion of patients, the systemic toxicity accompanied by long-term administration or distribution in non-targeted sites and the comprised efficacy caused by undesirable bioavailability, are still unsettled problems lying across the full remission of RA. So far, these existing limitations have inspired comprehensive academic researches on nanomedicines for RA treatment. A variety of versatile nanocarriers with controllable physicochemical properties, tailorable drug release pattern or active targeting ability were fabricated to enhance the drug delivery efficiency in RA treatment. This review aims to provide an up-to-date progress regarding to RA treatment using nanomedicines in the last 5 years and concisely discuss the potential application of several newly emerged therapeutic strategies such as inducing the antigen-specific tolerance, pro-resolving therapy or regulating the immunometabolism for RA treatments.
“…NΦs play a significant role not only in the inflammation and autoimmune reactions [ 45 ] but also in cancer. [ 46–48 ] NΦ contribution to the tumor progression is dual: they can promote [ 49–51 ] or inhibit [ 52–55 ] tumor growth.…”
Section: In Search Of the Optimal Cell Carrier For Nanoparticle Deliverymentioning
confidence: 99%
“…In vivo studies provide a mechanistic understanding of how NΦs can help to increase the concentration of NPs in the target tissue. So far, the efficacy of NΦ‐based drug delivery has been proved for curing inflammation, [ 144–149 ] stroke, [ 150 ] rheumatoid arthritis, [ 45 ] and cancer. [ 148,149,151–160 ] Table 2 summarizes animal studies, where NΦs have been used to enhance NP accumulation in tumors.…”
Section: Mechanisms Of Neutrophil‐associated Nanoparticles Delivery: Hitchhiking Cell Following Cell or Mimicking Cellmentioning
The application of cell carriers for transporting nanodrugs to the tumor draws much attention as the alternative to the passive drug delivery. In this concept, the neutrophil (NΦ) is of special interest as this cell is able to uptake nanoparticles (NPs) and cross the vascular barrier in response to tumor signaling. There is a growing body of literature describing NP–NΦ interactions in vitro and in vivo that demonstrates the opportunity of using these cells to improve the efficacy of cancer therapy. However, a number of conceptual and technical issues need to be resolved for translating the technology into clinics. The current review summarizes the recent advances and challenges associated with NP–NΦ interactions, with the special focus on the complex interplay between the NP internalization pathways and the modulation of NΦ activity, and its potential consequences for nanodrug delivery.
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