Introduction. Paclitaxel (PTX) is a major chemotherapy drug used for treatment of different types of solid tumors. It belongs to the class of tubulin-targeting drugs, causing interferences in normal function of microtubules during cell division. Devitalized microfragmented adipose tissue (DMAT) was engineered into a biocompatible scaffold for long-term drug delivery of PTX. Thus, pharmacokinetics and pharmacodynamics properties of DMAT uploaded with PTX (DMAT-PTX) was investigated into a mouse model prior to clinical evaluation in pharmaco-oncology. Methods. DMAT was prepared by devitalization (by freezing/thawing procedure) and disaggregation of lipoaspirate obtained by human donors. PTX was internalized by shaking into DMAT prior administration. For the pharmacokinetic and biodistribution experiments, BALB/cOlaHsd mice were injected, either subcutaneously (s.c., n=12) or intraperitoneally (i.p., n=12) with 10 mg/kg of DMAT-PTX. After 2, 24, 72 and 168 hrs post treatment, blood, livers and kidneys from all mice were collected. From mice treated s.c. also the site of DMAT-PTX injection was removed and stored until use. PTX was extracted from samples, either by solid phase extraction or by monophasic liquid extraction, and then analysed in LC-MS/MS. Results. DMAT-PTX after i.p. injections showed a higher Cmax compared to s.c. delivery (1904 vs 279 ng/mL in plasma at 2 h), although after 24 h the plasma levels were higher in s.c. treated animals (19.1 vs 6.1 ng/mL). Similar results were obtained for kidney and liver. In addition, slow release of PTX from DMAT-PTX specimens was demonstrated also by analysing its kinetic disappearance from the site of injection: PTX ranged from 380 µg/g at 2h to 1.5 µg/g at 7 days. Conclusions. The analysis of PTX at the site of DMAT-PTX injection shows that this new lipophilic delivery system is able to produce a slow and long-lasting release of PTX, suggesting its possible application in counteracting tumour relapsing after surgical resection.
In-vivo pharmacokinetic of paclitaxel released by devitalized microfragmented fat tissue: potential application in chemotherapy / M.V. DEI CAS, A. Pessina, P. Mirco, P. Fabio, G. Alessandri, R.C. Paroni. ((Intervento presentato al convegno Riunione dei giovani biochimici dell'area milanese tenutosi a Gargnano nel 2019.
In-vivo pharmacokinetic of paclitaxel released by devitalized microfragmented fat tissue: potential application in chemotherapy
M.V. DEI CAS;A. Pessina;R.C. Paroni
2019
Abstract
Introduction. Paclitaxel (PTX) is a major chemotherapy drug used for treatment of different types of solid tumors. It belongs to the class of tubulin-targeting drugs, causing interferences in normal function of microtubules during cell division. Devitalized microfragmented adipose tissue (DMAT) was engineered into a biocompatible scaffold for long-term drug delivery of PTX. Thus, pharmacokinetics and pharmacodynamics properties of DMAT uploaded with PTX (DMAT-PTX) was investigated into a mouse model prior to clinical evaluation in pharmaco-oncology. Methods. DMAT was prepared by devitalization (by freezing/thawing procedure) and disaggregation of lipoaspirate obtained by human donors. PTX was internalized by shaking into DMAT prior administration. For the pharmacokinetic and biodistribution experiments, BALB/cOlaHsd mice were injected, either subcutaneously (s.c., n=12) or intraperitoneally (i.p., n=12) with 10 mg/kg of DMAT-PTX. After 2, 24, 72 and 168 hrs post treatment, blood, livers and kidneys from all mice were collected. From mice treated s.c. also the site of DMAT-PTX injection was removed and stored until use. PTX was extracted from samples, either by solid phase extraction or by monophasic liquid extraction, and then analysed in LC-MS/MS. Results. DMAT-PTX after i.p. injections showed a higher Cmax compared to s.c. delivery (1904 vs 279 ng/mL in plasma at 2 h), although after 24 h the plasma levels were higher in s.c. treated animals (19.1 vs 6.1 ng/mL). Similar results were obtained for kidney and liver. In addition, slow release of PTX from DMAT-PTX specimens was demonstrated also by analysing its kinetic disappearance from the site of injection: PTX ranged from 380 µg/g at 2h to 1.5 µg/g at 7 days. Conclusions. The analysis of PTX at the site of DMAT-PTX injection shows that this new lipophilic delivery system is able to produce a slow and long-lasting release of PTX, suggesting its possible application in counteracting tumour relapsing after surgical resection.
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