Metabolite-derived artificial polymers designed for drug targeting, cell penetration and bioresorption.
The use of poly(beta-malic acid) and poly(l-lysine citramide) carriers to transport doxorubicin (Dox) within K562 myeloblastic cells was studied by taking advantage of laser microspectrofluorometry (L-MSF). This technique provided a means to monitor and to quantify the penetration of Dox molecules in the cytoplasm and in the nucleus of Dox-sensitive and Dox-resistant cells. Comparison was made between polymer-drug conjugates more or less hydrophobised by C2, C7 and C12 aliphatic substituents and by the Dox attached to the polymer backbone as pendent chains. Furthermore, a method was proposed to introduce a cleavable non-peptidic spacer of the lactyllactyl-type between the poly(L-lysine citramide) backbone and the drug. It is shown that: Dox was released from the conjugates by a non-enzymatic route in the absence of cells, the Dox-uptake by cells was slower for the conjugates than for the free drug, and the hydrophobisation promoted the penetration of the released drug within the nucleus, even in the case of Dox-resistant cells. However, no reversion of the resistance was observed.
Abdellaoui
K
K
CRBA URA CNRS 1465, Faculty of Pharmacy, Montpellier I University, 15, Ave. Charles Flahault, 34060 Montpellier, France.
Boustta
M
M
Vert
M
M
Morjani
H
H
Manfait
M
M
D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D008293:Malates / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011107:Polylysine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011108:Polymers / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D013050:Spectrometry, Fluorescence / Q000379:methods
D008293:Malates; D011108:Polymers; C510489:poly(lysine citramide); C121060:poly(malic acid); D011107:Polylysine; D004317:Doxorubicin