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. 2022 Dec 12;12(54):35484-35493.
doi: 10.1039/d2ra06306a. eCollection 2022 Dec 6.

Folic acid functionalization for targeting self-assembled paclitaxel-based nanoparticles

Eleonora Colombo  1 , Davide Andrea Coppini  1 , Simone Maculan  1 , Pierfausto Seneci  1 , Benedetta Santini  1 , Filippo Testa  2 , Lucia Salvioni  2 , Giovanni Maria Vanacore  3 , Miriam Colombo  2 , Daniele Passarella  1
Affiliations

Folic acid functionalization for targeting self-assembled paclitaxel-based nanoparticles

Eleonora Colombo et al. RSC Adv. .

Abstract

Hetero-nanoparticles self-assembled from a conjugate bearing folic acid as the targeting agent, and another bearing paclitaxel as the active agent are reported. Hetero-nanoparticles containing varying percentages of folic acid conjugates are characterised, and their biological activity is determined.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. Schematic representation of targeted hetero-NPs, with folic acid highlighted in detail – pteroic acid in red, l-glutamic acid in blue.
Fig. 2
Fig. 2. Chemical structure of paclitaxel (top, 1) and folic acid conjugates (bottom, 2).
Scheme 1
Scheme 1. Synthesis of conjugate 1. a: DIPEA, HATU, dry THF, rt, 18 h, 30%, b: EDC·HCl, DMAP, rt, 22 h, 52%.
Scheme 2
Scheme 2. Synthesis of linker-self-assembly inducer 12. a: Boc2O, NaOH/diox, rt, 20 h, quant.; b: 3, HATU, DIPEA, dry THF, rt, 23 h, 94%; c: TFA, dry CH2Cl2, 0 °C to rt, 20 h, quant.; d: 8, HATU, DIPEA, dry THF, rt, 21 h, 73%; e: TFA, dry CH2Cl2, 0 °C to rt, 18 h, 90%.
Scheme 3
Scheme 3. Retrosynthetic pathway for target folic acid conjugate 2.
Scheme 4
Scheme 4. Synthesis of l-glutamic acid Cα-TMSE ester 18. a: (1) CDI, dry CH2Cl2, 0 °C to rt, 1 h; (2) TMSEtOH, rt, 19 h, 54%; b: H2, Pd/C, dry EtOH, rt, 3 h, 91%; c: pTsOH·H2O, diox/H2O, 60 °C, 3 h, quant.
Scheme 5
Scheme 5. Synthesis of N-protected, C-activated pteroic acid 17. a: (1) CDI, dry DMSO, 50 °C, 5 h; (2) TMSEtOH, 50 °C, 21 h, 51%.
Scheme 6
Scheme 6. Synthesis of activated protected folic acid. a: MTBD, dry DMSO, rt, 21 h, 33%; b: NHS, EDC, dry DMF, rt, 19 h, 94%.
Scheme 7
Scheme 7. Synthesis of folic acid conjugate 2. a: TEA, dry DMSO, rt, 5 h, 40%; b: (1) 1 M TBAF, dry DMSO, rt, 19 h; (2) 0.2 M NaOAc, dry DMSO, rt, 10 min, 66%.
Fig. 3
Fig. 3. TEM micrographs of nanoparticles formed by self-assembly hNP2. All samples were stained with uranyl acetate solution.
Fig. 4
Fig. 4. Cell viability for HeLa cells treated for 72 h with hNP1 to hNP4 at equivalent PTX concentrations (400 nM to 50 μM), and with self-assembly inducer 5 and free PTX 6 (312.5 nM to 5 μM) as control. Reported values are the mean ± SD (n = 3) normalized against untreated sample.
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