## 2 Materials and Methods
### Synthesis of L-Glutamine Derivative **4** and **5**
#### 2.3.5 (S)-S(1,4-Diamino-1,5-dioxo-9,12,15-trioxa-6-azaicosan-20-yl)-ethanethiouote 23  
Compound **22** (60 mg, 0.174 mmol) was dissolved in MeOH (1.7 mL, 0.1 M). Thioacetic acid (0.23 mmol) and DPAP (0.035 mmol) were added to this solution and the reaction was stirred at r.t. under UV light exposure at 365 nm. After 2 h, TLC (CH\({}_{2}\)Cl\({}_{2}\)/MeOH/NH\({}_{3}\) (aq) 7.3:0.2) indicated the complete conversion of the starting compound; the reaction was concentrated and the residue was purified by flash chromatography (silica gel, eluent CH\({}_{2}\)Cl\({}_{2}\)/MeOH/NH\({}_{3}\) (aq) 8.5:1.5:0.1). A total of 29 mg (0.07 mmol) of thioester **23** was obtained (47% yield). \({}^{1}\)H NMR (500 MHz, CD\({}_{3}\)OD) \(\delta\) 4.32 (dd, J = 8.4, 5.7 Hz, 1H, H4), 3.66-3.60 (m, 6H, -CH\({}_{2}\)CH\({}_{2}\)O-), 3.60-3.53 (m, 4H, -CH\({}_{2}\)CH\({}_{2}\)O-), 3.47 (t, J = 6.5 Hz, 2H, H12a,b), 3.40 (t, J = 5.4 Hz, 1H, H6a), 3.36 (t, J = 5.5 Hz, 1H, H6b), 2.87 (t, J = 7.3 Hz, 2H, H16a,b), 2.34-2.26 (m, 5H, CH\({}_{3}\)COSCH\({}_{2}\), H2a,b), 2.11-2.01 (m, 1H, H3a), 1.95-1.86 (m, 1H, H3b), 1.63-1.55 (m, 4H, H13a,b, H15a,b) and 1.47-1.39 (m, 2H, H14a,b). \({}^{13}\)C NMR (101 MHz, CD\({}_{3}\)OD) \(\delta\) 197.53 (CH\({}_{3}\)C(O)S-), 173.91 (C5), 173.30 (C1), 72.04, 71.62, 71.56, 71.28, 71.14 and 70.44 (-CH\({}_{2}\)CH\({}_{2}\)O-), 54.38 (C4), 40.39 (C6), 32.56 (C2), 30.62 (C13), 30.52 (CH\({}_{3}\)C(O)S-), 30.17 (C15), 29.77 (C16), 29.10 (C3) and 26.39 (C14). MS: \(m/z=422.6\) [M+H]\({}^{+}\), 444.5 [M+Na]\({}^{+}\). 3.6 (S)-2-Amino-N1-(2-(2-(2-((5-mercaptoptoptop)|oxy)ethoxy)ethoxy)ethyl) pentanediaimide (dimer) **4**  
Compound **23** (10 mg, 0.0237 mmol) was dissolved in 0.6 mL of MeOH (previously degassed under a stream of argon) and 0.06 mmol of sodium methoxide was added. The reaction was stirred at r.t., and after 24 h, a sample of the crude was analyzed by \({}^{1}\)H-NMR to check the complete thioester deprotection. The spectrum clearly indicated the disappearance of the triplet at 2.9 ppm (-CH\({}_{2}\)-SAc) and of the singlet at 2.3 ppm (CH\({}_{3}\)C(O)S-). A new triplet at 2.65 ppm was present, indicating the formation of a disulfide bond. The reaction was then acidified with HCl 1 N (final pH = 6) and the solvent evaporated. The crude was directly used for the preparation of the nanoparticles. \({}^{1}\)H NMR (500 MHz, CD\({}_{3}\)OD) \(\delta\) 4.31 (dd, J = 8.6, 5.6 Hz, 1H, H4), 3.68-3.58 (m, 8H, -CH\({}_{2}\)CH\({}_{2}\)O-), 3.56 (t, J = 5.5 Hz, 2H, -CH\({}_{2}\)CH\({}_{2}\)O-), 3.49 (t, J = 6.5 Hz, 2H, H12a,b), 3.44-3.33 (m, 2H, H6a,b), 2.70 (t, J = 7.2 Hz, 2H, H16a,b), 2.30 (t, J = 7.6 Hz, 2H, H2a,b), 2.11-2.03 (m, 1H, H3a), 1.96-1.90 (m, 1H, 3b), 1.71 (dt, J = 14.7, 7.3 Hz, 2H, H15a,b), 1.65-1.56 (m, 2H, H13a,b) and 1.54-1.43 (m, 2H, H14a,b). \({}^{13}\)C NMR (101 MHz, CDCl\({}_{3}\)) \(\delta\) 174.01 (C5), 173.33 (C1), 72.13, 71.50, 71.47, 71.24, 71.08 and 70.55 (-CH\({}_{2}\)CH\({}_{2}\)O-), 54.49 (C4), 40.33 (C6), 39.54 (C16), 32.55 (C2), 30.26 (C13), 30.00 (C15), 29.01 (C3) and 26.03 (C14). MS: \(m/z=\) 758.1 [M+H]\({}^{+}\). 2.3.7. Tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-5-oxo-9,12,15-trioxa-6-azaicos-19-enoate **24**  
Boc-L-glutamic acid 1-tert-butyl ester (149 mg, 0.49 mmol) and compound **20** (0.58 mmol) were dissolved in CH\({}_{2}\)Cl\({}_{2}\) (4.9 mL, 0.1 M) under argon and 0.98 mmol of Et\({}_{3}\)N was added; the solution was stirred at r.t. for 15 min. The temperature was set to 0 \({}^{\circ}\)C and HOBt (0.73 mmol) and DCC (0.73 mmol) were added. The reaction was stirred at r.t. until TLC (CH\({}_{2}\)Cl\({}_{2}\)/MeOH 9.5:0.5) indicated the disappearance of the starting material. The reaction was recovered as described for compound **22** and the product was purified by flash chromatography (silica gel, eluent CH\({}_{2}\)Cl\({}_{2}\)/MeOH 9.8:0.2), affording compound **24** (207 mg, 0.47 mmol, 95% yield).