Size Control and Biological Properties of PAMAM-Cored Multiarm Block Copolymers

Abstract

Size is one of the crucial factors influencing the biological properties of nanomedicines. However, the size control of nanomaterials is still very challenging, and the size effect on their biological properties is worth studying. Herein, we present the synthesis and size control of a series of multiarm block copolymers with the third-generation PAMAM (G3 PAMAM) as the core. The multiarm copolymers were synthesized by the ring-opening polymerization of N-carboxyanhydride of the L-glutamic acid-5tert-butylester [Glu(OtBu)-NCA] monomer with the amineterminated PAMAM as the initiator, followed by the synthesis of the poly(carboxybetaine) (PCB) block via the atom transfer radical polymerization of the 2-(dimethylamino)ethyl methacrylate monomer, the reaction with tert-butyl bromoacetate, and the deprotection of the tert-butyl ester groups. The polyglutamic acid (PGA) block provided abundant reactive groups for the functionalization of the multiarm block copolymers, and the PCB block imparted excellent water solubility and anti-protein adsorption capability. We synthesized three multiarm copolymers with diameters of 15, 24, and 41 nm, respectively, by tuning the polymerization degrees of the arms. Doxorubicin was coupled to the PGA block through the acylhydrazone linkage, which resulted in a pH-sensitive drug release and a drug loading of over 20%. We systematically investigated the size effects on their cellular uptake, cytotoxicity, endocytic pathway, biodistribution, tumor penetration, and antitumor activity. This work is helpful for the design of polymeric nano-drug carriers for tumor therapy.

Enhancing the tumor penetration of multiarm polymers by collagenase modification

“…The third-generation (G3) PAMAM-cored multiarm copolymer DP-1 was synthesized following the procedures published in our previous work. 49 As shown in Scheme 1, to conjugate Col to the multiarm copolymers, we introduced first an azido group at the end of each arm through the reaction with NaN 3 , and then a linker with an alkynyl group and a maleimide group through Cu( i )-catalyzed alkyne–azide 1,3-dipolar cycloaddition (CuAAC), affording DPMal. The acylhydrazine groups in DPMal were used to link the antitumor drug DOX through the acid-sensitive acylhydrazone linkage, affording DPDMal.…”

“…The DP-1 and DPD-1 were synthesized following the procedures published in our previous work. 49 2.4 Synthesis of PAMAM-PGA 20 -b-PCB 37 -N 3 PAMAM-PGA 20 -b-PCB 37 (2 g, 5.57 μmol), NaN 3 (232 mg, 3.57 mmol), and TEA (364 mg, 3.59 mmol) were dissolved in 20 mL of water and stirred at 70 °C for 3 days. Thereafter, the mixture was dialyzed against water using a dialysis membrane with a molecular weight cutoff of 14 kDa for 2 days.…”

“…The third-generation (G3) PAMAM-cored multiarm copolymer DP-1 was synthesized following the procedures published in our previous work. 49 As shown in Scheme 1, to conjugate Col to the multiarm copolymers, we introduced first an azido group at the end of each arm through the reaction with NaN S3. † Furthermore, they also have high colloidal stability in PBS and cell culture media, with no significant change in hydrodynamic diameter over two weeks (Fig.…”