Abstract
Biogenic polyamines are essential for cell growth and differentiation, while polyamine analogues exert antitumor activity in multiple experimental model systems, including breast and lung cancer. Dendrimers are widely used for drug delivery in vitro and in vivo. We report the bindings of biogenic polyamines, spermine (spm), and spermidine (spmd), and their synthetic analogues, 3,7,11,15-tetrazaheptadecane.4HCl (BE-333) and 3,7,11,15,19-pentazahenicosane.5HCl (BE-3333) to dendrimers of different compositions, mPEG-PAMAM (G3), mPEG-PAMAM (G4) and PAMAM (G4). FTIR and UV-visible spectroscopic methods as well as molecular modeling were used to analyze polyamine binding mode, the binding constant and the effects of polyamine complexation on dendrimer stability and conformation. Structural analysis showed that polyamines bound dendrimers through both hydrophobic and hydrophilic contacts with overall binding constants of K spm-mPEG-G3 = 7.6×104 M−1, K spm-mPEG-PAMAM-G4 = 4.6×104 M−1, Kspm-PAMAM-G4 = 6.6×104 M−1, K spmd-mPEG-G3 = 1.0×105 M−1, K spmd-mPEG-PAMAM-G4 = 5.5×104 M−1, Kspmd-PAMAM-G4 = 9.2×104 M−1, K BE-333-mPEG-G3 = 4.2×104 M−1, K Be-333-mPEG-PAMAM-G4 = 3.2×104 M−1, KBE-333-PAMAM-G4 = 3.6×104 M−1, K BE-3333-mPEG-G3 = 2.2×104 M−1, K Be-3333-mPEG-PAMAM-G4 = 2.4×104 M−1, KBE-3333-PAMAM-G4 = 2.3×104 M−1. Biogenic polyamines showed stronger affinity toward dendrimers than those of synthetic polyamines, while weaker interaction was observed as polyamine cationic charges increased. The free binding energies calculated from docking studies were: −3.2 (spermine), −3.5 (spermidine) and −3.03 (BE-3333) kcal/mol, with the following order of binding affinity: spermidine-PAMAM-G-4>spermine-PAMMAM-G4>BE-3333-PAMAM-G4 consistent with spectroscopic data. Our results suggest that dendrimers can act as carrier vehicles for delivering antitumor polyamine analogues to target tissues.
Highlights
Polyamine analogues (Fig. 1) exert antitumor activity in multiple experimental model systems, including breast and lung cancer models and they are being used in clinical trials [1,2,3,4,5]
Synthetic polyamines can mimic some of the self-regulatory functions of biogenic polyamines but are unable to substitute for natural polyamines in their growth promoting role [6,7,8,9,10,11,12,13]
The spectral changes observed are attributed to the hydrophilic interactions of polyamine polar groups with dendrimer NH2, C-O and C-N groups
Summary
Polyamine analogues (Fig. 1) exert antitumor activity in multiple experimental model systems, including breast and lung cancer models and they are being used in clinical trials [1,2,3,4,5]. Synthetic polymers with a specific shape and size play important roles in the development of modern drug and gene delivery systems [27,28,29]. Since dendrimers have a large number of terminal groups to which drug molecules can be attached, they can carry drug molecules with a high efficiency. They contain several binding sites for hydrophobic, hydrophilic, cationic and anionic drugs. In developing dendrimers for drug delivery, it is important to use dendrimers with low toxicity and excellent biocompatibility. Dendrimers such as PAMAM (polyamidoamine) and polypropyleneimine (PPI) are toxic. Conjugate formation can alter the binding affinity of dendrimers in general since a part of the functional pendant groups are removed by conjugation
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