Review on the targeted conjugation of anticancer drugs doxorubicin and tamoxifen with synthetic polymers for drug delivery.

In this review, the binding and loading efficacy (LE) of anticancer drugs doxorubicin (DOX), tamoxifen (Tam) and its metabolites 4-hydroxytamoxifen (4-Hydroxytam) and endoxifen (Endox) with several synthetic polymers poly(ethylene glycol) (PEG), methoxypoly (ethylene glycol) polyamidoamine (mPEG-PAMAM-G3), and polyamidoamine (PAMAM-G4) dendrimers were compared in aqueous solution at pH 7.4. The results of multiple spectroscopic methods, transmission electron microscopy (TEM) and molecular modeling of conjugated drug-polymer were examined. Structural analysis showed that drug-polymer conjugation occurs mainly via H-bonding and hydrophobic contacts. The order of binding is PAMAM-G4 > mPEG-PAMAM-G3 > PEG-6000 with 4-hydroxttamoxifen forming more stable conjugate than tamoxifen and endoxifen. Doxorubicin shows stronger affinity for PAMAM-G4 than tamoxifen and its metabolites. The drug LE was 30-55%. TEM showed significant changes in the carrier morphology upon drug encapsulation. Modeling also showed that drug is located in the surface and in the internal cavities of PAMAM with DOX forming more stable polymer conjugates.

Targeted conjugation of breast anticancer drug tamoxifen and its metabolites with synthetic polymers.

Conjugation of antitumor drug tamoxifen and its metabolites, 4-hydroxytamxifen and ednoxifen with synthetic polymers poly(ethylene glycol) (PEG), methoxypoly (ethylene glycol) polyamidoamine (mPEG-PAMAM-G3) and polyamidoamine (PAMAM-G4) dendrimers was studied in aqueous solution at pH 7.4. Multiple spectroscopic methods, transmission electron microscopy (TEM) and molecular modeling were used to characterize the drug binding process to synthetic polymers. Structural analysis showed that drug-polymer binding occurs via both H-bonding and hydrophobic contacts. The order of binding is PAMAM-G4>mPEG-PAMAM-G3>PEG-6000 with 4-hydroxttamoxifen forming more stable conjugate than tamoxifen and endoxifen. Transmission electron microscopy showed significant changes in carrier morphology with major changes in the shape of the polymer aggregate as drug encapsulation occurred. Modeling also showed that drug is located in the surface and in the internal cavities of PAMAM with the free binding energy of -3.79 for tamoxifen, -3.70 for 4-hydroxytamoxifen and -3.69kcal/mol for endoxifen, indicating of spontaneous drug-polymer interaction at room temperature.

Structural analysis of doxorubicin-polymer conjugates.

Synthetic polymers poly(ethylene glycol) (PEG), methoxypoly (ethylene glycol) polyamidoamine (mPEG-PAMAM-G3) and polyamidoamine (PAMAM-G4) dendrimers were used for encapsulation of antibiotic drug doxorubicin (Dox) and its analogue N-(trifluoroacetyl) doxorubicin (FDox) in aqueous solution at pH 7.4. Multiple spectroscopic methods, transmission electron microscopy (TEM) and molecular modeling were used to characterize the drug binding process to synthetic polymers. Structural analysis showed that drug-polymer binding occurs via both H-bonding and hydrophobic contacts. The order of binding is PAMAM-G4>mPEG-PAMAM-G3>PEG-6000 with Dox forming more stable conjugate than FDox. Transmission electron microscopy showed significant changes in carrier morphology with major changes in the shape of the polymer aggregate as drug encapsulation occurred. Modeling also showed that drug is located in the surface and in the internal cavities of PAMAM with the free binding energy of -4.14 kcal/mol for Dox and -3.93 kcal/mol for FDox, indicating of spontaneous drug-polymer interaction at room temperature.

Applications of chitosan nanoparticles in drug delivery.

We have reviewed the binding affinities of several antitumor drugs doxorubicin (Dox), N-(trifluoroacetyl) doxorubicin (FDox), tamoxifen (Tam), 4-hydroxytamoxifen (4-Hydroxytam), and endoxifen (Endox) with chitosan nanoparticles of different sizes (chitosan-15, chitosan-100, and chitosan-200 KD) in order to evaluate the efficacy of chitosan nanocarriers in drug delivery systems. Spectroscopic and molecular modeling studies showed the binding sites and the stability of drug-polymer complexes. Drug-chitosan complexation occurred via hydrophobic and hydrophilic contacts as well as H-bonding network. Chitosan-100 KD was the more effective drug carrier than the chitosan-15 and chitosan-200 KD.

Encapsulation of biogenic and synthetic polyamines by nanoparticles PEG and mPEG-anthracene.

Synthetic polymers play a major role in 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) with poly(ethylene glycol) PEG-3000, PEG-8000 and methoxy poly(ethylene glycol) anthracene (PEG-anthracene). Fourier transform infrared (FTIR), UV-visible and fluorescence spectroscopic were used to analyze polyamine binding mode, the binding constant and the effect of PEG compositions on polyamine-polymer interaction. Structural analysis showed that polyamines bind PEG through hydrophobic and hydrophilic contacts with overall binding constants of Kspm-PEG-3000=3.1×10(4)M(-1), Kspmd-PEG-3000=5.5×10(4)M(-1), KBE-333-PEG-3000=2.5×10(4)M(-1), KBE-3333-PEG-3000=1.5×10(5)M(-1), Kspm-PEG-8000=4.1×10(5)M(-1), Kspmd-PEG-8000=7.5×10(5)M(-1), KBE-333-PEG-8000=4.5×10(4)M(-1), KBE-3333-PEG-8000=2.2×10(5)M(-1), Kspm-mPEG-ant=6.5×10(5)M(-1), Kspmd-mPEG-ant=1.1×10(6)M(-1), KBE-333-mPEG-ant=2.2×10(5)M(-1) and KBE-3333-mPEG-ant=6.9×10(4)M(-1). The number of binding sites (n) occupied by polyamines were from 0.2 to 0.5. Biogenic polyamines showed stronger affinity toward polymer complexation than synthetic polyamines, while weaker interaction was observed as polyamine cationic charges increased. Our results suggest that PEG and its derivative can act as carriers for delivering antitumor polyamine analogues to target tissues.