Postpolymerization Modification of Poly(2-vinyl-4,4-dimethyl azlactone) as a Versatile Strategy for Drug Conjugation and Stimuli-Responsive Release.

Postpolymerization modification of highly defined "scaffold" polymers is a promising approach for overcoming the existing limitations of controlled radical polymerization such as batch-to-batch inconsistencies, accessibility to different monomers, and compatibility with harsh synthesis conditions. Using multiple physicochemical characterization techniques, we demonstrate that poly(2-vinyl-4,4-dimethyl azlactone) (PVDMA) scaffolds can be efficiently modified with a coumarin derivative, doxorubicin, and camptothecin small molecule drugs. Subsequently, we show that coumarin-modified PVDMA has a high cellular biocompatibility and that coumarin derivatives are liberated from the polymer in the intracellular environment for cytosolic accumulation. In addition, we report the pharmacokinetics, biodistribution, and antitumor efficacy of a PVDMA-based polymer for the first time, demonstrating unique accumulation patterns based on the administration route (i.e., intravenous vs oral), efficient tumor uptake, and tumor growth inhibition in 4T1 orthotopic triple negative breast cancer (TNBC) xenografts. This work establishes the utility of PVDMA as a versatile chemical platform for producing polymer-drug conjugates with a tunable, stimuli-responsive delivery.

Comparative Investigation of the Hydrolysis of Charge-Shifting Polymers Derived from an Azlactone-Based Polymer.

Poly 2-vinyl-4,4-dimethylazlactone (PVDMA) has received much attention as a "reactive platform" to prepare charge-shifting polycations via post-polymerization modification with tertiary amines that possess primary amine or hydroxyl reactive handles. Upon hydrolysis of the resulting amide or ester linkages, the polymers can undergo a gradual transition in net charge from cationic to anionic. Herein, a systematic investigation of the hydrolysis rate of PVDMA-derived charge-shifting polymers is described. PVDMA is modified with tertiary amines bearing either primary amine, hydroxyl, or thiol reactive handles. The resulting polymers possess tertiary amine side chains connected to the backbone via amide, ester, or thioester linkages. The hydrolysis rates of each PVDMA derivative are monitored at 25 and 50 °C at pH values of 5.5, 7.5, and 8.5, respectively. While the hydrolysis rate of the amide-functionalized PVDMA is negligible over the period investigated, the hydrolysis rates of the ester- and thioester-functionalized PVDMA increase with increasing temperature and pH. Interestingly, the hydrolysis rate of the thioester-functionalized PVDMA appears to be more rapid than the ester-functionalized PVDMA at all pH values and temperatures investigated. It is believed that these results can be utilized to inform the future preparation of PVDMA-based charge-shifting polymers for biomedical applications.

Interfacial vs Bulk Phenomena Effects on the Surface Tensions of Aqueous Magnetic Surfactants in Uniform Magnetic Fields.

The literature clearly reports that magnetic surfactant systems respond to magnetic fields. This manuscript investigates if the responses are because the magnetic fields directly alter the interfacial properties or if the surface-active properties are independent of the paramagnetic fluid responses. It uses uniform and gradient magnetic fields to determine the magnetically induced changes to the surface tensions independent of bulk paramagnetic fluid effects for ionic magnetic surfactants. The magnetically induced decrease in surface tensions is small compared to the bulk paramagnetic fluid effects. The reported decrease in surface tensions is significantly smaller than those previously found in the literature, which reported a combined interfacial and bulk paramagnetic effect. The magnetically induced surface tension changes are a function of the degree of association, α, of the magnetic moiety with the surfactant's amphiphilic structure. Therefore, the proposed answer to the question is that as α approaches zero, the magnetic properties of the magnetic surfactant system approaches the behavior of an ordinary paramagnetic fluid. For magnetic surfactants with α approaching one, there is a measurable interfacial response. For example in this study, a magnetic surfactant with α = 0.92 had a 2.5 times greater magnetically induced change in surface tension compared to a magnetic surfactant with α = undetectable, even thought they had similar magnetic moments.

Stability of Ionic Magnetic Surfactants in Aqueous Solutions: Measurement Techniques and Impact on Magnetic Processes.

Predicting the behavior of magnetic surfactants in magnetic fields is critical for designing magnetically driven processes such as chemical separations or the tuning of surface tensions. The ability of magnetic fields to alter the interfacial properties of magnetic surfactant solutions may be dependent upon the strength of association between the magnetic and surfactant moieties of the surfactant molecules. This research shows that the stability of a magnetic surfactant in an aqueous environment is dependent upon the type of complex that contains the paramagnetic ion, and these findings provide valuable insight for the design of magnetic surfactants for applications in aqueous media. The surfactants investigated were ionic surfactants, which contained paramagnetic counterions. This investigation looked at both anionic and cationic surfactants; it utilized solution conductivity, cyclic voltammetry (CV), sampled current voltammetry (SCV), and solution pH measurements to qualitatively evaluate the stability of the magnetic counterions in aqueous solution. In addition, solution conductivity was used to quantify the degree of binding between the paramagnetic ions and surfactant micelles in solution. These results indicate metal halide-based cationic surfactants are unstable in aqueous solutions. We hypothesize that this instability results in the difference in the magnetic response of the anionic vs cationic surfactants examined in this study.