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.

Improved nanoformulation and bio-functionalization of linear-dendritic block copolymers with biocompatible ionic liquids.

Linear-dendritic block copolymers (LDBCs) have emerged as promising materials for drug delivery applications, with their hybrid structure exploiting advantageous properties of both linear and dendritic polymers. LDBCs have promising encapsulation efficiencies that can be used to encapsulate both hydrophobic and hydrophilic dyes for bioimaging, cancer therapeutics, and small biomolecules. Additionally, LDBCS can be readily functionalized with varying terminal groups for more efficient targeted delivery. However, depending on structural composition and surface properties, LDBCs also exhibit high dispersities (D), poor shelf-life, and potentially high cytotoxicity to non-target interfacing blood cells during intravenous drug delivery. Here, we show that choline carboxylic acid-based ionic liquids (ILs) electrostatically solvate LDBCs by direct dissolution and form stable and biocompatible IL-integrated LDBC nano-assemblies. These nano-assemblies are endowed with red blood cell-hitchhiking capabilities and show altered cellular uptake behavior ex vivo. When modified with choline and trans-2-hexenoic acid, IL-LDBC dispersity dropped by half compared to bare LDBCs, and showed a significant shift of the cationic surface charge towards neutrality. Proton nuclear magnetic resonance spectroscopy evidenced twice the total amount of IL on the LDBCs relative to an established IL-linear PLGA platform. Transmission electron microscopy suggested the formation of a nanoparticle surface coating, which acted as a protective agent against RBC hemolysis, reducing hemolysis from 73% (LDBC) to 25% (IL-LDBC). However, dramatically different uptake behavior of IL-LDBCs vs. IL-PLGA NPs in RAW 264.7 macrophage cells suggests a different conformational IL-NP surface assembly on the linear versus the linear-dendritic nanoparticles. These results suggest that by controlling the physical chemistry of polymer-IL interactions and assembly on the nanoscale, biological function can be tailored toward the development of more effective and more precisely targeted therapies.

Heteroacene-Based Amphiphile as a Molecular Scaffold for Bioimaging Probes.

The challenges faced with current fluorescence imaging agents have motivated us to study two nanostructures based on a hydrophobic dye, 6H-pyrrolo[3,2-b:4,5-b']bis [1,4]benzothiazine (TRPZ). TRPZ is a heteroacene with a rigid, pi-conjugated structure, multiple reactive sites, and unique spectroscopic properties. Here we coupled TRPZ to a tert-butyl carbamate (BOC) protected 2,2-bis(hydroxymethyl)propanoic acid (bisMPA) dendron via azide-alkyne Huisgen cycloaddition. Deprotection of the protected amine groups on the dendron afforded a cationic terminated amphiphile, TRPZ-bisMPA. TRPZ-bisMPA was nanoprecipitated into water to obtain nanoparticles (NPs) with a hydrodynamic radius that was <150 nm. For comparison, TRPZ-PG was encapsulated in pluronic-F127 (Mw = 12 kD), a polymer surfactant to afford NPs almost twice as large as those formed by TRPZ-bisMPA. Size and stability studies confirm the suitability of the TRPZ-bisMPA NPs for biomedical applications. The photophysical properties of the TRPZ-bisMPA NPs show a quantum yield of 49%, a Stokes shift of 201 nm (0.72 eV) and a lifetime of 6.3 ns in water. Further evidence was provided by cell viability and cellular uptake studies confirming the low cytotoxicity of TRPZ-bisMPA NPs and their potential in bioimaging.