Star-polymer unimolecular micelle nanoparticles to deliver a payload across the blood-brain barrier.

Nanocarrier-mediated therapeutic delivery to brain tissue is impeded by tightly controlled transportation across the blood-brain barrier (BBB). Herein, we report a well-defined core-shell star-shaped unimolecular micelle (star-UMM; a single polymer entity) as an efficient BBB-breaching nanoparticle for brain-specific administration of the fluorescent anticancer drug doxorubicin and mapping of brain tissues by the near-infrared biomarker IR780 in mice. The star-UMM was engineered by precisely programming the polymer topology having hydrophobic and hydrophilic polycaprolactone blocks and in-built with lysosomal enzyme-biodegradation stimuli to deliver the payloads at intracellular compartments.

Melt Polycondensation Strategy to Access Unexplored l-Amino Acid and Sugar Copolymers.

Biodegradable polymers from bioresources are highly in demand for the development of sustainable polymer platforms for commodity plastics and in the biomedical field. Here, an elegant one-pot synthetic strategy is developed, for the first time, to access unexplored hybrid polymers from two naturally abundant resources: carbohydrates (sugars) and l-amino acids. A bottleneck in the synthetic strategy is overcome by tailor-making d-mannitol-based six- and five-membered bicyclic acetalized diols, and their structures are confirmed by single-crystal X-ray diffraction and 2D NMR spectroscopy.

Structural Engineering of l-Aspartic Amphiphilic Polyesters for Enzyme-Responsive Drug Delivery and Bioimaging in Cancer Cells.

Design and development of amphiphilic polyesters based on bioresources are very important to cater to the ever-growing need for biodegradable polymers in biomedical applications. Here, we report structural engineering of enzyme-responsive amphiphilic polyesters based on l-amino acid bioresources and study their drug delivery aspects in the cancer cell line. For this purpose, an l-aspartic acid-based polyester platform is chosen, and two noncovalent forces such as hydrogen bonding and side-chain hydrophobic interactions are introduced to study their effect on the aqueous self-assembly of nanoparticles.

Size- and Shape-controlled Biodegradable Polymer Brushes Based on l-Amino Acid for Intracellular Drug Delivery and Deep-Tissue Penetration.

We report size- and shape-controlled polymer brushes based on l-amino acid bioresource and study the role of polymer topology on the enzymatic biodegradation and deep-tissue penetration under in vitro and in vivo. For this purpose, l-tyrosine-based propargyl-functionalized monomer is tailor-made and polymerized via solvent-free melt polycondensation strategy to yield hydrophobic and clickable biodegradable poly(ester-urethane)s. Postpolymerization click chemistry strategy is applied to make well-defined amphiphilic one-dimensional rodlike and three-dimensional spherical polymer brushes by merely varying the lengths of PEG-azides in the reaction.

Zwitterionic Strategy to Stabilize Self-Immolative Polymer Nanoarchitecture under Physiological pH for Drug Delivery In Vitro and In Vivo.

The major bottleneck in using polymer nanovectors for biomedical application, particularly those based on self-immolative poly(amino ester) (PAE), lies in their uncontrolled autodegradation at physiological pH before they can reach the intended target. Here, an elegant triblock-copolymer strategy is designed to stabilize the unstable PAE chains via zwitterionic interactions under physiological pH (pH 7.4) and precisely program their enzyme-responsive biodegradation specifically within the intracellular compartments, ensuring targeted delivery of the cargoes.

Melt Polycondensation Strategy for Amide-Functionalized l-Aspartic Acid Amphiphilic Polyester Nano-assemblies and Enzyme-Responsive Drug Delivery in Cancer Cells.

Aliphatic polyesters are intrinsically enzymatic-biodegradable, and there is ever-increasing demand for safe and smart next-generation biomaterials including drug delivery nano-vectors in cancer research. Using bioresource-based biodegradable polyesters is one of the elegant strategies to meet this requirement; here, we report an l-amino acid-based amide-functionalized polyester platform and explore their lysosomal enzymatic biodegradation aspects to administrate anticancer drugs in cancer cells. l-Aspartic acid was chosen and different amide-side chain-functionalized di-ester monomers were tailor-made having aromatic, aliphatic, and bio-source pendant units.

Theranostic FRET Gate to Visualize and Quantify Bacterial Membrane Breaching.

Designing new antimicrobial-cum-probes to study real-time bacterial membrane breaching and concurrently developing inquisitorial image-based analytical tools is essential for the treatment of infectious diseases. An array of aggregation-induced emission (AIE) polymers (donor) consisting of neutral, anionic, and cationic charges were designed and employed as antimicrobial theranostic gatekeepers for the permeabilization of the peptidoglycan layer-adherable crystal violet (CV, acceptor). An AIE-active tetraphenylethylene (TPE)-tagged polycaprolactone biodegradable platform was chosen, and their self-assembled tiny amphiphilic nanoparticles were employed as a gatekeeper in the construction of bacterial membrane-reinforced fluorescent resonance energy transfer (FRET) probes.

Structural Engineering of Star Block Biodegradable Polymer Unimolecular Micelles for Drug Delivery in Cancer Cells.

The present investigation reports the structural engineering of biodegradable star block polycaprolactone (PCL) to tailor-make aggregated micelles and unimolecular micelles to study their effect on drug delivery aspects in cancer cell lines. Fully PCL-based star block copolymers were designed by varying the arm numbers from two to eight while keeping the arm length constant throughout. Multifunctional initiators were exploited for stepwise solvent-free melt ring-opening polymerization of ε-caprolactone and γ-substituted caprolactone to construct star block copolymers having a PCL hydrophobic core and a carboxylic PCL hydrophilic shell, respectively.

l-Amino Acid Based Phenol- and Catechol-Functionalized Poly(ester-urethane)s for Aromatic π-Interaction Driven Drug Stabilization and Their Enzyme-Responsive Delivery in Cancer Cells.

Exploiting aromatic π-interaction for the stabilization of polyaromatic anticancer drugs at the core of the polymer nanoassemblies is an elegant approach for drug delivery in cancer research. To demonstrate this concept, here we report one of the first attempts on enzyme-responsive polymers from aryl-unit containing amino acid bioresources such as l-tyrosine and 3,4-dihydroxy-l-phenylalanine (l-DOPA). A silyl ether protection strategy was adopted to make melt polymerizable monomers, which were subjected to solvent free melt polycondensation to produce silyl-protected poly(ester-urethane)s.

Tertiary-Butylbenzene Functionalization as a Strategy for β-Sheet Polypeptides.

β-Sheet forming polypeptides are one of the least explored synthetic systems due to their uncontrolled precipitation in the ring-opening polymerization (ROP) synthetic methodology. Here, a new -butylbenzene functionalization approach is introduced to overcome this limitation by sterically controlling the propagating polymer chains, and homogeneous polymerization with good control over chain growth was accomplished. New bulky -carboxyanhydride monomers were designed having -butylbenzene pendant by multistep organic synthesis, and N-heterocyclic carbene was explored as a catalyst to make high-molecular-weight and narrow polydisperse soluble polypeptides.

Fluorescent ABC-Triblock Polymer Nanocarrier for Cisplatin Delivery to Cancer Cells.

Monitoring intracellular administration of non-luminescent anticancer drugs like cisplatin is a very challenging task in cancer research. Perylenebisimide (PBI) chromophore tagged fluorescent ABC-triblock polycaprolactone (PCL) nanoscaffold was engineered having carboxylic acid blocks for the chemical conjugation of cisplatin at the core and hydrophilic PEG blocks at the periphery. The amphiphilic ABC triblock Pt-prodrug was self-assembled into <200 nm nanoparticles and exhibited excellent shielding against drug detoxification by the glutathione (GSH) species in the cytosol.

Self-Reporting Polysaccharide Polymersome for Doxorubicin and Cisplatin Delivery to Live Cancer Cells.

We report self-reporting fluorescent polysaccharide polymersome nanoassemblies for enzyme-responsive intracellular delivery of two clinical anticancer drugs doxorubicin (DOX) and cisplatin to study the real-time drug-releasing aspects by fluorescent resonance energy transfer (FRET) bioimaging in live cancer cells. Fluorescent polymersomes were tailor-made by tagging an aggregation-induced emission (AIE) optical chromophore, tetraphenylethylene (TPE), and a plant-based vesicular directing hydrophobic unit through enzyme-biodegradable aliphatic ester chemical linkages in the polysaccharide dextran. The blue-luminescent polymersome self-assembled in water and exhibited excellent encapsulation capability for the red-luminescent anticancer drug DOX.

Biodegradable Polymer Theranostic Fluorescent Nanoprobe for Direct Visualization and Quantitative Determination of Antimicrobial Activity.

We report a biodegradable fluorescent theranostic nanoprobe design strategy for simultaneous visualization and quantitative determination of antibacterial activity for the treatment of bacterial infections. Cationic-charged polycaprolactone (PCL) was tailor-made through ring-opening polymerization methodology, and it was self-assembled into well-defined tiny 5.0 ± 0.

Enzyme-Responsive Theranostic FRET Probe Based on l-Aspartic Amphiphilic Polyester Nanoassemblies for Intracellular Bioimaging in Cancer Cells.

The present study reports one of the first attempts on the design and development of an enzymatic-biodegradable theranostic fluorescence resonance energy transfer (FRET) probe constructed on l-amino acid polymer nanoassemblies and demonstrates the proof-of-concept in live cell bioimaging. l-Aspartic acid was converted into amide or carbamate pendants containing bis-carboxylic acid ester monomers, and they were subjected to melt polymerization along with commercial diols to produce amphiphilic aliphatic polyesters. Nanoparticles of size <200 nm were obtained because of self-assembly of these amphiphilic polyesters in an aqueous medium.

Development of l-Amino-Acid-Based Hydroxyl Functionalized Biodegradable Amphiphilic Polyesters and Their Drug Delivery Capabilities to Cancer Cells.

Hydroxyl-functionalized amphiphilic polyesters based on l-amino acid bioresources were designed and developed, and their nanoassemblies were explored as intracellular enzyme-biodegradable scaffolds for delivering anticancer drugs and fluorophores to cancer cells. To accomplish this task, acetal-masked multifunctional dicarboxylic ester monomer from l-aspartic acid was tailor-made, and it was subjected to solvent-free melt transesterification polycondensation with commercial diols to produce acetal-functionalized polyesters. Acid-catalyzed postpolymerization deprotection of these acetal-polyesters produced amphiphilic hydroxyl-functionalized polyesters.

Biotin-Tagged Polysaccharide Vesicular Nanocarriers for Receptor-Mediated Anticancer Drug Delivery in Cancer Cells.

Biotin-conjugated multistimuli-responsive polysaccharide vesicular nanocarriers are designed and developed, for the first time, to accomplish receptor-mediated endocytosis in cancer cells and to deliver anticancer drugs to intracellular compartments. For this purpose, a new renewable hydrophobic unit was custom designed with redox-degradable disulfide and enzyme-biodegradable aliphatic ester chemical linkages, and it was conjugated along with biotin on the dextran backbone. The dextran derivative self-assembled into nanovesicles of <200 nm in size, which were characterized by dynamic and static light scattering, electron, and atomic force microscopes.

Polymer Nanovesicle-Mediated Delivery of MLN8237 Preferentially Inhibits Aurora Kinase A To Target RalA and Anchorage-Independent Growth in Breast Cancer Cells.

The small GTPase RalA is a known mediator of anchorage-independent growth in cancers and is differentially regulated by adhesion and aurora kinase A (AURKA). Hence, inhibiting AURKA offers a means of specifically targeting RalA (over RalB) in cancer cells. MLN8237 (alisertib) is a known inhibitor of aurora kinases; its specificity for AURKA, however, is compromised by its poor solubility and transport across the cell membrane.

Multistimuli-Responsive Amphiphilic Poly(ester-urethane) Nanoassemblies Based on l-Tyrosine for Intracellular Drug Delivery to Cancer Cells.

Multistimuli-responsive l-tyrosine-based amphiphilic poly(ester-urethane) nanocarriers were designed and developed for the first time to administer anticancer drugs in cancer tissue environments via thermoresponsiveness and lysosomal enzymatic biodegradation from a single polymer platform. For this purpose, multifunctional l-tyrosine monomer was tailor-made with a PEGylated side chain at the phenolic position along with urethane and carboxylic ester functionalities. Under melt dual ester-urethane polycondensation, the tyrosine monomer reacted with diols to produce high molecular weight amphiphilic poly(ester-urethane)s.

Fluorescent-Tagged Biodegradable Polycaprolactone Block Copolymer FRET Probe for Intracellular Bioimaging in Cancer Cells.

The present investigation reports a new fluorophore-tagged biodegradable polycaprolactone (PCL) block copolymer FRET-probe for intracellular imaging in cancer therapy. A hydroxyl functionalized π-conjugated oligo-phenylenevinylene (OPV) chromophore was tailor-made, and it was incorporated in a -butyl ester substituted polycaprolactone block copolymer via ring opening polymerization. This blue-luminescent OPV-PCL triblock self-assembled as <200 nm spherical nanoparticles (FRET donor), and it encapsulated water insoluble Nile red (NR, FRET acceptor) to yield an OPV-NR FRET probe.

π-Conjugate Fluorophore-Tagged and Enzyme-Responsive l-Amino Acid Polymer Nanocarrier and Their Color-Tunable Intracellular FRET Probe in Cancer Cells.

The present investigation accounts one of the first example of enzyme-responsive and π-conjugate-tagged l-amino acid amphiphilic polymer and their fluorescence resonance energy transfer (FRET) probes for color-tunable intracellular bioimaging in cancer cells. Melt polymerizable oligo-phenylenevinylene (OPV) π-conjugated diol was tailor-made and subjected to thermo-selective melt transesterification reaction with multifunctional l-aspartic acid monomer to yield OPV-tagged amphiphilic luminescent polyesters. These amphiphilic polyesters self-assembled through strong aromatic π-π stacking and hydrophilic/hydrophobic noncovalent forces into <200 nm size blue-luminescent nanoparticles in aqueous medium.

Cisplatin-Stitched Polysaccharide Vesicles for Synergistic Cancer Therapy of Triple Antagonistic Drugs.

New cisplatin-stitched polysaccharide vesicular nanocarrier is developed for combination therapy of three clinical important antagonistic drugs together to accomplish synergistic cancer therapy in breast cancer treatment. Carboxylic functionalized dextran was tailor-made for the chemical conjugation of cisplatin, and a renewable hydrophobic unit was anchored in the backbone to interdigitize the chains to self-assemble as cisplatin-stitched polysaccharide nanovesicles. Water-soluble DNA-intercalating drug doxorubicin·HCl (DOX) and water insoluble topoisomerase type I inhibitor drug camptothecin (CPT) were encapsulated in these vesicles to produce dual or triple drug-loaded vesicular nanocarrier.

Development of l-Tyrosine-Based Enzyme-Responsive Amphiphilic Poly(ester-urethane) Nanocarriers for Multiple Drug Delivery to Cancer Cells.

New classes of enzymatic-biodegradable amphiphilic poly(ester-urethane)s were designed and developed from l-tyrosine amino acid resources and their self-assembled nanoparticles were employed as multiple drug delivery vehicles in cancer therapy. The amine and carboxylic acid functional groups in l-tyrosine were converted into dual functional ester-urethane monomers and they were subjected to solvent free melt polycondensation with hydrophilic polyethylene glycols to produce comb-type poly(ester-urethane)s. The phenolic unit in the l-tyrosine was anchored with hydrophobic alkyl side chain to bring appropriate amphiphilicity in the polymer geometry to self-assemble them as stable nanoscaffolds in aqueous medium.

Triple Block Nanocarrier Platform for Synergistic Cancer Therapy of Antagonistic Drugs.

A unique biodegradable triple block nanocarrier (TBN) is designed and developed for synergistic combination therapy of antagonistic drugs for cancer treatment. The TBN was built with hydrophilic polyethylene glycol (PEG) outer shell; a middle hydrophobic and biodegradable polycaprolactone (PCL) block for encapsulating anthracycline anticancer drug like doxorubicin (DOX), and an inner carboxylic-functionalized polycaprolactone (CPCL) core for cisplatin (CP) drug conjugation. TBN-cisplatin drug conjugate self-assembled as stable nanoparticles in saline (also in PBS) wherein the hydrophobic PCL block functions as a shield for Pt-drug stability against GSH detoxification.

Structural Engineering of Biodegradable PCL Block Copolymer Nanoassemblies for Enzyme-Controlled Drug Delivery in Cancer Cells.

Biodegradable block copolymer chemical structures were engineered as drug nanocarriers to precisely program the enzyme-controlled release of anticancer drugs at intracellular compartments in cancer cells. New classes of amide and ester side chain-substituted caprolactone monomers were designed by multistep organic synthesis and polymerized under ring opening processes to make new classes of substituted polycaprolactone--polyethylene glycol copolymers. These block copolymers were self-assembled as stable nanoparticles of <200 nm in water.