Robust Colloidal Nanoparticles of Pyrrolopyrrole Cyanine J-Aggregates with Bright Near-Infrared Fluorescence in Aqueous Media: From Spectral Tailoring to Bioimaging Applications.

Colloidal nanoparticles (NPs) containing near-infrared-fluorescent J-aggregates (JAGGs) of pyrrolopyrrole cyanines (PPcys) stabilized by amphiphilic block co-polymers were prepared in aqueous medium. JAGG formation can be tuned by means of the chemical structure of PPcys, the concentration of chromophores inside the polymeric NPs, and ultrasonication. The JAGG NPs exhibit a narrow emission band at 773 nm, a fluorescence quantum yield comparable to that of indocyanine green, and significantly enhanced photostability, which is ideal for long-term bioimaging.

Unimolecular Micelles of Amphiphilic Cyclodextrin-Core Star-Like Copolymers with Covalent pH-Responsive Linkage of Anticancer Prodrugs.

Multifunctional stable and stimuli-responsive drug delivery systems are important for efficient cancer treatment due to their advantages such as enhanced cancer-targeting efficiency, improved pharmacokinetics, minimized drug leaching, and reduced undesirable side effects. Here we report a robust and pH-responsive anticancer drug delivery system based on unimolecular micelles of star-like amphiphilic copolymers. The polymers (denoted as CPOFs) were facilely synthesized via one-step atom transfer radical polymerization of functionalizable benzoaldehyde and hydrophilic poly[(oligo ethylene glycol) methyl ether methacrylate] as comonomers from the core of heptakis [2,3,6-tri-o-(2-bromo-2-methyl propionyl]-ß-cyclodextrin as the initiator. Doxorubicin (DOX) as an anticancer drug was covalently linked to the benzoaldehyde groups of CPOFs through pH-sensitive Schiff-base bonds. The DOX-conjugated polymers, denoted as CPOF-DOX, formed robust unimolecular micelles with an average diameter of 18 nm in aqueous media. More importantly, these unimolecular micelles showed higher drug loading capacity and more controllable drug release characteristics, compared to our previous unimolecular micelles of ß-cyclodextrin-poly(lactic acid)-b-poly[(oligo ethylene glycol) methyl ether methacrylates] that physically encapsulated DOX via hydrophobic interaction. Moreover, the CPOF-DOX unimolecular micelles could be internalized by human cervical cancer HeLa cells in a stepwise way and showed less cytotoxicity compared to carrier-free DOX. We foresee that CPOF-DOX would provide a promising robust and controllable anticancer drug delivery system for future animal study and clinical trials for cancer treatment.

Hydrophobic-Sheath Segregated Macromolecular Fluorophores: Colloidal Nanoparticles of Polycaprolactone-Grafted Conjugated Polymers with Bright Far-Red/Near-Infrared Emission for Biological Imaging.

This article describes molecular design, synthesis and characterization of colloidal nanoparticles containing polycaprolactone-grafted conjugated polymers that exhibit strong far red/near-infrared (FR/NIR) fluorescence for bioimaging. Specifically, we synthesized two kinds of conjugated polymer bottle brushes (PFTB(out)-g-PCL and PFTB(in)-g-PCL) with different positions of the hexyl groups on the thiophene rings. A synthetic amphiphilic block copolymer PCL-b-POEGMA was employed as surfactants to encapsulate PFTB-g-PCL polymers into colloidal nanoparticles (denoted as "nanoREDs") in aqueous media. The chain length of the PCL side chains in PFTB-g-PCL played a critical role in determining the fluorescence properties in both bulk solid states and the colloidal nanoparticles. Compared to semiconducting polymer dots (Pdots) composed of PFTB(out) without grafted PCL, nanoRED(out) showed at least four times higher fluorescence quantum yield (∼20%) and a broader emission band centered at 635 nm. We further demonstrated the application of this new class of nanoREDs for effective labeling of L929 cells and HeLa cancer cells with good biocompatibility. This strategy of hydrophobic-sheath segregated macromolecular fluorophores is expected to be applicable to a broad range of conjugated polymers with tunable optical properties for applications such as bioimaging.

Contrast-enhanced photoacoustic imaging in the second near-infrared window using semiconducting polymer nanoparticles.

Photoacoustic imaging (PAI) is a fast growing deep-tissue imaging modality. However, light scattering and absorption in biological tissues limit imaging depth. Short near-infrared wavelengths (650 to 950 nm) are widely used for PAI. Using longer near-infrared wavelengths reduces scattering. We demonstrate deep-tissue contrast-enhanced in vivo photoacoustic imaging at a wavelength of 1064 nm. An ultranarrow bandgap semiconducting polymer poly (thienoisoindigo-alt-diketopyrrolopyrrole) (denoted as PIGD) is designed and demonstrated for imaging at 1064 nm. By embedding colloidal nanoparticles (NPs) of PIGD in chicken-breast tissue, an imaging depth of ∼5 cm is achieved. Intravenous injection of PIGD NPs in living rats showed brain vascular images with ∼2 times higher contrast compared with the brain vascular images without any contrast agent. Thus, PIGD NPs as an NIR-II contrast agent opens new opportunities for both preclinical and clinical imaging of deep tissues with enhanced contrast.

Multifunctional polymeric micelles loaded with doxorubicin and poly(dithienyl-diketopyrrolopyrrole) for near-infrared light-controlled chemo-phototherapy of cancer cells.

Polymeric micelles loaded with multiple therapeutic modalities are important to overcome challenges such as drug resistance and improve the therapeutic efficacy. Here we report a new polymer micellar drug carrier that integrates chemotherapy and photothermal therapy in a single platform. Specifically, a narrow bandgap poly(dithienyl-diketopyrrolopyrrole) (PDPP) polymer was encapsulated together with a model anticancer drug doxorubicin (DOX) in the hydrophobic cores of polymeric micelles formed by Pluronic F127, an amphiphilic poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymer. The PDPP polymer served as an organic photothermal agent that absorbs near-infrared light (700-1000nm) and transforms into heat efficiently. The dual functional micelles co-loaded with PDPP and DOX in the hydrophobic compartment showed good colloidal stability after being stored at 4°C at least over two months, and remained visibly stable after 808-nm laser irradiation. The loaded DOX had negligible effect on the size and photothermal property of the micelles. The release of DOX from the micelles could be enhanced by the "breathing" effect of shrinking/swelling of the micelles induced by the temperature change, owing to the thermosensitive nature of the F127 polymers. Importantly, the ternary F127/PDPP/DOX micelles under 808-nm laser irradiation showed enhanced cytotoxicity against cancer cells such as HeLa cells, compared to F127 micelles containing single modality of either PDPP or DOX only.

Fluorescent Poly(glycerol-co-sebacate) Acrylate Nanoparticles for Stem Cell Labeling and Longitudinal Tracking.

The stable presence of fluorophores within the biocompatible and biodegradable elastomer poly(glycerol-co-sebacate) acrylate (PGSA) is critical for monitoring the transplantation, performance, and degradation of the polymers in vivo. However, current methods such as physically entrapping the fluorophores in the polymer matrix or providing a fluorescent coating suffer from rapid leakage of fluorophores. Covalent conjugation of fluorophores with the polymers and the subsequent core-cross-linking are proposed here to address this challenge. Taking rhodamine as the model dye and PGSA nanoparticles (NPs) as the model platform, we successfully showed that the synthesized rhodamine-conjugated PGSA (PGSAR) NPs only released less than 30% rhodamine at day 28, whereas complete release of dye occurred for rhodamine-encapsulated PGSA (PGSA-p-R) NPs at day 7 and 57.49% rhodamine was released out for the un-cross-linked PGSAR NPs at day 28. More excitingly, PGSAR NPs showed a strong quantum yield enhancement (26.24-fold) of the fluorophores, which was due to the hydrophobic environment within PGSAR NPs and the restricted rotation of (6-diethylamino-3H-xanthen-3-ylidene) diethyl group in rhodamine after the conjugation and core-cross-linking. The stable presence of dye in the NPs and enhanced fluorescence allowed a longitudinal tracking of stem cells both in vitro and in vivo for at least 28 days.

Unimolecular micelles of amphiphilic cyclodextrin-core star-like block copolymers for anticancer drug delivery.

Well-defined star-like amphiphilic polymers composed of a ß-cyclodextrin core, from which 21 hydrophobic poly(lactic acid) arms and hydrophilic poly(ethylene glycol) arms are grafted sequentially, form robust and uniform unimolecular micelles that are biocompatible and efficient in the delivery of anticancer drugs.

Highly fluorescent and bioresorbable polymeric nanoparticles with enhanced photostability for cell imaging.

We report a facile and general strategy for enhancing the photostability of organic fluorophores for bioimaging applications. As a proof of concept, bright and robust fluorescence was observed in solid states of a well-defined synthetic polymer polycaprolactone consisting of di(thiophene-2-yl)-diketopyrrolopyrrole covalently linked in the middle of the polymer chain as a biocompatible and bioresorbable matrix. The nanoparticles prepared through a nanoprecipitation process of these polymers could be internalized by both tumor cells and stem cells with little cytotoxicity. Moreover, these highly fluorescent nanoparticles exhibited significantly enhanced photostability compared to commercial quantum dots or physical blends of dye/polymer complexes in cell imaging and long-term tracing.