Self-Assembly of Precisely Fluorinated Albumin for Dual Imaging-Guided Synergistic Chemo-Photothermal-Photodynamic Cancer Therapy.

Although albumin has been extensively used in nanomedicine, it is still challenging to fluorinate albumin into fluorine-19 magnetic resonance imaging (19F MRI)-traceable theranostics because existing strategies lead to severe 19F signal splitting, line broadening, and low 19F MRI sensitivity. To this end, 34-cysteine-selectively fluorinated bovine serum albumins (BSAs) with a sharp singlet 19F peak have been developed as 19F MRI-sensitive and self-assembled frameworks for cancer theranostics. It was found that fluorinated albumin with a non-binding fluorocarbon and a long linker is crucial for avoiding 19F signal splitting and line broadening. With the fluorinated BSAs, paclitaxel (PTX) and IR-780 were self-assembled into stable, monodisperse, and multifunctional nanoparticles in a framework-promoted self-emulsion way. The high tumor accumulation, efficient cancer cell uptake, and laser-triggered PTX sharp release of the BSA nanoparticles enabled 19F MRI-near infrared fluorescence imaging (NIR FLI)-guided synergistic chemotherapy (Chemo), photothermal and photodynamic therapy of xenograft MCF-7 cancer with a high therapeutical index in mice. This study developed a rational synthesis of 19F MRI-sensitive albumin and a framework-promoted self-emulsion of multifunctional BSA nanoparticles, which would promote the development of protein-based high-performance biomaterials for imaging, diagnosis, therapy, and beyond.

Rational design of pH-activated upconversion luminescent nanoprobes for bioimaging of tumor acidic microenvironment and the enhancement of photothermal therapy.

The development of effective and safe tumor photothermal therapeutic strategies has attracted considerable attention. Herein, we synthesized tumor microenvironment (TME)-activatable self-assembling organic nanotheranostics (NRhD-PEG-X NPs (X = 1, 2, 3, and 4)) for precise tumor targeting and upconversion image-guided photothermal therapy (PTT). The amphiphilic polymer NRhD-PEG-X consisted of upconversion luminescent probes (NRhD) modified with polyethylene glycol (PEG) of various lengths. The continuous external irradiation-free photothermal NRhD-PEG-4 NPs with pKa 6.70 displayed high sensitivity and selectivity to protons, resulting in the turn-on upconversion luminescence and enhanced photothermal properties in the acidic TME without asynchronous therapy and side effects. This nanotheranostic offers acidic activatability, tumor targetability, and PTT enhancement, thus allowing autofluorescence-free upconversion luminescent imaging-guided precision PTT. Our strategy affords a paradigm to develop activatable theranostic nanoplatforms for precision medicine. STATEMENT OF SIGNIFICANCE: As a hyperthermia-based treatment, activatable photothermal therapy (PTT) is highly significant in tumor treatment. Herein, we develop acidic tumor microenvironment-activatable nanotheranostics for upconversion luminescent imaging-guided diagnosis and precision tumor-targeted PTT. PEGylation of upconversion dyes not only could self-assemble to yield organic nanoparticles in water, but it could also significantly improve biocompatibility, stability, and circulation time and tune significantly the pKa value of nanoparticles. In an acidic tumor microenvironment, NRhD-PEG-4 NPs with pKa 6.70 show high sensitivity to release NRhDH+-PEG-4 NPs, which exhibit good upconversion luminescence and enhanced photothermal effect. Therefore, upconversion luminescence imaging-guided precision PTT has high potential to enhance cancer diagnostic and therapeutic efficiency.

Dual-light triggered metabolizable nano-micelles for selective tumor-targeted photodynamic/hyperthermia therapy.

Phototherapy, including photodynamic and photothermal therapies, is a non-invasive photo-triggered tumor treatment. Combination therapy and new synergistic therapeutic reagents may hold promise for improving these treatments. Herein, we report an amphiphilic iridium-based photosensitizer (C14-IP2000) loaded with a hydrophobic photo-thermal drug (ZnPc) to form nano-micelles (ZNPs) for dual-light triggered tumor phototherapy. The C14-IP2000 was contained within ZNPs consisting of an iridium complex core decorated with hydrophilic polyethylene glycol chains to extend the time in blood circulation, and two hydrophobic carbon chains to enhance the loading capacity and the hydrophobic interaction with the loaded reagent. The designed ZNPs showed effective blood circulation, passive tumor targeting ability, remarkable photodynamic conversion ability, and good photothermal conversion capability, and therefore may be used for combined tumor ablation. Our results demonstrated that the amphipathic bionic structure of ZNPs not only enables self-assembled reagent fabrication with prolonged circulation time and favorable metabolic characteristics for tumor combination therapy, but also provides a nanostructure strategy for the modification of functionalized reagents.

Methotrexate-based amphiphilic prodrug nanoaggregates for co-administration of multiple therapeutics and synergistic cancer therapy.

The goal of nanomedicine is to seek strategies that are more efficient to address various limitations and challenges faced by conventional medicines, including lack of target specificity, poor bioavailability, premature degradability, and undesired side effects. Self-assembling drug amphiphiles represent a prospective nanomedicine for cancer therapy owing to their favorable route of administration and therapeutic efficiency compared with pristine drug counterparts. In this work, we report a class of self-deliverable prodrug amphiphiles consisting of the hydrophilic drug methotrexate (MTX) and the hydrophobic anticancer drugs camptothecin (CPT) and doxorubicin (DOX) for targeted and combinational chemotherapy. The disulfide bond and hydrazone bond, which are subject to stimuli-triggered bond cleavage, were introduced to link these therapeutic agents and form two prodrug amphiphiles, named as MTX-CPT and MTX-DOX, respectively, which could self-assemble into stable prodrug nanoaggregates (NAs) in aqueous media. MTX molecules in the prodrug NAs facilitated NA uptake into tumor cells with high expression of folic acid receptors (FRs). This systemic study provided clear evidence of the synergistic therapeutic effect by co-administrating dual prodrug NAs on various tumor cells in vitro and a xenograft tumor model in vivo. The obtained prodrug amphiphiles provide an efficient strategy for the design of multifunctional drug delivery systems and elaborate therapeutic nanoplatforms for cancer chemotherapy. STATEMENT OF SIGNIFICANCE: This work presents two kinds of prodrug amphiphiles that are carrier free and integrate targeted drug delivery, stimuli-triggered drug release, synergistic therapy, and theranostic function into a single system. Reduction/acid active prodrug amphiphiles can self-assemble into micellar nanoaggregates (NAs) at a very low critical aggregation concentration. These NAs exhibit superior stability in physiological environment and disassemble in the presence of tumor cells expressing folic acid receptors or the high glutathione or in low pH tumoral endosomal environment. The induced disassembly of prodrug NAs can "switch on" the inherent fluorescence of the internalized camptothecin or doxorubicin for the detection of tumor cells. Compared to a single type of prodrug NA, co-administration of dual prodrug combination can produce an evident synergistic therapeutic effect against various tumor cells in vitro and inhibit xenograft tumor growth in vivo. The methotrexate-based prodrug amphiphiles may provide a potential strategy for developing multifunctional nanoplatforms and delivery of multiple therapeutics in chemotherapy.

A novel self-assembled nanoparticle platform based on pectin-eight-arm polyethylene glycol-drug conjugates for co-delivery of anticancer drugs.

The application of non-toxic carriers to increase drug loading, multi-drug delivery, and extremely small size of nano-drugs to construct a tremendous transmission system is the goal for all researchers to be pursued. The proposal of natural pectin nano-platform for delivery of multiple drugs is critical for biomedical research, especially a particle size of below 100nm with high yield. Here we design a new core-shell structure pectin-eight-arm polyethylene glycol-ursolic acid/hydrooxycampothecin nanoparticle (Pec-8PUH NPs) through a special self-assembly method for stabilizing and dispersing particles, improving water-solubility, and achieving drug controlled release. The obtained Pec-8PUH NPs possessed appropriate size (~91nm), drug-loaded efficiency and encapsulation efficiency through the regulation of eight-arm polyethylene glycol. In addition, Pec-8PUH NPs could enhance cell cytotoxicity, shorten blood retention time (7.3-fold UA, 7.2-fold HCPT) and more effective cellular uptake than free drugs, which exhibited an obvious synergistic effect of UA and HCPT by the co-delivery. 4T1 tumor-bearing mice also showed a higher survival rate than free UA and free HCPT. The result further shows that this novel drug delivery system has a promising potential for anti-cancer combination therapy.

"Nano-Ginseng" for Enhanced Cytotoxicity AGAINST Cancer Cells.

Panax ginseng has high medicinal and health values. However, the various and complex components of ginseng may interact with each other, thus reducing and even reversing therapeutic effects. In this study, we designed and fabricated a novel "nano-ginseng" with definite ingredients, ginsenoside Rb1/protopanaxadiol nanoparticles (Rb1/PPD NPs), completely based on the protopanaxadiol-type extracts. The optimized nano-formulations demonstrated an appropriate size (~110 nm), high drug loading efficiency (~96.8%) and capacity (~27.9 wt %), long half-time in systemic circulation (nine-fold longer than free PPD), better antitumor effects in vitro and in vivo, higher accumulation at the tumor site and reduced damage to normal tissues. Importantly, this process of "nano-ginseng" production is a simple, scalable, green economy process.