Cancer cells exhibit slightly elevated levels of reactive oxygen species (ROS) compared with normal cells, and approximately 90% of intracellular ROS is produced in mitochondria. In situ ...mitochondrial ROS amplification is a promising strategy to enhance cancer therapy. Here we report cancer cell and mitochondria dual-targeting polyprodrug nanoreactors (DT-PNs) covalently tethered with a high content of repeating camptothecin (CPT) units, which release initial free CPT in the presence of endogenous mitochondrial ROS (mtROS). The in situ released CPT acts as a cellular respiration inhibitor, inducing mtROS upregulation, thus achieving subsequent self-circulation of CPT release and mtROS burst. This mtROS amplification endows long-term high oxidative stress to induce cancer cell apoptosis. This current strategy of endogenously activated mtROS amplification for enhanced chemodynamic therapy overcomes the short lifespan and action range of ROS, avoids the penetration limitation of exogenous light in photodynamic therapy, and is promising for theranostics.
The rational design of theranostic nanoparticles exhibiting synergistic turn-on of therapeutic potency and enhanced diagnostic imaging in response to tumor milieu is critical for efficient ...personalized cancer chemotherapy. We herein fabricate self-reporting theranostic drug nanocarriers based on hyperbranched polyprodrug amphiphiles (hPAs) consisting of hyperbranched cores conjugated with reduction-activatable camptothecin prodrugs and magnetic resonance (MR) imaging contrast agent (Gd complex), and hydrophilic coronas functionalized with guanidine residues. Upon cellular internalization, reductive milieu-actuated release of anticancer drug in the active form, activation of therapeutic efficacy (>70-fold enhancement in cytotoxicity), and turn-on of MR imaging (∼9.6-fold increase in T 1 relaxivity) were simultaneously achieved in the simulated cytosol milieu. In addition, guanidine-decorated hPAs exhibited extended blood circulation with a half-life up to ∼9.8 h and excellent tumor cell penetration potency. The hyperbranched chain topology thus provides a novel theranostic polyprodrug platform for synergistic imaging/chemotherapy and enhanced tumor uptake.
The increased threat of antibiotic resistance has created an urgent need for new strategies. Herein, polyprodrug antimicrobials are proposed to mimic antimicrobial peptides appended with a concurrent ...drug release property, exhibiting broad‐spectrum antibacterial activity and especially high potency to inhibit methicillin‐resistant Staphylococcus aureus (MRSA) without inducing resistance. Two series of polyprodrug antimicrobials are fabricated by facile polymerization of triclosan prodrug monomer (TMA) and subsequent quaternization of hydrophilic poly(N,N‐dimethylaminoethyl methacrylate) (PDMAEMA), affording PDMAEMA‐b‐PTMA and PQDMA‐b‐PTMA, respectively. Optimized samples with proper hydrophobic ratio are screened out, which exhibit remarkable bacterial inhibition and low hemolysis toward red blood cells. Furthermore, synergistic antibacterial mechanisms contribute to the bacteria killing, including serious membrane damage, increased out‐diffusion of cytosolic milieu across the membrane, and intracellular reductive milieu‐mediated triclosan release. No detectable resistance is observed for polyprodrug antimicrobials against MRSA, which is demonstrated to be better than commercial triclosan and vancomycin against in vivo MRSA‐infected burn models and a promising approach to the hurdle of antibiotic resistance in biomedicine.
Polyprodrug antimicrobials with remarkable membrane damage and concurrent drug release are proposed to treat the infection and antibiotic resistance of methicillin‐resistant Staphylococcus aureus (MRSA), exhibiting low hemolysis toward red blood cells and good antibacterial selectivity. Remarkable membrane damage and further intracellular triclosan release synergistically kill MRSA, possessing undetectable resistance compared with commercial antibiotics. Polyprodrug antimicrobials are promising to treat drug‐resistant bacteria in biomedicine.
Solution self-assembly of block copolymers (BCPs) typically generates spheres, rods, and vesicles. The reproducible bottom-up fabrication of stable planar nanostructures remains elusive due to their ...tendency to bend into closed bilayers. This morphological vacancy renders the study of shape effects on BCP nanocarrier-cell interactions incomplete. Furthermore, the fabrication of single BCP assemblies with built-in drug delivery functions and geometry-optimized performance remains a major challenge. We demonstrate that PEG-b-PCPTM polyprodrug amphiphiles, where PEG is poly(ethylene glycol) and PCPTM is polymerized block of reduction-cleavable camptothecin (CPT) prodrug monomer, with >50 wt % CPT loading content can self-assemble into four types of uniform nanostructures including spheres, large compound vesicles, smooth disks, and unprecedented staggered lamellae with spiked periphery. Staggered lamellae outperform the other three nanostructure types, exhibiting extended blood circulation duration, the fastest cellular uptake, and unique internalization pathways. We also explore shape-modulated CPT release kinetics, nanostructure degradation, and in vitro cytotoxicities. The controlled hierarchical organization of polyprodrug amphiphiles and shape-tunable biological performance opens up new horizons for exploring next-generation BCP-based drug delivery systems with improved efficacy.
Photodynamic therapy (PDT) has been proposed in cancer treatment for decades, but its clinical translation is significantly impeded by the low yield of ROS, poor tissue penetration depth of most ...current photosensitizers, and short lifetime of ROS. These limitations directly affect the therapeutic effect of PDT in cancer therapy. Here we proposed a new strategy by collaboratively integrating rare-earth doped upconversion nanoparticles (UCNP) with graphene quantum dot (GQD) for highly efficacious PDT, based on the merits of UCNP, which can emit UV–vis light under near-infrared light (NIR) excitation, and GQD, which can produce 1O2 efficiently. For GQD-decorated UCNP nanoparticles (UCNP-GQD), the emission light from UCNP can further excite GQD with prominent 1O2 generation for NIR-triggered PDT. Furthermore, a hydrophilic rhodamine derivative, TRITC, is covalently tethered to afford the resultant UCNP-GQD/TRITC, possessing distinct mitochondrial targeting property. Thus mitochondrial specific PDT with in-situ1O2 burst in mitochondria induces sharp decrease of mitochondrial membrane potential, which initiates the tumor cell apoptosis irreversibly. Importantly, in vivo experiments demonstrate the tumor inhibition of mitochondrial targeting UCNP-GQD/TRITC with improved therapeutic efficiency compared with non-targeting UCNP-GQD. The proposed strategy highlights the advantages of precision organelles-specific PDT in cancer therapy.
Pulsed laser can excite light absorber to generate photoacoustic (PA) effect, that is, when the absorber is irradiated with pulsed laser, the absorbed light energy is converted into local heat to ...cause rapid thermoelastic expansion and generate acoustic wave. The generated PA signal has been widely employed for the diagnosis of many diseases with superb contrast, high penetrability and sensitivity. In addition, with the increase of pulsed laser energy, the resulting PA shockwave and cavitation can promote efficient drug release at lesion sites to potentiate the resulting therapeutic efficacy. Furthermore, the PA shockwave/cavitation can mechanically inhibit disease and produce reactive species. In this Concept article, the principle and research status of pulsed laser excited disease theranostics are briefly summarized, extra suggestions are proposed to inspire extensive PA probes and photodynamic materials as well as novel methodologies.
Pulsed laser excited photoacoustic effect is increasingly employed for the diagnosis and treatment of diverse diseases. Pulsed laser irradiation is observed to generate reactive species by photosensitization‐free nanocapsules, which potentially broadens the scope of general photosensitizers via facile light mode switching from continuous to pulsed one. In this Concept article, the research status of pulsed laser excited disease theranostics is summarized to inspire novel methodologies and extra photoacoustic and photodynamic materials.
Combination chemotherapy with both hydrophobic and hydrophilic therapeutic drugs is clinically vital toward the treatment of persistent cancers. Though conventional liposomes and polymeric vesicles ...possessing hydrophobic bilayers and aqueous interiors can serve as codelivery nanocarriers, it remains a considerable challenge to achieve synchronized release of both types of drugs due to distinct encapsulation mechanisms; premature release of water‐soluble cargos from unstable liposomes and ruptured vesicles is also a major concern. Herein, the fabrication of physiologically stable polyprodrug‐gated crosslinked vesicles (GCVs) via the self‐assembly of camptothecin (CPT) polyprodrug amphiphiles and in situ bilayer crosslinking through traceless sol–gel reaction is reported. Polyprodrug‐GCVs possess high CPT loading (>30 wt%) and minimized leakage of encapsulated hydrophilic doxorubicin (DOX) hydrochloride due to the suppressed permeability of crosslinked membrane, exhibiting extended blood circulation (t
1/2 > 13 h) with caged cytotoxicity in physiological circulation. Upon cellular uptake by cancer cells, cytosolic reductive milieu‐triggered CPT unplugging from vesicle bilayers is demonstrated to generate hydrophilic mesh channels and make the membrane highly permeable. Concurrently, it will promote DOX corelease from hydrophilic lumen (≈36‐fold increase). The reduction‐activated combination chemotherapeutic potency based on polyprodrug‐GCVs is confirmed by both in vitro and in vivo explorations.
Concurrent drug unplugging and permeabilization of polyprodrug‐gated crosslinked vesicles (GCVs) are activated by cytosolic glutathione (GSH) for cancer combination chemotherapy. The GCVs exhibit high camptothecin (CPT) loading content, minimized leakage of encapsulated hydrophilic doxorubicin (DOX), caged cytotoxicity, and extended blood circulation. In cancer cells, cytosolic GSH triggers CPT unplugging and concurrent formation of hydrophilic channels to promote DOX corelease.
Bacteria biofilm has extracellular polymeric substances to protect bacteria from external threats, which is a stubborn problem for human health. Herein, a kind of gasifiable nanodroplet is fabricated ...to ablate Staphylococcus aureus (S. aureus) biofilm. Upon NIR pulsed laser irradiation, the nanodroplets can gasify to generate destructive gas shockwave, which further potentiates initial acoustic cavitation effect, thus synergistically disrupting the protective biofilm and killing resident bacteria. More importantly, the gasification can further promote antibiotic release in deep biofilm for residual bacteria eradication. The nanodroplets not only exhibit deep biofilm penetration capacity and high potency to ablate biofilms, but also good biocompatibility without detectable side effects. In vivo mouse implant model indicates that the nanodroplets can accumulate at the S. aureus infected implant sites. Upon pulsed laser treatment, the nanodroplets efficiently eradicate bacteria biofilm in implanted catheter by synergistic contribution of gas shockwave-enhanced cavitation and deep antibiotic release. Current phase changeable nanodroplets with synergistic physical and chemical therapeutic modalities are promising to combat complex bacterial biofilms with drug resistance, which provides an alternative visual angle for biofilm inhibition in biomedicine.
Fluorescence and photoacoustic imaging have different advantages in cancer diagnosis; however, combining effects in one agent normally requires a trade-off as the mechanisms interfere. Here, based on ...rational molecular design, we introduce a smart organic nanoparticle whose absorbed excitation energy can be photo-switched to the pathway of thermal deactivation for photoacoustic imaging, or to allow opposed routes for fluorescence imaging and photodynamic therapy. The molecule is made of a dithienylethene (DTE) core with two surrounding 2-(1-(4-(1,2,2-triphenylvinyl)phenyl)ethylidene)malononitrile (TPECM) units (DTE-TPECM). The photosensitive molecule changes from a ring-closed, for photoacoustic imaging, to a ring-opened state for fluorescence and photodynamic effects upon an external light trigger. The nanoparticles' photoacoustic and fluorescence imaging properties demonstrate the advantage of the switch. The use of the nanoparticles improves the outcomes of in vivo cancer surgery using preoperative photoacoustic imaging and intraoperative fluorescent visualization/photodynamic therapy of residual tumours to ensure total tumour removal.
We report on the fabrication of dynamic covalent shell cross-linked (SCL) micelles with hydrophobic cores conjugated with photocaged chemotherapeutic drugs and coronas functionalized with ligands for ...tumor cell targeting. Two types of amphiphilic diblock copolymers, P(CL-g-CPT)-b-P(OEGMA-co-MAEBA)-CPT and PCL-b-P(OEGMA-co-MAEBA-co-FA), were synthesized via the combination of ring-opening copolymerization (ROP) of ε-caprolactone (CL) and 2-bromo-ε-caprolactone (CL-Br), atom transfer radical polymerization (ATRP) of oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA) and p-(methacryloxyethoxy) benzaldehyde (MAEBA) comonomers, and “click” post-functionalization with photocaged camptothecin (CPT) prodrug and alkynyl-functionalized folic acid (FA) moieties, respectively. Mixed micelles coassembled from PCL-b-P(OEGMA-co-MAEBA-co-FA) and P(CL-g-CPT)-b-P(OEGMA-co-MAEBA)-CPT possess hydrophobic cores conjugated with photocaged CPT prodrugs and hydrophilic outer coronas covalently attached with aldehyde groups and FA moieties for subsequent shell cross-linking and cancer cell targeting. Shell cross-linking was performed at pH 6.2 upon addition of difunctional cross-linker, dithiol bis(propanoic dihydrazide) (DTP), under the catalysis of aniline. The obtained FA-decorated SCL micelles contain acylhydrazone and disulfide linkages in the outer coronas, which can be de-cross-linked under two biologically relevant conditions, mildly acidic or reductive microenvironments, that is, endosomal/lysosomal pH or high GSH level in the cytosol. The cleavage of caged CPT drug within the cores of SCL micelles can be effectively actuated under photo irradiation, whereas its diffusion out of micellar nanocarriers can be further modulated by pH and thiol levels due to the dually responsive nature of DTP cross-linker. Compared with the control, FA-decorated SCL micelles can more efficiently enter folate-receptor expressing cancer cells than folate-receptor deficient ones. Cell viability assays revealed that SCL micelles displayed at least ∼9.7-fold enhanced cytotoxicity upon light irradiation. The reported targeting ligand decorated and prodrug-conjugated dynamic covalent SCL micelles exert intricate control concerning micellar stability, cancer cell targeting, photo-triggered parent drug release with photoactivated cytotoxicity, and tunable drug release profiles. All of these augur well for their potential application as a novel integrated platform for targeted drug delivery in cancer chemotherapy.
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