Wendong Ke

A Near-Infrared Photothermal Effect-Responsive Drug Delivery System Based on Indocyanine Green and Doxorubicin-Loaded Polymeric Micelles Mediated by Reversible Diels-Alder Reaction

Near-infrared light (NIR) possesses great advantages for light-responsive controllable drug release, such as deep tissue penetration and low damage to healthy tissues. Herein, a NIR-responsive drug delivery system is developed based on a NIR dye, indocyanine green (ICG), and anticancer drug, doxorubicin (DOX)-loaded thermoresponsive block copolymer micelles, in which the drug release can be controlled via NIR irradiation. First, block copolymers, poly(oligo(ethylene glycol) methacrylate)-block-poly(furfuryl methacrylate) (POEGMA-b-PFMA), are synthesized by sequential reversible addition-fragmentation chain-transfer (RAFT) polymerization, followed by modification with N-octyl maleimide through Diels-Alder (DA) reaction to produce POEGMA-b-POMFMA. The self-assembly of POEGMA-b-POMFMA by nano-precipitation in aqueous solution affords the polymeric micelles which are used to simultaneously encapsulate ICG and DOX. Upon irradiation by NIR light (805 nm), the loaded DOX is released rapidly from the micelles due to partial retro DA reaction and local temperature increase-induced faster drug diffusion by the photothermal effect. Cytotoxicity evaluation and intracellular distribution observation demonstrate significant synergistic effects of NIR-triggered drug release, photothermal, and chemotherapy toward cancer cells under NIR irradiation.

Polymer Prodrug-Based Nanoreactors Activated by Tumor Acidity for Orchestrated Oxidation/Chemotherapy

Therapeutic nanoreactors have been proposed to treat cancers through in situ transformation of low-toxicity prodrugs into toxic therapeutics in the body. However, the in vivo applications are limited by low tissue-specificity and different tissue distributions between sequentially injected nanoreactors and prodrugs. Herein, we construct a block copolymer prodrug-based polymersome nanoreactor that can achieve novel orchestrated oxidation/chemotherapy of cancer via specific activation at tumor sites. The block copolymers composed of poly(ethylene glycol) (PEG) and copolymerized monomers of camptothecin (CPT) and piperidine-modified methacrylate [P(CPTMA-co-PEMA)] were optimized to self-assemble into polymersomes in aqueous solution for encapsulation of glucose oxidase (GOD) to obtain GOD-loaded polymersome nanoreactors (GOD@PCPT-NR). GOD@PCPT-NR maintained inactive in normal tissues upon systemic administration. After deposition in tumor tissues, tumor acidity-triggered protonation of PPEMA segments resulted in high permeability of the polymersome membranes and oxidation reaction of diffused glucose and O2 under the catalysis of GOD. The activation of the reaction generated H2O2, improving the oxidative stress in tumors. Simultaneously, a high level of H2O2 further activated PCPTMA prodrugs, releasing active CPT drugs. High tumor oxidative stress and released CPT drugs synergistically killed cancer cells and suppressed tumor growth via oxidation/chemotherapy. Our study provides a new strategy for engineering therapeutic nanoreactors in an orchestrated fashion for cancer therapy.

Self-sufficing H2O2-responsive nanocarriers through tumor-specific H2O2 production for synergistic oxidation-chemotherapy

One of distinct features in tumor tissues is the elevated concentration of reactive oxygen species (ROS) during tumor immortality, proliferation and metastasis. However, ROS-responsive materials are rarely utilized in the field of in vivo tumoral ROS-responsive applications due to the fact that the intrinsic ROS level in the tumors could not escalate to an adequate level that the developed materials can possibly respond. Herein, palmitoyl ascorbate (PA) as a prooxidant for hydrogen peroxide (H2O2) production in tumor tissue is strategically compiled into a H2O2-responsive camptothecin (CPT) polymer prodrug micelle, which endowed the nanocarriers with self-sufficing H2O2 stimuli in tumor tissues. Molecular oncology manifests the hallmarks of tumoral physiology with deteriorating propensity in eliminating hazardous ROS. H2O2 production was demonstrated to specifically sustain in tumors, which not only induced tumor cell apoptosis by elevated oxidation stress but also served as autochthonous H2O2 resource to trigger CPT release for chemotherapy. Excess H2O2 and released CPT could penetrate into cells efficiently, which showed synergistic cytotoxicity toward cancer cells. Systemic therapeutic trial revealed potent tumor suppression of the proposed formulation via synergistic oxidation-chemotherapy. This report represents a novel nanomedicine platform combining up-regulation of tumoral H2O2 level and self-sufficing H2O2-responsive drug release to achieve novel synergistic oxidation-chemotherapy.

Therapeutic Vesicular Nanoreactors with Tumor-Specific Activation and Self-Destruction for Synergistic Tumor Ablation

Polymeric nanoreactors (NRs) have distinct advantages to improve chemical reaction efficiency, but the in vivo applications are limited by lack of tissue-specificity. Herein, novel glucose oxidase (GOD)-loaded therapeutic vesicular NRs (theraNR) are constructed based on a diblock copolymer containing poly(ethylene glycol) (PEG) and copolymerized phenylboronic ester or piperidine-functionalized methacrylate (P(PBEM-co-PEM)). Upon systemic injection, theraNR are inactive in normal tissues. At a tumor site, theraNR are specifically activated by the tumor acidity via improved permeability of the membranes. Hydrogen peroxide (H2 O2 ) production by the catalysis of GOD in theraNR increases tumor oxidative stress significantly. Meanwhile, high levels of H2 O2 induce self-destruction of theraNR releasing quinone methide (QM) to deplete glutathione and suppress the antioxidant ability of cancer cells. Finally, theraNR efficiently kill cancer cells and ablate tumors via the synergistic effect.

Matrix Metalloproteinase-Responsive Multifunctional Peptide-Linked Amphiphilic Block Copolymers for Intelligent Systemic Anticancer Drug Delivery

The amphiphilic block copolymer anticancer drug nanocarriers clinically used or in the progress of clinical trials frequently suffer from modest final therapeutic efficacy due to a lack of intelligent features. For example, the biodegradable amphiphilic block copolymer, poly(ethylene glycol)-b-poly(d,l-lactide) (PEG-PDLLA) has been approved for clinical applications as a paclitaxel (PTX) nanocarrier (Genexol-PM) due to the optimized pharmacokinetics and biodistribution; however, a lack of intelligent features limits the intracellular delivery in tumor tissue. To endow the mediocre polymer with smart properties via a safe and facile method, we introduced a matrix metalloproteinase (MMP)-responsive peptide GPLGVRGDG into the block copolymer via efficient click chemistry and ring-opening polymerization to prepare PEG-GPLGVRGDG-PDLLA (P1). P1 was further self-assembled into micellar nanoparticles (NPs) to load PTX, which show MMP-2-triggered dePEGylation due to cleavage of the peptide linkage. Moreover, the residual VRGDG sequences are retained on the surface of the NPs after dePEGylation, which can serve as ligands to facilitate the cellular uptake. The cytotoxicity of PTX loaded in P1 NPs against 4T1 cells is significantly enhanced as compared with free PTX or PTX-loaded PEG-GPLGVRG-PDLLA (P2) and PEG-PDLLA (P3) NPs. In vivo studies confirmed that PTX-loaded P1 NPs show prolonged blood circulation, which are similar to P2 and P3 NPs but exhibit more-efficient accumulation in the tumor site. Ultimately, PTX-loaded P1 NPs display statistically significant improvement of antitumor activity against tumor-bearing mice via systemic administration. Therefore, the strategy by facile incorporation of a responsive peptide linkage between PEG and PDLLA is a promising approach to improving the therapeutic efficacy of anticancer-drug-loaded amphiphilic block copolymer micelles.

Finely Tuned Thermo-Responsive Block Copolymer Micelles for Photothermal Effect-Triggered Efficient Cellular Internalization

Although biodegradable amphiphilic block copolymer micelles have been widely applied in the clinical applications as drug delivery nanocarriers, low-efficiency cellular internalization frequently reduces therapeutic efficacy of the loaded drugs. Here, photothermal effect-promoted cellular internalization of finely tuned thermo-responsive amphiphilic biodegradable block copolymer nanocarriers via noninvasive stimuli of near-infrared (NIR) light irradiation is demonstrated. Amphiphilic block copolymers, poly(ε-caprolactone)-block-poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (PCL-b-P(NIPAM-co-DMA)), are prepared with finely tuned compositions of P(NIPAM-co-DMA) for desirable lower critical solution temperature of the block copolymer micelles in aqueous solution. The block copolymers are then used to co-encapsulate doxorubicin and indocyanine green, which show high encapsulation efficiency and significant photothermal effect upon exposure to NIR light irradiation. The photothermal effect-induced collapse and hydrophilic-to-hydrophobic transition of P(NIPAM-co-DMA) shells significantly enhance the interactions between drug-loaded micelles and cell membranes, which dramatically promote the cellular internalization of the micelles and therapeutic efficacy of loaded anticancer drugs.

Intracellular glutathione-depleting polymeric micelles for cisplatin prodrug delivery to overcome cisplatin resistance of cancers

&NA; The intrinsic or acquired cisplatin resistance of cancer cells frequently limits the final therapeutic efficacy. Detoxification by the high level of intracellular glutathione (GSH) plays critical roles in the majority of cisplatin‐resistant cancers. In this report, we designed an amphiphilic diblock copolymer composed of poly(ethylene glycol) (PEG) and polymerized phenylboronic ester‐functionalized methacrylate (PBEMA), PEG‐b‐PBEMA, which can self‐assemble into micelles in aqueous solutions to load hydrophobic cisplatin prodrug (Pt(IV)). Pt(IV)‐loaded PEG‐b‐PBEMA micelles (PtBE‐Micelle) reverse cisplatin‐resistance of cancer cells through improving cellular uptake efficiency and reducing intracellular GSH level. We found that the cellular uptake amount of platinum from PtBE‐Micelle was 6.1 times higher than that of free cisplatin in cisplatin‐resistant human lung cancer cells (A549R). Meanwhile, GSH concentration of A549R cells was decreased to 32% upon treatment by PEG‐b‐PBEMA micelle at the phenyl borate‐equivalent concentration of 100 &mgr;M. PtBE‐Micelle displayed significantly higher cytotoxicity toward A549R cells with half maximal inhibitory concentration (IC50) of cisplatin‐equivalent 0.20 &mgr;M compared with free cisplatin of 33.15 &mgr;M and Pt(IV)‐loaded PEG‐b‐poly(&egr;‐caprolactone) micelles of cisplatin‐equivalent 0.75 &mgr;M. PtBE‐Micelle can inhibit the growth of A549R xenograft tumors effectively. Accordingly, PEG‐b‐PBEMA micelles show great potentials as drug delivery nanocarriers for platinum‐based chemotherapy toward cisplatin‐resistant cancers.

Smart Asymmetric Vesicles with Triggered Availability of Inner Cell-Penetrating Shells for Specific Intracellular Drug Delivery

Smart nanocarriers attract considerable interest in the filed of precision nanomedicine. Dynamic control of the interaction between nanocarriers and cells offers the feasibility that in situ activates cellular internalization at the targeting sites. Herein, we demonstrate a novel class of enzyme-responsive asymmetric polymeric vesicles self-assembled from matrix metalloproteinase (MMP)-cleavable peptide-linked triblock copolymer, poly(ethylene glycol)-GPLGVRG-b-poly(ε-caprolactone)-b-poly(3-guanidinopropyl methacrylamide) (PEG-GPLGVRG-PCL-PGPMA), in which the cell-penetrating PGPMA segments asymmetrically distribute in the outer and inner shells with fractions of 9% and 91%, respectively. Upon treatment with MMP-2 to cleave the stealthy PEG shell, the vesicles undergo morphological transformation into fused multicavity vesicles and small nanoparticles, accompanied by redistribution of PGPMA segments with 76% exposed to the outside. The vesicles after dePEGylation show significantly increased cellular internalization efficiency (∼10 times) as compared to the original ones due to the triggered availability of cell-penetrating shells. The vesicles loading hydrophobic anticancer drug paclitaxel (PTX) in the membrane exhibit significantly enhanced cytotoxicity against MMP-overexpressing HT1080 cells and multicellular spheroids. The proposed vesicular system can serve as a smart nanoplatform for in situ activating intracellular drug delivery in MMP-enriched tumors.

Integrated Nanoparticles To Synergistically Elevate Tumor Oxidative Stress and Suppress Antioxidative Capability for Amplified Oxidation Therapy

The improved antioxidant system of cancer cells renders them well-adaptive to the intrinsic oxidative stress in tumor tissues. On the other hand, cancer cells are more sensitive to elevated tumor oxidative stress as compared with normal cells due to their deficient reactive oxygen species-eliminating systems. Oxidation therapy of cancers refers to the strategy of killing cancer cells through selectively increasing the oxidative stress in tumor tissues. In this article, to amplify the oxidation therapy, we develop integrated nanoparticles with the properties to elevate tumor oxidative stress and concurrently suppress the antioxidative capability of cancer cells. The amphiphilic block copolymer micelles of poly(ethylene glycol)-b-poly[2-((((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)carbonyl)oxy)ethyl methacrylate] (PEG-b-PBEMA) are integrated with palmitoyl ascorbate (PA) to form hybrid micelles (PA-Micelle). PA molecules at pharmacologic concentrations serve as a prooxidant to upregulate the hydrogen peroxide (H2O2) level in tumor sites and the PBEMA segment exhibits H2O2-triggered release of quinone methide for glutathione depletion to suppress the antioxidative capability of cancer cells, which synergistically and selectively kill cancer cells for tumor growth suppression. Given the significantly low side toxicity against normal tissues, this novel integrated nanoparticle design represents a novel class of nanomedicine systems for high-efficiency oxidation therapy with the potentials to be translated to clinical applications.

Oxygen-independent combined photothermal/photodynamic therapy delivered by tumor acidity-responsive polymeric micelles

ABSTRACT Tumor hypoxia strikingly restricts photodynamic therapy (PDT) efficacy and limits its clinical applications in cancer therapy. The ideal strategy to address this issue is to develop oxygen‐independent PDT systems. Herein, the rationally designed tumor pH‐responsive polymeric micelles are devised to realize oxygen‐independent combined PDT and photothermal therapy (PTT) under near‐infrared light (NIR) irradiation. The triblock copolymer, poly(ethylene glycol)‐b‐poly(&egr;‐caprolactone)‐b‐poly(2‐(piperidin‐1‐yl)ethyl methacrylate) (PEG‐b‐PCL‐b‐ PPEMA), was prepared to co‐encapsulate cypate and singlet oxygen donor (diphenylanthracene endoperoxide, DPAE) via self‐assembly to obtain the micellar delivery system (C/O@N‐Micelle). C/O@N‐Micelle showed remarkable tumor accumulation and improved cellular internalization (2.1 times) as the pH value was changed from 7.4 during blood circulation to 6.8 in tumor tissues. The micelles could produce a potent hyperthermia for PTT of cypate under 808 nm NIR irradiation, which simultaneously induced thermal cycloreversion of DPAE generating abundant singlet oxygen for PDT without participation of tumor oxygen. Finally, the photothermally triggered PDT and PTT combination achieved efficient tumor ablation without remarkable systemic toxicity in an oxygen‐independent manner. This work represents an efficient strategy for oxygen‐independent combined PDT and PTT of cancers under NIR irradiation through co‐encapsulation of cypate and DPAE into tumor pH‐responsive polymeric micelles. Graphical abstract Figure. No caption available.