Iron ion-coordinated carrier-free supramolecular co-nanoassemblies of dual DNA topoisomerase-targeting inhibitors for tumor suppression.

Overexpressed DNA topoisomerase II alpha (TOP-2A) is closely related to the invasion and metastasis of malignant breast tumors. Mitoxantrone (MTX) has been identified as a TOP-2A inhibitor with significant inhibitory activity against breast tumors. The tumor-homing ability of MTX has been further enhanced by using nanodrug delivery systems (nano-DDSs), reducing off-target side effects. However, conventional MTX nano-DDSs are still limited by low drug-loading capacity and material carrier-related toxicity. In this study, we developed metal iron-coordinated carrier-free supramolecular co-nanoassemblies of dual DNA topoisomerase-targeting inhibitors with high drug loading for superimposed DNA damage-augmented tumor regression. By introducing iron ions (Ⅲ) and another TOP-2A inhibitor quercetin (QU) onto the building blocks, Fe3+-mediated QU-MTX co-nanoassemblies are fabricated (QU-MTX-Fe) via intermolecular coordination interactions. The PEGylated co-nanoassemblies (P-QU-MTX-Fe) exhibit distinct advantages over QU/MTX solution (Sol) alone or MTX-QU mixture Sol in terms of therapeutic efficacy and systemic toxicity. Meanwhile, P-QU-MTX-Fe could efficiently suppress primary and distal breast tumor relapse by activating the CD 8+-mediated antitumor immune response. Overall, such iron-coordinated nanomedicines provide insights into the rational design of drug-likeness compounds with undesirable therapeutic performance for cancer therapy. STATEMENT OF SIGNIFICANCE: Aimed at the key target TOP-2A in the malignant breast tumor, the metal coordination-mediated supramolecular co-assemble strategy of one-target dual inhibitors was firstly proposed for superimposed DNA damage for cancer therapy. Multiple interactions involving π-π stacking interactions, hydrogen bonds and coordination forces maintained the stability of co-nanoassemblies. Meanwhile, this co-nanoassemblies not only had potentials to increase therapeutic efficacy and decrease systemic toxicity, but also activated the CD 8+-mediated antitumor immune response against distal breast tumor relapse. Such a facile and safe nanoplatform is expected to provide an important prospective for promoting the clinical transformation of drug-likeness compounds in the suppression of difficult-to-treat breast tumor.

[Normalization of the ratio of nitric oxide and peroxynitrite by promoting eNOS dimer activity is a new direction for diabetic nephropathy treatment].

Diabetic nephropathy is a microvascular complication of diabetes. Its etiology involves metabolic disorder-induced endothelial dysfunction. Endothelium-derived nitric oxide (NO) plays an important role in a number of physiological processes, including glomerular filtration and endothelial protection. NO dysregulation is an important pathogenic basis of diabetic nephropathy. Hyperglycemia and dyslipidemia can lead to oxidative stress, chronic inflammation and insulin resistance, thus affecting NO homeostasis regulated by endothelial nitric oxide synthase (eNOS) and a conglomerate of related proteins and factors. The reaction of NO and superoxide (O2.-) to form peroxynitrite (ONOO-) is the most important pathological NO pathway in diabetic nephropathy. ONOO- is a hyper-reactive oxidant and nitrating agent in vivo which can cause the uncoupling of eNOS. The uncoupled eNOS does not produce NO but produces superoxide. Thus, eNOS uncoupling is a critical contributor of NO dysregulation. Understanding the regulatory mechanism of NO and the effects of various pathological conditions on it could reveal the pathophysiology of diabetic nephropathy, potential drug targets and mechanisms of action. We believe that increasing the stability and activity of eNOS dimers, promoting NO synthesis and increasing NO/ONOO- ratio could guide the development of drugs to treat diabetic nephropathy. We will illustrate these actions with some clinically used drugs as examples in the present review.

Elaborately Engineering a Self-Indicating Dual-Drug Nanoassembly for Site-Specific Photothermal-Potentiated Thrombus Penetration and Thrombolysis.

Thrombotic cardio-cerebrovascular diseases seriously threaten human health. Currently, conventional thrombolytic treatments are challenged by the low utilization, inferior thrombus penetration, and high off-target bleeding risks of most thrombolytic drugs, resulting in unsatisfactory treatment outcomes. Herein, it is proposed that these challenges can be overcome by precisely integrating the conventional thrombolytic strategy with photothermal therapy. After co-assembly engineering optimization, a fibrin-targeting peptide-decorated nanoassembly of DiR (a photothermal probe) and ticagrelor (TGL, an antiplatelet drug) is prepared for thrombus-homing delivery, abbreviated as FT-DT NPs. The elaborately engineered nanoassembly shows multiple advantages, including simple preparation with high drug co-loading capacity, synchronous delivery of two drugs with long systemic circulation, thrombus-targeted accumulation with self-indicating function, as well as photothermal-potentiated thrombus penetration and thrombolysis with high therapeutic efficacy. As expected, FT-DT NPs not only show bright fluorescence signals in the embolized vessels, but also perform photothermal/antiplatelet synergistic thrombolysis in vivo. This study offers a simple and versatile co-delivery nanoplatform for imaging-guided photothermal/antiplatelet dual-modality thrombolysis.

Photosensitizer-driven nanoassemblies of homodimeric prodrug for self-enhancing activation and synergistic chemo-photodynamic therapy.

Carrier-free prodrug-nanoassemblies have emerged as promising nanomedicines. In particular, the self-assembled nanoparticles (NPs) composed of homodimeric prodrugs with ultrahigh drug loading have attracted broad attention. However, most homodimeric prodrugs show poor self-assembly ability due to their symmetric structures. Herein, we developed photosensitizer-driven nanoassemblies of homodimeric prodrug for self-enhancing activation and chemo-photodynamic synergistic therapy. Methods: In this work, a pyropheophorbide a (PPa)-driven nanoassemblies of an oxidation-responsive cabazitaxel homodimer (CTX-S-CTX) was fabricated (pCTX-S-CTX/PPa NPs). The assembly mechanisms, aggregation-caused quenching (ACQ) effect alleviation, singlet oxygen generation, self-enhancing prodrug activation, cellular uptake, intracellular reactive oxygen species (ROS) generation and synergistic cytotoxicity of pCTX-S-CTX/PPa NPs were investigated in vitro. Moreover, the pharmacokinetics, ex vivo biodistribution and in vivo therapeutic efficacy of pCTX-S-CTX/PPa NPs were studied in mice bearing 4T1 tumor. Results: Interestingly, PPa was found to drive the assembly of CTX-S-CTX, which cannot self-assemble into stable NPs alone. Multiple intermolecular forces were found to be involved in the assembly process. Notably, the nanostructure was destroyed in the presence of endogenous ROS, significantly relieving the ACQ effect of PPa. In turn, ROS generated by PPa under laser irradiation together with the endogenous ROS synergistically promoted prodrug activation. As expected, the nanoassemblies demonstrated potent antitumor activity in a 4T1 breast cancer BALB/c mice xenograft model. Conclusion: Our findings offer a simple strategy to facilitate the assembly of homodimeric prodrugs and provide an efficient nanoplatform for chemo-photodynamic therapy.

Oxidation-strengthened disulfide-bridged prodrug nanoplatforms with cascade facilitated drug release for synergetic photochemotherapy.

One of the major barriers in utilizing prodrug nanocarriers for cancer therapy is the slow release of parent drug in tumors. Tumor cells generally display the higher oxidative level than normal cells, and also displayed the heterogeneity in terms of redox homeostasis level. We previously found that the disulfide bond-linkage demonstrates surprising oxidation-sensitivity to form the hydrophilic sulfoxide and sulphone groups. Herein, we develop oxidation-strengthened prodrug nanosystem loaded with pyropheophorbide a (PPa) to achieve light-activatable cascade drug release and enhance therapeutic efficacy. The disulfide bond-driven prodrug nanosystems not only respond to the redox-heterogeneity in tumor, but also respond to the exogenous oxidant (singlet oxygen) elicited by photosensitizers. Once the prodrug nanoparticles (NPs) are activated under irradiation, they would undergo an oxidative self-strengthened process, resulting in a facilitated drug cascade release. The IC50 value of the PPa@PTX-S-S NPs without irradiation was 2-fold higher than those of NPs plus irradiation. In vivo, the PPa@PTX prodrug NPs display prolonged systemic circulation and increased accumulation in tumor site. The PPa@PTX-S-S NPs showed much higher efficiency than free PTX or the PPa@PTX-C-C NPs to suppress the growth of 4T1 tumors. Therefore, this novel oxidation-strengthened disulfide-bridged prodrug-nanosystem has a great potential in the enhanced efficacy of cancer synergetic photochemotherapy.

An exosome-like programmable-bioactivating paclitaxel prodrug nanoplatform for enhanced breast cancer metastasis inhibition.

Metastasis is closely associated with high breast cancer mortality. Although nanotechnology-based anti-metastatic treatments have developed rapidly, the anti-metastasis efficiency is still far from satisfactory, mainly due to the poor recognition of circulating tumor cells (CTCs) in blood. Herein, we developed an exosome-like sequential-bioactivating prodrug nanoplatform (EMPCs) to overcome the obstacle. Specifically, the reactive oxygen species (ROS)-responsive thioether-linked paclitaxel-linoleic acid conjugates (PTX-S-LA) and cucurbitacin B (CuB) are co-encapsulated into polymeric micelles, and the nanoparticles are further decorated with exosome membrane (EM). The resulting EMPCs could specifically capture and neutralize CTCs during blood circulation through the high-affinity interaction between cancer cell membrane and homotypic EM. Following cellular uptake, EMPCs first release CuB, remarkably blocking tumor metastasis via downregulation of the FAK/MMP signaling pathway. Moreover, CuB obviously elevates the intracellular oxidative level to induce a sequential bioactivation of ROS-responsive PTX-S-LA. In vitro and in vivo results demonstrate that EMPCs not only exhibit amplified prodrug bioactivation, prolonged blood circulation, selective targeting of homotypic tumor cells, and enhanced tumor penetration, but also suppress tumor metastasis through CTCs clearance and FAK/MMP signaling pathway regulation. This study proposes an integrated approach for mechanism-based inhibition of tumor metastasis and manifests a promising potential of programmable-bioactivating prodrug nanoplatform for cancer metastasis inhibition.

Cytochrome P450 enzyme-mediated auto-enhanced photodynamic cancer therapy of co-nanoassembly between clopidogrel and photosensitizer.

Reactive oxygen species (ROS)-based photodynamic therapy (PDT) has a widespread application in cancer therapy. Nevertheless, the efficiency of PDT is far from satisfactory. One major impediment is the overexpression of glutathione (GSH) in tumor cells, which could deplete the level of PDT-generated ROS. Herein, we develop a novel type of cytochrome P450 enzyme-mediated auto-enhanced photodynamic co-nanoassembly between clopidogrel (CPG) and photosensitizer pyropheophorbide a (PPa). Methods: In this work, we prepare the co-assembled nanoparticles of CPG and PPa (CPG/PPa NPs) by using one-step precipitation method. The assembly mechanism, drug release behavior, GSH consumption, ROS generation, cellular uptake, cytotoxicity of CPG/PPa NPs are investigated in vitro. The mice bearing 4T1 tumor are employed to evaluate in vivo biodistribution and anti-tumor effect of CPG/PPa NPs. Results: Such CPG/PPa NPs could disrupt the intracellular redox homeostasis, resulting from the elimination of GSH by CPG active metabolite mediated by cytochrome P450 enzyme (CYP2C19). The in vivo assays reveal that CPG/PPa NPs not only increase the drug accumulation in tumor sites but also significantly suppress tumor growth in BALB/c mice bearing 4T1 tumor. With CPG-mediated GSH consumption and PPa-triggered ROS generation, CPG/PPa NPs show the enhanced PDT treatment effect by breaking intracellular redox balance. Conclusion: Our findings provide a valuable knowledge for the rational design of the PDT-based combinational cancer therapy.

Nanosponges of circulating tumor-derived exosomes for breast cancer metastasis inhibition.

Breast cancer contributes to high mortality rates as a result of metastasis. Tumor-derived exosomes facilitate the development of the premetastatic environment, interacting and inhibiting the normal function of immune cells, thereby forming an immunosuppressive microenvironment for tumor metastasis. Herein, the platelet and neutrophil hybrid cell membrane (PNM) was embellished on a gold nanocage (AuNC) surface called nanosponges and nanokillers (NSKs). NSKs can simultaneously capture and clear the circulating tumor cells (CTCs) and tumor-derived exosomes via high-affinity membrane adhesion receptors, effectively cutting off the connection between exosomes and immune cells. Bionic NSK is loaded with doxorubicin (DOX) and indocyanine green (ICG) for synergic chemo-photothermal therapy. NSKs show greater cellular uptake, deeper tumor penetration, and higher cytotoxicity to tumor cells in comparison to non-coated AuNCs or single-coated AuNCs in vitro. In vivo, the multipurpose NSKs could not only completely ablate the primary tumor but also inhibit breast cancer metastasis with high efficiency in xenograft and orthotopic breast tumor-bearing models. Thus, NSKs could be a promising nanomedicine for the future clinical intervention of breast cancer metastasis.

Bioactivatable Pseudotripeptidization of Cyclic Dipeptides To Increase the Affinity toward Oligopeptide Transporter 1 for Enhanced Oral Absorption: An Application to Cyclo(l-Hyp-l-Ser) (JBP485).

The cyclic dipeptides generally present lower affinity toward intestinal oligopeptide transporter 1 (PEPT1) than the linear dipeptides. JBP485 (cyclo(l-Hyp-l-Ser)) is a low-affinity substrate of PEPT1 with poor oral bioavailability. However, JBP923 (l-Hyp-l-Ser) is a high-affinity substrate of PEPT1 with high oral absorption. We hypothesize that the bioactivatable pseudo-tripeptidization prodrug strategy is promising to increase the affinity of cyclic dipeptides toward PEPT1. To test our hypothesis, we design five amino acid ester prodrugs of JBP485. Compared with JBP485, the optimal prodrug (JBP485-3-CH2-O-valine, J3V) demonstrates improved affinity of PEPT1, oral bioavailability in rats and beagle dogs. Moreover, J3V can dose-dependently protect against liver injury. Additionally, J3V is stable in the gastrointestinal tract, beneficial to the PEPT1-mediated membrane transport, and is bioactivated in the enterocytes and hepatic cells, essential to elicit its bioactivity. In summary, the bioactivatable pseudo-tripeptidization strategy shows potential in increasing affinity of PEPT1 to enhance oral bioavailability of cyclic dipeptides.

Probing the impact of sulfur/selenium/carbon linkages on prodrug nanoassemblies for cancer therapy.

Tumor cells are characterized as redox-heterogeneous intracellular microenvironment due to the simultaneous overproduction of reactive oxygen species and glutathione. Rational design of redox-responsive drug delivery systems is a promising prospect for efficient cancer therapy. Herein, six paclitaxel-citronellol conjugates are synthesized using either thioether bond, disulfide bond, selenoether bond, diselenide bond, carbon bond or carbon-carbon bond as linkages. These prodrugs can self-assemble into uniform nanoparticles with ultrahigh drug-loading capacity. Interestingly, sulfur/selenium/carbon bonds significantly affect the efficiency of prodrug nanoassemblies. The bond angles/dihedral angles impact the self-assembly, stability and pharmacokinetics. The redox-responsivity of sulfur/selenium/carbon bonds has remarkable influence on drug release and cytotoxicity. Moreover, selenoether/diselenide bond possess unique ability to produce reactive oxygen species, which further improve the cytotoxicity of these prodrugs. Our findings give deep insight into the impact of chemical linkages on prodrug nanoassemblies and provide strategies to the rational design of redox-responsive drug delivery systems for cancer therapy.

Self-Strengthened Oxidation-Responsive Bioactivating Prodrug Nanosystem with Sequential and Synergistically Facilitated Drug Release for Treatment of Breast Cancer.

Although environment-sensitive prodrug-based nanoparticles (NPs) have developed rapidly, lots of prodrug NPs still show poor selectivity and efficiency of parent drug bioactivation because of tumor heterogeneity. Herein, self-strengthened bioactivating prodrug-based NPs are fabricated via co-encapsulation of oxidation-responsive thioether-linked linoleic acid-paclitaxel conjugates (PTX-S-LA) and ß-lapachone (LPC) into polymeric micelles (PMs). Following cellular uptake, PMs first release LPC to significantly elevate the reactive oxidative species (ROS) level through NAD(P)H: quinone oxidoreductase-1 (NQO1) catalysis. Then, NQO1-generated ROS in combination with endogenous high ROS levels in tumor cells could synergistically facilitate PTX-S-LA to release the active cytotoxic agent PTX. Such a novel prodrug nanosystem exhibits self-strengthened prodrug bioactivation, ultraselective release, and cytotoxicity between cancer and normal cells, prolonged circulation time, and enhanced tumor accumulation, leading to high antitumor efficiency and superior biosafety. Our findings pave the new way for the rational design of oxidation-responsive prodrug NPs for high-efficacy cancer chemotherapy.

Transformative hyaluronic acid-based active targeting supramolecular nanoplatform improves long circulation and enhances cellular uptake in cancer therapy.

Hyaluronic acid (HA) is a natural ligand of tumor-targeted drug delivery systems (DDS) due to the relevant CD44 receptor overexpressed on tumor cell membranes. However, other HA receptors (HARE and LYVE-1) are also overexpressing in the reticuloendothelial system (RES). Therefore, polyethylene glycol (PEG) modification of HA-based DDS is necessary to reduce RES capture. Unfortunately, pegylation remarkably inhibits tumor cellular uptake and endosomal escapement, significantly compromising the in vivo antitumor efficacy. Herein, we developed a Dox-loaded HA-based transformable supramolecular nanoplatform (Dox/HCVBP) to overcome this dilemma. Dox/HCVBP contains a tumor extracellular acidity-sensitive detachable PEG shell achieved by a benzoic imine linkage. The in vitro and in vivo investigations further demonstrated that Dox/HCVBP could be in a "stealth" state at blood stream for a long circulation time due to the buried HA ligands and the minimized nonspecific interaction by PEG shell. However, it could transform into a "recognition" state under the tumor acidic microenvironment for efficient tumor cellular uptake due to the direct exposure of active targeting ligand HA following PEG shell detachment. Such a transformative concept provides a promising strategy to resolve the dilemma of natural ligand-based DDS with conflicting two processes of tumor cellular uptake and in vivo nonspecific biodistribution.

Self-facilitated ROS-responsive nanoassembly of heterotypic dimer for synergistic chemo-photodynamic therapy.

There is an urgent need to develop efficient combination drug delivery approaches to address the low efficiency of clinical cancer monotherapy. However, how to achieve high-efficient synchronous co-delivery and synergistic therapy remains a big challenge. Herein, we report a self-facilitated nanoassembly of a heterotypic chemo-photodynamic dimer for multimodal cancer therapy. A reactive oxygen species (ROS)-responsive dimer of paclitaxel (PTX) and pyropheophorbide a (PPa) is rationally designed and synthesized. The "Two-in-One" dimer serves as both carrier material and cargo, could self-assemble into nanoparticles in water with ultrahigh co-loading capacity and self-facilitated ROS-responsive drug release. The endogenous ROS overproduced in tumor cells together with PPa-generated ROS under laser irradiation synergistically facilitate on-demand drug release from the nano-assembly. The disintegration of nanoassembly triggered by ROS effectively addresses the dilemma of aggregation-caused quenching (ACQ) effect of photosensitizer (PPa). Both in vitro and in vivo results suggest that PTX-initiated chemotherapy in combination with PPa-mediated PDT exhibits synergistic antitumor activity. Our findings provide a strategy for the rational design of nanocarrier for high-efficient synergetic cancer therapy.

Bioinspired nanoplatelets for chemo-photothermal therapy of breast cancer metastasis inhibition.

Breast cancer is associated with high mortality due to tumor metastasis. The anti-metastasis efficacy of photochemotherapy is strictly limited by poor targeting capability with respect to circulating tumor cells (CTCs) in blood and lymph. Herein, we decorate the platelet membrane (PM) on a surface of nanoparticles (NPs), referred to as nanoplatelets. A chemotherapeutic drug, doxorubicin (DOX), and an FDA-approved photothermal agent, indocyanine green (ICG), are co-encapsulated into the biomimetic nanoplatelets. Nanoplatelets possess immune surveillance-escaping capability and specifically capture and clear CTCs in both blood and lymphatic circulations via high-affinity interactions between the P-Selectin of PM and CD44 receptors of tumor cells. PM-coated NPs show greater cellular uptake in MDA-MB-231 breast cancer cells and further elicit higher cytotoxicity to tumor cells relative to uncoated NPs. In vivo, we disclose that the multifunctional nanoplatelets not only completely ablate the primary tumor but also inhibit breast cancer metastasis with high efficiency in the three established xenograft or orthotopic breast tumor-bearing mice models. We conclude that such biomimetic nanoplatelets represent a promising strategy of coating a surface of nanoparticles with platelet membrane to actively capture and destroy CTCs in blood and lymph in breast cancer anti-metastasis therapy.

Polydopamine-modified ROS-responsive prodrug nanoplatform with enhanced stability for precise treatment of breast cancer.

Development of smart stimuli-responsive prodrug nanomaterials for fast drug release and efficient antitumor therapy has attracted great attention in recent years. However, the inherent instability of naked prodrugs in the blood is an important challenge limiting their biomedical applications. Although a number of strategies have been taken to prevent prodrugs from hydrolyzing due to blood composition, most of these strategies are unsatisfactory. Here, we designed an extraordinary ROS-triggered prodrug nanoplatform fabricated by using a single thioether linker to conjugate PTX with 6-maleimidocaproic acid (MAL), resulting in the PTX-S-MAL prodrug self-assembling into uniform size nanoparticles; then the prodrug nanoplatform was modified with a polydopamine coating and PEGylation to confer high solubility and stability. In in vitro experiments, the polydopamine-modified ROS-responsive prodrug nanosystem showed a high sensitivity in term of various H2O2 concentrations, and the PDA coating on the surface of the prodrug nanosystem didn't affect the drug release properties. Moreover, the excellent polydopamine-modified ROS-triggered prodrug nanoplatform selectively and rapidly releases PTX in response to the ROS overproduced in tumor cells, but showed less cytotoxicity against normal cells. In in vivo experiments, the prepared polydopamine-modified prodrug-nanosystem obviously enhances the stability and tumor accumulation of prodrug, producing a remarkably improved breast cancer treatment with minimal side effects. Our studies demonstrated that this modified nanoplatform could significantly improve chemotherapy efficiency, which will find great potential in cancer treatment.

Insight into the preformed albumin corona on in vitro and in vivo performances of albumin-selective nanoparticles.

Preformed albumin corona of albumin-nonselective nanoparticles (NPs) is widely exploited to inhibit the unavoidable protein adsorption upon intravenous administration. However, very few studies have concerned the preformed albumin corona of albumin-selective NPs. Herein, we report a novel type of albumin-selective NPs by decorating 6-maleimidocaproyl polyethylene glycol stearate (SA) onto PLGA NPs (SP NPs) surface, taking albumin-nonselective PLGA NPs as control. PLGA NPs and SP NPs were prepared by emulsion-solvent evaporation method and the resultant NPs were in spherical shape with an average diameter around 180 nm. The corresponding albumin-coating PLGA NPs (PLGA@BSA NPs) and albumin-coating SP NPs (SP@BSA NPs) were formulated by incubating SP NPs or PLGA NPs with bovine serum albumin solution, respectively. The impact of albumin corona on particle characteristics, stability, photothermal effect, cytotoxicity, cell uptake, spheroid penetration and pharmacokinetics was investigated. In line with previous findings of preformed albumin coating, PLGA@BSA NPs exhibited higher stability, cytotoxicity, cell internalization and spheroid penetration performances in vitro, and longer blood circulation time in vivo than those of albumin-nonselective PLGA NPs, but albumin-selective SP NPs is capable of achieving a comparable in vitro and in vivo performances with both SP@BSA NPs and PLGA@BSA NPs. Our results demonstrate that SA decorated albumin-selective NPs pave a versatile avenue for optimizing nanoparticulate delivery without preformed albumin corona.

Exploring the relationship of hyaluronic acid molecular weight and active targeting efficiency for designing hyaluronic acid-modified nanoparticles.

Although it is reported that the targeting ability of hyaluronic acid (HA)-based nanoparticles (NPs) is molecular weight (MW) dependent, the influence of HA MW on targeting efficiency of HA-functionalized NPs and the underlying mechanism remain elusive. In this study, we constituted three HA-functionalized Dox-loaded NPs (Dox/HCVs) different HA MWs (7, 63, and 102 kDa) and attempted to illustrate the effects of HA MW on the targeting efficiency. The three Dox/HCVs had similar physiochemical and pharmaceutical characteristics, but showed different affinity to CD44 receptor. Furthermore, Dox/HCV-63 exerted the best targeting effect and the highest cytotoxicity compared with Dox/HCV-7 and Dox/HCV-102. It was interesting to found that both the HA-CD44 binding affinity and induced CD44 clustering by HA-based NPs were HA MW-dependent, the two of which determine the apparent targeting efficacy of Dox/HCV NPs in the conflicting directions. Those results laid a good foundation for rationally designing HA-based NPs in cancer therapy.

A novel oral prodrug-targeting transporter MCT 1: 5-fluorouracil-dicarboxylate monoester conjugates.

Monocarboxylate transporter 1 (MCT1) is responsible for oral absorption of short-chain monocarboxylic acids from small intestine, hence, it's likely to serve as an ideal design target for the development of oral prodrugs. However, potential application of MCT1 to facilitate the oral delivery is still unclear. Irregular oral absorption, poor permeability and bioavailability greatly limit the oral delivery efficiency of 5-fluorouracil (5-FU). Herein, we design three 5-FU-fatty acid conjugates targeting intestinal MCT1 with different lipophilic linkages. Interestingly, due to high MCT1 affinity and good gastrointestinal stability, 5-FU-octanedioic acid monoester prodrug exhibited significant improvement in membrane permeability (13.1-fold) and oral bioavailability (4.1-fold) compared to 5-FU. More surprisingly, stability experiment in intestinal homogenates showed that 5-FU prodrugs could be properly activated to release 5-FU within intestinal cells, which provides an ideal foundation for the improvement of oral bioavailability. In summary, good gastrointestinal stability, high membrane permeability and appropriate intestinal cell bioactivation are the important factors for high-efficiency 5-FU oral prodrugs, and such work provides a good platform for the development of novel oral prodrugs targeting intestinal transporters.

Light-activatable dual-source ROS-responsive prodrug nanoplatform for synergistic chemo-photodynamic therapy.

In the context of prodrug nanomedicines for cancer therapy, one of the great challenges is the slow and variable release of the parent drug in tumors. Recently, many smart redox-sensitive nanocarriers have been developed to address this problem. However, due to significant tumor heterogeneity, some redox-sensitive nanomedicines still show poor selectivity in drug release. Herein, we report the design and synthesis of a ROS-triggered prodrug nanoplatform fabricated with oxidation-responsive cabazitaxel (CTX) prodrugs for synergistic chemo-photodynamic therapy, thioether-/selenoether-linked conjugates of CTX and oleic acid (OA). These prodrugs can be readily self-assembled into nanoparticles, with pyropheophorbide a (PPa) co-encapsulated into the prodrug-nanosystem for combination therapy. The dual-source ROS-responsive prodrug nanosystems selectively and rapidly release CTX not only in response to endogenous ROS overproduced in tumor cells, but also to exogenous PPa-generated ROS under laser irradiation. Moreover, the selenium-containing linkage demonstrates significant advantages over a sulfur-containing linkage in terms of ROS-triggered drug release and cytotoxicity. The prepared prodrug-nanosystems significantly prolong the systemic circulation and tumor distribution of both CTX and PPa, thereby demonstrating synergistic chemo-photodynamic therapy in vivo. All these drug delivery advantages render the nanosystem extremely promising for cancer treatment.

Self-Assembly of a Pure Photosensitizer as a Versatile Theragnostic Nanoplatform for Imaging-Guided Antitumor Photothermal Therapy.

Imaging-guided diagnosis and phototherapy has been emerging as promising theragnostic strategies for detection and treatment of cancer. 1,1'-Dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR) has been widely investigated for in vivo imaging and photothermal therapy (PTT). However, the tumor-homing ability and PTT efficiency of DiR is greatly limited by its extremely low water solubility and nonspecific distribution in off-target tissues. Herein, a facile nanoassembly of pure DiR is reported as a theragnostic nanocarrier platform for imaging-guided antitumor phototherapy. Self-assembly of DiR has almost no effect on its in vitro photothermal efficacy when compared with DiR solution. Interestingly, the PEGylated nanoassemblies of DiR showed distinct advantages over DiR solution and non-PEGylated nanoassemblies in terms of systemic circulation and tumor-homing capability in vivo. As a result, PEGylated DiR nanoassemblies demonstrate potent photothermal tumor therapy in BALB/c mice bearing 4T1 xenograft tumors. Such a pure photosensitizer-based nanoassembly holds great potential as a versatile platform for efficient imaging-guided cancer therapy.