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Herein, we combined a derivative of cisplatin (CP) and the chemosensitizer lonidamine (LND) to design an amphiphilic prodrug, in which the ratio of LND to cisplatin was fixed at 2:1. Diaminedichlorodihydroxyplatinum (DH-CP) is a hydrophilic cisplatin derivative. Due to its appropriate amphiphilicity, this prodrug could self-assemble into stable nanoparticles (denoted as LNP-NPs). Under the action of excessive glutathione (GSH) in tumor cells, DH-CP could be reduced to cytotoxic cisplatin. In addition, the released LND could inhibit the metabolic process of tumor cells, and improving the sensitivity of tumor cells to cisplatin. In vitro studies demonstrated that LNP-NPs displayed significantly cytotoxicity on breast cancer cells, and the cell viability after co-incubation for 48 h (CP 16 μg/mL) were 18.77% (MCF-7) and 20.01% (EMT6), respectively. LNP-NPs could also significantly inhibit the growth of MCF-7 tumor-like spheroids, which were realized through the high coordination and cooperation between CP and LND. Therefore, the carrier-free drug delivery system based on LND and DH-CP is expected to achieve a good synergistic anti-tumor effect.

Carrier-free drug self-delivery systems consisting of amphiphilic drug-drug conjugate (ADDC) with well-defined structure and nanoscale features have drawn much attention in tumor drug delivery. Herein, we report a simple and effective strategy to prepare ADDC using derivatives of cisplatin (CP) and dasatinib (DAS), which further self-assembled to form reduction-responsive nanoparticles (CP-DDA NPs). DAS was modified with succinic anhydride and then connected with CP derivative by ester bonds. The size, micromorphology and in vitro drug release of CP-DDA NPs were characterized. The biocompatibility and bioactivity of these carrier-free nanoparticles were then investigated by HepG2 cells and H22-tumor bearing mice. In vitro and in vivo experiments proved that CP-DDA NPs had excellent anti-tumor activity and significantly reduced toxicities. This study provides a new strategy to design the carrier-free nanomedicine composed of CP and DAS for synergistic tumor treatment., Graphical abstract A carrier-free, reduction-sensitive nanoparticle based on cisplatin and dasatinib for synergistic antitumor Image, graphical abstract

Traditional chemotherapy exhibits a certain therapeutic effect toward malignant cancer, but easily induce tumor multidrug resistance (MDR), thereby resulting in the progress of tumor recurrence or metastasis. In this work, we deigned ternary hybrid nanodrugs (PEI/DOX@CXB-NPs) to simultaneously combat against tumor MDR and metastasis. In vitro results demonstrate this hybrid nanodrugs could efficiently increase cellular uptake at pH 6.8 by the charge reversal, break lysosomal sequestration by the proton sponge effect and trigger drugs release by intracellular GSH, eventually leading to higher drugs accumulation and cell-killing in drug-sensitive/resistant cells. In vivo evaluation revealed that this nanodrugs could significantly inhibit MDR tumor growth and simultaneously prevent A549 tumor liver/lung metastasis owing to the specifically drugs accumulation. Mechanism studies further verified that hybrid nanodrugs were capable of down-regulating the expression of MDR or metastasis-associated proteins, lead to the enhanced anti-MDR and anti-metastasis effect. As a result, the multiple combination strategy provided an option for effective cancer treatment, which could be potentially extended to other therapeutic agents or further use in clinical test., Graphical abstract Ternary hybrid nanodrugs were fabricated and exhibited the stepwise response to pH/GSH stimuli, thereby improving in vivo targeting delivery and high-effectively treating MDR and metastatic tumor.Image 1

Tumor microenvironment (TME) is known to play a critical role in cancer progression and contributes to treatment failure or success. Herein, a versatile nanoplatform [HAFOE-Ce6/Pt-NPs(O2)] with cis...

Phycocyanin (PC) is considered to be an effective natural photosensitizer, but it has not been well utilized as its inefficient biostability and intracellular accumulation. To overcome these limitations, the nano-sized PC particles (LAPC/DOX) were developed by grafting with lactobionic acid (LA) and loading with doxorubicin (DOX). Compared to the PC solution, the storage-stability and photostability of PC particles were remarkably increased, and the formation of nanoparticles further improved its biostability. Besides, CLSM images confirmed that LA could also enhance cellular uptake, resulting in more intracellular PC and DOX accumulation. MTT assay revealed that LAPC/DOX caused the highest cytotoxicity by combined chemo-photodynamic therapy. Finally, LAPC/DOX could efficiently accumulate and spread in tumoral multicellular spheroids, resulting in the enhanced growth inhibition. Overall, the LAPC/DOX is effective in cancer treatment, which provides new insights for the usage of functional proteins in vivo.

Nanoscale hydroxyapatite (nHA) is considered as a promising drug carrier or therapeutic agent against malignant tumors. But the strong agglomeration tendency and lack of active groups seriously hamper their usage in vivo. To address these issues, we fabricated an organic-inorganic hybrid nanosystem composed of poly(acrylic acid) (PAA), nHA, and indocyanine green (ICG), and further modified with glucose to give a targeting nanosystem (GA@HAP/ICG-NPs). These hybrid nanoparticles (∼90 nm) showed excellent storage and physiological stability assisted by PAA and had a sustained drug release in an acidic tumor environment. In vitro cell experiments confirmed that glucose-attached particles significantly promoted cellular uptake and increased intracellular ICG and Ca2+ concentrations by glucose transporter 1 (GLUT1)-mediated endocytosis. Subsequently, the excessive Ca2+ induced cell or organelle damage and ICG triggered photothermal and photodynamic effects (PTT/PDT) under laser irradiation, resulting in enhanced cell toxicity and apoptosis. In vivo tests revealed that the hybrid nanosystem possessed good hemocompatibility and biosafety, facilitating in vivo circulation and usage. NIR imaging further showed that tumor tissues had more drug accumulation, resulting in the highest tumor growth inhibition (87.89%). Overall, the glucose-targeted hybrid nanosystem was an effective platform for collaborative therapy and expected to be further used in clinical trials.

To achieve an ideal drug delivery platform with precise composition and high tumor selectivity, the PEGylated dual-drug backboned prodrug was synthesized via the copolymerization between diamine monomer of ortho ester and cisplatin- demethylcantharidin conjugate (Pt(IV)-1), and then terminated by mPEG550-active ester. The amphipathic prodrug could self-assemble into nano-prodrugs, which endowed the precise structure and high drug loading. Moreover, the nano-prodrugs exhibited physicochemical stability at physiological pH (7.4) for stable blood circulation, DePEGylation and dynamic size change for selective tumor accumulation and enhanced cellular internalization at tumoral extracellular pH (6.8), and efficient drug release for synergetic apoptosis and cytotoxicity at tumoral intracellular pH (5.0)/glutathione. Thus, the precise dual-drug backboned nano-prodrugs with detachable PEGylation, dynamic size change and efficient drug release could be potentially translated for clinically selective cancer treatment. Statement of significance Few nanomedicines have been clinically used for cancer treatment and little progress has been made in the last decades due to the unprecise composition and unsatisfactory tumor selectivity. Herein, the PEGylated dual-drug backboned nano-prodrugs were successfully constructed by rational design and endowed the defined structure, precise drug ratio, extraordinary high drug loading and reduction/pH dual sensitivity. The nano-prodrugs further exhibited the stable storage and blood circulation through PEGylation and low critical micelle concentration, enhanced tumor accumulation and cellular uptake via extracellular DePEGylation and dynamic size translation, and synergetic cytotoxicity via intracellular efficient drug release, respectively. This study can open a new avenue for easy industrial manufacture and quality control, and highly selective chemotherapy appealing for clinical translation. .

TPGS approved by FDA can be used as a P-gp inhibitor to effectively reverse multi-drug resistance (MDR) and as an anticancer agent for synergistic antitumor effects. However, the comparatively high critical micelle concentration (CMC), low drug loading (DL) and poor tumor target limit its further clinical application. To overcome these drawbacks, the pH-sensitive star-shaped TPGS copolymers were successfully constructed via using pentaerythritol as the initial materials, ortho esters as the pH-triggered linkages and TPGS active-ester as the terminated MDR material. The amphiphilic star-shaped TPGS copolymers could self-assemble into free and doxorubicin (DOX)-loaded micelles at neutral aqueous solutions. The micelles exhibited the lower CMC (8.2 × 10−5 mg/ml), higher DL (10.8%) and long-term storage and circulation stability, and showed enhanced cellular uptake, apoptosis, cytotoxicity, and growth inhibition for in vitro MCF-7/ADR and/or MCF-7/ADR multicellular spheroids and in vivo MCF-7/ADR tumors via efficiently targeted drug release at tumoral intracellular pH (5.0), MDR reversal of TPGS, and synergistic effect of DOX and TPGS. Therefore, the pH-sensitive micelles self-assembled from star-shaped TPGS copolymers with ortho ester linkages are potentially useful to clinically transform for enhanced MDR cancer treatment., Graphical abstract pH-sensitive micelles self-assembled from star-shaped TPGS copolymers for enhanced apoptosis, cytotoxicity, and growth inhibition for in vitro MCF-7/ADR multicellular spheroids and in vivo MCF-7/ADR tumors.Image, graphical abstract

Cancer is still a major threat to human health at present. Developing new types of integrated nanoplatforms for the accurate diagnosis and effective treatment of cancer is very significant. Herein, an intelligent dual-stage core-shell cancer theranostic nanoplatform (Fe3+@Au1Ag24@PbP) with NIR laser/tumor-microenvironment (TME) co-responsiveness and multi-modal imaging-therapy was successfully prepared, which was composed of the precisely structured oil-soluble Au1Ag24 nanoclusters (NCs) and Fe3+ ions easily assembled within the oil and aqueous phases of the polyethylene glycol (PEG) block grafted polyketal (PK) copolymer (PK-b-PEG, PbP) vesicles, respectively. In this system, we were delighted to find that the prepared Au1Ag24 NCs possess multi-photoresponsive properties, endowing the nanoplatform with photoacoustic (PA)/photothermal (PT) imaging and synergetic photothermal therapy (PTT)/photodynamic therapy (PDT) for cancer under near-infrared (NIR) laser irradiation. On the other hand, Fe3+ ions exhibit multi-TME response and regulation behaviors, including as catalysts for the decomposition of endogenous hydrogen peroxide (H2O2) in the solid tumor to produce O2 and as the oxidizing agent for the consumption of the intracellular GSH to avoid the reduction of the generated 1O2; therefore, the synchronously formed Fe2+ ions from the redox of Fe3+ with GSH could further react with H2O2 to produce hydroxyl radical (˙OH), which induced ferroptosis-based cancer treatment. The PbP shell possesses TME/pH sensitivity for controlled drug release and passive targeting, causing a large increase in Au1Ag24/Fe3+ accumulation within the weakly acidic tumor region and reducing the side effects on normal tissues. Both in vitro and in vivo experiments demonstrate that the Fe3+@Au1Ag24@PbP nanoplatform presented excellent PA/PT imaging-guided synergetic PTT/PDT/ferroptosis effects toward tumor cells and tumors. This integrating multi-responsive and multi-modal theranostic nanoplatform paves a new way for effective cancer therapy.

This study was conducted to construct a multifunctional nanodrug delivery system (NDDS) to deplete glutathione (GSH) in tumor cells and amplify oxidative stress, enhancing the synergistic effect of chemotherapy and photodynamic therapy (PDT). l-Buthionine-sulfoximine (BSO) and chlorin e6 (Ce6) were loaded into mesoporous silicon nanoparticles (MSN), and then MSN were modified with oxidized hyaluronic acid (OHA) as a pore-blocking agent. Cisplatin (Pt(II)) was further loaded by a coordination reaction with carboxyl groups in OHA to yield a multifunctional NDDS (denoted as MSN@OHA-Ce6/BSO/Pt). The physicochemical properties and antitumor activity of the prepared nanoparticles were characterized in detail. In vitro and in vivo experiments demonstrated that OHA was shed from MSN@OHA-Ce6/BSO/Pt under acidic conditions in tumors, resulting in the release of free BSO, Ce6, and Pt(II). The released BSO could reduce intracellular GSH expression by 48.8 %, effectively enhancing the PDT effect of Ce6 and the chemotherapy effect of Pt(II). Finally, the tumor inhibitory rate (vs saline) reached 73.8 % ± 2.5 % for MSN@OHA-Ce6/BSO/Pt in A549/DDP tumor-bearing nude mice. Therefore, the multifunctional NDDS significantly enhanced the synergistic effect of PDT and chemotherapy.

Extreme hypoxia inside solid tumors is the primary barrier against the advance of chemotherapy and photodynamic therapy (PDT). To address this problem, a hybrid nano-enzyme prodrug system was developed to alleviate hypoxia as well as simultaneously sensitize chemo-photodynamic therapy. Lactobionic acid (LA) and doxorubicin (DOX) precursor (cis-aconitic anhydride-linked doxorubicin, CAD) were pre-conjugated onto the side chain of catalase (CAT), then co-assembled with chlorin e6 (Ce6) to form LA-CAT-CAD@Ce6 nanoparticles (LCC@Ce6-NPs). LA as the active-targeting ligand increased cellular internalization, CAD as the pH-sensitive component triggered rapid drug release, Ce6 as the photosensitizer induced reactive oxygen species (ROS) generation, and CAT decomposed intracellular H2O2 to produce oxygen in situ. Oxygen production efficiently decreased the expression of hypoxia-inducible factor-1α (HIF-1α) and P-glycoprotein (P-gp), which enhanced chemotherapy efficiency. In addition, sufficient oxygen further amplified PDT-mediated cell-killing and apoptosis in hypoxic tumor. In vivo studies showed that combined chemo-photodynamic therapy by LCC@Ce6-NPs led to the most effective inhibition of tumor growth (TGI>90%), and even partially ablated tumor. Thus, this nano-enzyme prodrug platform can be a potentially effective treatment in clinical cancer therapy, and married to other therapeutic agents. Statement of Significance Hypoxia in solid tumors seriously impedes the efficacy of chemotherapy or photodynamic therapy. Herein, we designed hybrid nano-enzyme prodrug particles to improve hypoxia-mediated limitations on cancer therapy. Lactobionic acid (LA) as the hydrophilic outer layer of particles increased cellular uptake by receptor-mediated endocytosis, and cis-aconitic anhydride-linked doxorubicin (CAD) as the pH sensitive component inside particles efficiently triggered DOX and Ce6 release. More importantly, catalase (CAT) as the backbone of particles was capable of greatly relieving tumor hypoxia through catalyzing the decomposition of H2O2 in situ. Oxygen re-generation not only prevented hypoxia-mediated chemo-resistance, but also amplified PDT-induced ROS cell-killing ability. As a result, the multiple combination action of this nano-system could simultaneously sensitize chemo-photodynamic therapy, thus significantly enhancing tumor therapy.

Multidrug resistance (MDR) is one of the major obstacles to clinical cancer chemotherapy. Herein, we designed new pH-sensitive pluronic micelles with the synergistic effects of oxidative therapy and MDR reversal. Pluronic (P123) was modified with α-tocopheryl succinate (α-TOS) via an acid-labile ortho ester (OE) linkage to give a pH-sensitive copolymer (POT). Self-assembled POT micelles exhibited desirable size (~80 nm), excellent anti-dilution ability, high drug loading (~85%), acid-triggered degradation and drug release behaviours. In vitro cell experiments verified that POT micelles could significantly reverse MDR through suppressing the function of drug effluxs mediated by P123 and induce more reactive oxygen species (ROS) generation mediated by α-TOS, resulting in enhanced cytotoxicity and apoptosis in MDR cells. In vivo studies further revealed that DOX-loaded POT micelles (POT-DOX) possessed the highest drug accumulation (3.03% ID/g at 24 h) and the strongest tumour growth inhibition (TGI 83.48%). Pathological analysis also indicated that POT-DOX could induce more apoptosis or necrosis at the site of tumour without distinct damage to normal tissues. Overall, these smart POT micelles have great potential as promising nano-carriers for MDR reversal and cancer treatment.

Multidrug resistance (MDR) seriously hinders therapeutic efficacy in clinical cancer treatment. Herein, we reported new polymeric prodrug micelles with tumor-targeting and acid-sensitivity properties based on two different pluronic copolymers (F127 and P123) for enhancing tumor MDR reversal and chemotherapy efficiency in breast cancer. Hybrid micelles were composed of phenylboric acid (PBA)-modified F127 (active-targeting group) and doxorubicin (DOX)-grafted P123 (prodrug groups), which were named as FBP-CAD. FBP-CAD exhibited good stability in a neutral environment and accelerated drug release under mildly acidic conditions by the cleavage of β-carboxylic amides bonds. In vitro studies demonstrated that FBP-CAD significantly increased cellular uptake and drug concentration in MCF-7/ADR cells through the homing ability of PBA and the anti-MDR effect of P123. In vivo testing further indicated that hybrid micelles facilitated drug accumulation at tumor sites as well as reduced side effects to normal organs. The synergistic effect of active-targeting and MDR-reversal leads to the highest tumor growth inhibition (TGI 78.2%). Thus, these multifunctional micelles provide a feasible approach in nanomedicine for resistant-cancer treatment.

Although surface PEGylation of nanomedicines can decrease serum protein adsorption in vivo, it also blocks uptake by tumor cells. This dilemma could be overcome by employing detachably PEGylated strategy at tumoral extracellular microenvironment to achieve improved cellular uptake while prolonged circulation times. Herein, the amphiphilic graft copolymers with pH-sensitive ortho ester-linked mPEG in side chains and polyurethanes in backbone, can self-assemble into the free and doxorubicin (DOX)-loaded micelles. The pH-sensitive micelles could undergo several characteristics as follows: (i) PEGylated shells for stability in sodium dodecyl sulfonate (SDS) solution; (ii) DePEGylation via degradation of ortho ester linkages at tumoral extracellular pH (6.5) for gradually dynamic size changes and effective release of DOX; and (iii) enhanced cellular uptake and cytotoxicity via positive DOX. Moreover, the dynamic micelles with detachable PEGylation could quickly penetrate the centers of SH-SY5Y multicellular spheroids (MCs) and strongly inhibit tumor growth in vitro and in vivo, and might be considered as promising and effective drug carriers in tumor therapy., Graphical abstract Dynamic micelles with detachable PEGylation at tumoral extracellular pH, self-assembled from ortho ester-linked PEGylated polyurethanes, could quickly penetrate multicellular spheroids (MCs) and strongly inhibit tumor growth in vitro and in vivo.Image, graphical abstract

Currently, the polysaccharide-based nano-prodrug crosslinked by stimuli-responsive synergetic prodrug is of great demand, owing to its excellent stability, synergetic effect and tumor selectivity, and circumventing the dilemma of dose-limiting toxicity and immunogenicity induced by that crosslinked or grafted via a single drug. Herein, the dynamic carboxymethyl chitosan (CMCS)-based nano-prodrugs with precise structure were facilely fabricated, via crosslinking reaction between CMCS and water-soluble synergistic small molecule prodrug (cisplatin-demethylcantharidin conjugate) and further stabilization by glutaraldehyde. The pH/glutathione (GSH)-responsive double-crosslinked structure endowed the nano-prodrugs with long-term storge and circulation stability at physiological pH, and dynamic transitions at tumor sites including extracellular surface amino protonation and intracellular efficient drug release, which promoted selective tumor accumulation and synergistic cytotoxicity, therefore achieving robust tumor suppression while decreasing side effects. Thus, the dynamic precise CMCS-based nano-prodrugs crosslinked by water-soluble synergistic prodrug have great potential for highly selective robust chemotherapy attractive for clinical translation.

To promote chemotherapeutic efficacy and easier clinical transformation, a series of pH-sensitive and dynamic drug delivery systems with facile two-step synthesis and simple structure have been successfully constructed by the tunable grafting reaction between pH-sensitive ortho ester and poly(vinyl alcohol). The amphipathic graft macromolecules (PVA- g-OE x, x represents the percentage of feed between ortho esters and hydroxyl groups of polyvinyl alcohol) could self-assemble into micelles and doxorubicin was embedded. These micelles exhibited pH-sensitivity to both extracellular and intracellular pH and demonstrated the following characteristics: (i) maintaining long-term storage and blood circulation stability at pH 7.4; (ii) responding to tumoral extracellular pH value following gradually larger nanoparticles for improved drug accumulation and retention; (iii) being sensitive to tumoral intracellular pH value following disintegration for rapid drug release to improve toxicity to tumor cells. Moreover, the doxorubicin-loaded micelle (PVA- g-OE30-DOX) showed similar cytotoxicity to free doxorubicin in vitro, but stronger tumor penetration and inhibition ability in vitro human liver carcinoma cell line multicellular tumor spheroids. In vivo biodistribution and tumor inhibition examinations demonstrated that PVA- g-OE30-DOX had more superior efficacy in significantly enhancing drug accumulation in tumor, restraining tumor growth while decreasing drug concentration in normal tissues. The pH-sensitive, dynamic graft polymer micelles via simple synthesis could be considered as a promising and effective drug carrier in tumor therapy.

To achieve enhanced cancer therapy, a sequentially dynamic polymeric drug delivery system (ortho ester-linked PEGylated poly(disulfide)s-based micelle-doxorubicin (PS-g-OEMPEG-DOX)) is successfully constructed. The PEGylated micelle can keep stable in sodium dodecyl sulfate (SDS) solution at pH 7.4, but be prone to DePEGylation and dynamic size changes via the hydrolysis of ortho ester linkages in side chains at tumoral extracellular pH value (6.5). Moreover, the micelle can rapidly release DOX via the cleavage of poly(disulfide)s in backbone at intracellular reductive milieu (10 mmol/L of dithiothreitol (DTT)). The dynamic micelle with detachable PEGylation achieves the stable blood circulation, improved cellular uptake and cytotoxicity, stronger in vitro penetration and inhibition of tumoral multicellular spheroids, and significant in vivo tumor accumulation and inhibition while decreasing side effects. Thus, the sequentially dynamic polymeric micelle with detachable PEGylation can be considered as a promising and effective drug delivery system in cancer therapy.

Chemotherapy fails to achieve an ideal gliomas therapy due to the limited delivery of chemotherapeutics across the blood brain barrier (BBB), difficult accumulation of drugs in the gliomas area, and off-target toxicity. Herein, the pH-triggered small molecule nano-prodrugs (Try-CA-NPs) emulsified from hydrophobic tryptamine (Try)-cinnamaldehyde (CA) twin drug were successfully prepared through a facile method. Try-CA-NPs exhibited long-term storage and circulation stability. Furthermore, liposoluble Try-CA-NPs could easily cross BBB and efficiently accumulate in brain, selectively target to gliomas cells via Try-mediated cellular uptake, and enhance cytotoxicity through intracellular pH-triggered endosomal escape and efficient drug release, and synergistic effect between CA and Try, therefore achieving the complete destruction of SH-SY5Y multicellular spheroids (MCs). Thus, the pH-triggered small molecule nano-prodrugs emulsified from Try-CA twin drug have the great potential for clinically targeted synergistic glioma therapy.

It remains a crucial challenge to achieve efficient cellular uptake in tumor cells for nanoscale drug delivery systems. This work described that two multi-functional pullulan nanogels were prepared by co-polymerization between methacrylated pullulan (Pullulan-M) and different crosslink agents, an acid-labile ortho ester-modified pluronic (L61-MOE) or non-acid-sensitive methacrylated pluronic (L61-M). The prepared nanogels showed a regular spherical structure with the size about 200 nm measured by dynamic light scattering and transmission electron microscopy (TEM). Doxorubicin as a model drug was successfully encapsulated into nanogels. As expected, Pul-L61-MOE showed pH-dependent DOX release, and 25% of DOX was released at pH 7.4 while 84.48% of DOX was released at pH 5.0. In vitro cellular uptake and MTT results indicated that pH-sensitive nanogels (Pul-L61-MOE) displayed higher cellular internalization and cytotoxicity than acid-insensitive nanogels (Pul-L61-M) and free DOX. Flow cytometry assay suggested these nanogels remarkably increased intracellular reactive oxygen species (ROS) level and induced more cell apoptosis by the function of pluronic. Finally, in vivo antitumor results indicated that the multi-functional nanogels exhibit supreme antitumor efficiency, and the tumor growth inhibition (TGI) was 83.37%. Therefore, the pH-sensitive pullulan nanogels can be potential nano-carriers for drug delivery in tumor treatment.

The frequent occurrence of multidrug resistance (MDR) in solid tumors is the major obstacle for nano-drug delivery systems (nDDS) to realize the successful cancer chemotherapy. Herein, we had prepared pH-responsive nanogels via cross-linking TPGS-grafted soy protein with an acid-labile ortho ester cross-linker (OEAM) to realize the efficient intracellular drugs release and accumulation, and subsequently enhance therapeutic effect in MDR tumor cells. These nanogels displayed a uniform size (~200 nm) and morphology, and the introduction of ortho ester bonds endowed nanogels stability in neutral environment and acid-degradability in acidic conditions. Cisplatin (CDDP) was successfully loaded into nanogels, which exhibited an accelerated drug release at low pH. The modification of TPGS efficiently improved cellular internalization and drug accumulation in A549/DDP cells by inhibiting the function of drug efflux pumps (MRP2 and ATP7A/7B), leading to higher cytotoxicity and apoptosis. Moreover, TPGS-grafted nanogels also showed better drug accumulation and penetration in tumor-like spheroids, and then remarkably inhibited tumor growth owing to the rapid drug release in acidic organelles. As a result, the TPGS-grafted and pH-sensitive soy protein nanogels have a great potential as a drugs carrier for the efficient cancer treatment.

This work described the preparation of two type nanogels based on the crosslinking between carboxymethyl chitosan (CMCS) and two different crosslink agents, an acid-labile cyclic ortho ester compound with dual epoxy end groups (OEDe) or corresponding non-sensitive ethyleneglycol diglycidyl ether (EGDE). The particle size, zeta potential, and micromorphology were characterized by dynamic light scattering and electron microscopy, respectively. Nanogels' stability was also investigated at physiological environments. Doxorubicin hydrochloride as a therapeutic drug model was efficiently embedded into nanogels. The pH-triggered size changing, degradation and drug release were then investigated at three different pH values. Cellular uptake and cytotoxicity evaluation demonstrated that NG1/DOX could be successfully degraded and efficiently release DOX in acid cell organelles, leading to higher cytotoxicity than NG2/DOX. The accumulation and penetration of these DOX-loaded nanogel were then investigated by tumor-like multicellular spheroids (MCTS). The results indicated that the acid-degradable nanogels can deliver more DOX into the inner of MCTS by the hydrolysis of ortho ester bonds, thus efficiently inhibit the growth of MCTS. All results suggested that the acid-degradable nanogels could be degraded in mildly acidic conditions and remain stable at physiological environment, which indicated that the acid-degradable nanogels would be potentially useful as drug carriers.

Cationic polymers have become one of the most promising synthetic vectors for gene transfection, however, their translation to the clinic has been severely hampered because of their high cytotoxici...

To achieve precise control of nano-carrier structure and drug release behavior, we designed a pH/redox dual-responsive polymeric prodrug by condensation polymerization using octahedrally coordinated cisplatin (Pt IV) and ortho ester monomer. The prodrug was then self-assembled with doxorubicin (DOX) in aqueous solution to give a synergetic drug delivery system. The polymer backbone can completely degrade and release cisplatin (Pt II) and DOX under the acidic and reductive environment of tumor cells, owing to the breakage of ortho ester bonds and the reduction of Pt (IV). The size and micromorphology of micelles were observed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). In vitro study of drug release, cellular uptake and cytotoxicity revealed that the micelles could be triggered intracellularly to release two drugs. In vivo drug distribution and antitumor activity also provide the evidence for the excellent antitumor effect of micelles.

Herein, pH-sensitive carboxymethyl chitosan (CMCS) nanoparticles with fluorinated surface modification were prepared for efficient drug delivery. N-(3-Aminopropyl)-imidazole was pre-grafted onto carboxymethyl chitosan to fabricate the pH-sensitive nanoparticles (AM NPs), then was surface-modified with perfluorobutyric anhydride to give the fluorinated nanoparticles (FM NPs). AM and FM NPs had a regular spherical structure with the size about 150–160 nm, which was kinetically stabled in the physical environment and showed pH-triggered drug release at mildly acidic conditions. A series of cell experiments verified that surface fluorination of nanoparticles could enhance cellular uptake and improve cytotoxicity in different tumor cells without the targeting recognition between host and ligands. Besides, fluorine-modified nanoparticles had longer-term blood circulation and more accumulation in tumor site, resulting in higher bioavailability and superior antitumor efficiency for anticancer drugs in vivo. These results suggested that the pH-sensitive and fluorinated nanoparticles had great potential as be efficient drug currieries for cancer chemotherapy.

In this work, the tumor-targeted ultra-pH-responsive conjugates (PBA/Dex-g-OE) and nontargeted conjugates (Dex-g-OE) were successfully prepared and could easily self-assemble into stable micelles with lower CMC values in neutral aqueous solution. Transmission electron microscopy and dynamic light scattering measurement indicated that the resulting micelles have desirable size distribution and regular spherical shape. The PBA/Dex-g-OE micelles possessed high stability in physiological condition and were pH sensitive to both extracellular and intracellular acidic conditions. Doxorubicin (DOX) was efficiently loaded to give the DOX-loaded micelles (PBA/Dex-g-OE-DOX and Dex-g-OE-DOX) with the desirable drug loading contents. In vitro cellular uptake and growth inhibition assays suggested that PBA/Dex-g-OE-DOX micelles were more efficiently internalized by monolayer tumor cells and three-dimensional multicellular tumor spheroids (MCTS) than nontargeted micelles (Dex-g-OE-DOX), leading to the fast and complete destruction of MCTS in vitro.

Herein, a diallyl disulfide (DADS)-crosslinked nanogel (NG) and an ortho ester-conjugated TPGS (T-OE) were synthesized using free radical copolymerization and transesterification, respectively. Then, T-OE was grafted onto the NG to fabricate a dual-functionalized nanogel (TNG), and both the NG and TNG possessed a uniform diameter (∼160 nm) and excellent stability. The DOX-loaded nanogel (NG/D and TNG/D) displayed appropriate release properties under reducing conditions. MCF-7/ADR cell experiments showed that although both the NG/D and TNG/D could increase the production of reactive oxygen species (ROS), only the TNG could effectively overcome the drug efflux by inducing mitochondrial depolarization and by interfering with the metabolism of ATP. Both the cell cytotoxicity and the MCF-7/ADR solid cancer assay indicated that TNG/D possessed a long-acting drug enrichment and enhanced the inhibition, resulting from the combined action of the high ROS level and the suppressed drug efflux. These results demonstrated that the T-OE-functionalized and the DADS-crosslinked NG had a great potential for use in the treatment of MCF-7/ADR tumours.

Herein, intestine-penetrating and pH-sensitive oral nanoparticles (NP2, ∼350 nm) with a double-layered structure have successfully been fabricated for enhanced oral delivery of doxorubicin with reduced systemic toxicity. Their core is composed of poly(ortho ester urethane) (POEU), which is biocompatible and acid-sensitive. Carboxymethyl chitosan (CMC) was used as the external coating layer, which effectively protected the nanoparticles in gastric fluid (pH 1.0). In addition, CMC-coated nanoparticles could promote penetration in the small intestine (pH 5.0–8.0) through tight-junction opening-mediated paracellular pathways, transcytosis, and lymphatic uptake of M cells. NP2 demonstrated good biocompatibility in vitro and in vivo. Doxorubicin-loaded NP2 (NP2/DOX) hardly released the loaded drug in the simulated gastric fluid (SGF), while 74.83% of DOX was released under mildly acidic conditions (pH 5.0). High bioavailability (75.4%) and reasonable drug distribution were achieved by passive targeting after oral administration of NP2/DOX. More importantly, continual NP2/DOX oral therapy could effectively inhibit the amplification of the H22 tumour without any noticeable systemic toxicity in vivo. These results demonstrated that NP2/DOX had great potential to overcome the obstacles of clinical oral delivery of DOX.

Low intracellular drugs concentration is one of the main representations of multidrug resistance (MDR), which often results in a weak or failed chemotherapy on cancer treatment. Herein, an acid-sensitive and pluronic L61-linked hyaluronic acid nanogels (HA-L61OE/NGs) were developed for solving this problem. The nanogels could well hold more drugs under neutral condition, while triggering efficiently drugs release (61.42% within 24 h) in acidic environment. In vitro cells experiments demonstrated that the nanogels greatly increased intracellular drugs concentration by CD44-mediated endocytosis and L61-mediated anti-MDR effect, resulting in the enhanced cell-killing in MDR cells. In vivo studies verified HA-L61OE/NGs could avoid drugs leakage in blood and reduce systemic toxicity. Subsequently, the specific accumulation and penetration of nanogels at tumor regions lead to the highest tumor growth inhibition (TGI, 77.42%). Overall, HA-L61OE/NGs were effective on MDR tumor therapy and expected to be further used in clinical trials.

In this study, we aim to develop the pH-sensitive and tumor-targeting nanogels based on the co-polymerization of three terminal allyl-functionalized components, including ortho ester-conjugated mPEG (mPEG-MOE), ortho ester crosslinker (OEAM) and phenylboronic acid (APBA). The hybrid nanogels displayed a typical spherical structure with a diameter around 200 nm observed by dynamic light scattering (DLS) and scanning electron microscopy (SEM). The prepared nanogels possessed a good stability in neutral conditions, while displayed pH-triggered drug release profiles. Furthermore, in vitro study of cellular uptake and cytotoxicity indicated that the nanogels possessed the highest drug accumulation and cytotoxicity against EMT6 cells. In vivo antitumor examination suggested that these nanogels brought out excellent efficacy in enhancing drug concentration, restraining tumor growth, and prolonged the survival time of tumor-bearing mice. Thus, the prepared multi-functional nanogels possess great potentials for drug delivery in tumor treatment.

The preferred cancer treatment is to achieve a high therapeutic effect as well as reduce side effects. In this study, we developed carrier-free nano drugs based on 5-fluorouracil (5FU) and cinnamaldehyde (CA) to meet the above goals. Two model drugs were spliced by acetal linkage and ester bond, which could self-assemble into nano drug particles (5FU–CA NPs) with a size of ∼170 nm. In vitro cell experiments showed 5FU–CA NPs were efficiently internalized by HepG2 cells. They then quickly exerted dual drug activities by the cleavage of acetal and ester bond, resulting in enhanced cell-killing efficacy and apoptosis. Synergistic mechanisms were achieved via the anti-metabolic effects mediated by 5FU–COOH and the oxidative damage induced by CA. In vivo anti-tumor evaluation further indicated that 5FU–CA NPs had higher tumor growth inhibition than 5FU–COOH/CA mixture (5FU–COOH + CA) and exhibited lower systemic toxicity under the same reducing dose of each drug. Overall, this is a successful synergistic anti-tumor attempt through rational self-assembly of drugs with different mechanisms and it can be extrapolated to other agents.

Tumor intrinsic or acquired multidrug resistance (MDR) is still one of the major obstacles to the success of nanomedicine. To address this, the pH-sensitive nanoparticles (L61-OE-CS) with MDR-reversal ability were prepared by the crosslinking between acid-labile ortho-ester-modified pluronic (L61-OE) and chitosan (CS) for efficient doxorubicin (DOX) delivery. The size and micromorphology of the prepared nanoparticles were observed by dynamic light scanning and scanning electron microscopy and the nanoparticles displayed a uniform spherical shape with a diameter around 200 nm. The pH-triggered morphology change of the nanoparticles was also observed by scanning electron microscope. Drug release profiles under different pH values showed that DOX release amount within 72 h reached 16% (pH 7.4) and 76.5% (pH 5.0), respectively. In vitro cellular uptake and MTT assay demonstrated that the ortho ester and pluronic-based nanoparticles had higher cytotoxicity than non-sensitive nanoparticles. In vivo antitumor experiments also proved the superiority of the dual-functional nanoparticles, and the tumor growth inhibition rate (TGI) on day 14 was higher than 80%. Therefore, L61-OE-CS nanoparticles have great potential to be used as drug carriers in anticancer therapy.

Chemotherapy efficiency of platinum(II) (Pt(II)) is often attenuated owing to the low intracellular drugs concentration and glutathione (GSH)-mediated detoxification. To address these problems, we fabricated a step-by-step responsive nanogel (~160 nm) by copolymerization between four functional monomers. Hydrophilic methoxypolyethylene glycols (mPEG) distributed randomly on the surface of particles endowed the nanogel with “stealth” property in blood circulation, while the chemical crosslinking inside particles by platinum(IV) (Pt(IV)) linker remarkably increased the stability of nanogel in vivo. These advantages of nanogels leaded to higher accumulation at tumor region (6.4% ID/g), followed by triggering the dePEGylation effect by the cleavage of ortho ester at tumoral extracellular pH. Meanwhile, the exposed phenylboric acid (PBA) could significantly increase cellular uptake and intracellular drugs levels by targteing sialic acid residues on the cells membrane. More importantly, this nanogels could further deplete intracellular glutathione (GSH) by the dual-regulation of platinum(IV) and arylboronic ester, resulting in enhanced platinum(II) toxicity both in vitro and in vivo, eventually achieving superior inhibition rate (79.14%) in A549/DDP tumor. Thus, the sequentially responsive nanogel could be considered as an effective strategy for cancer treatment.

Supplemental material, sj-pdf-1-jba-10.1177_0885328221989539 for Self-assembled 5-fluorouracil-cinnamaldehyde nanodrugs for greatly improved chemotherapy in vivo by Qin Fang, Xiaoxiao Xu, Longshun Yang, Yanbing Xue, Xu Cheng, Xin Wang and Rupei Tang in Journal of Biomaterials Applications

The main objective of this paper is to develop a self-delivered prodrug system with nanoscale characteristics to enhance the efficacy of tumor therapy. The pH-sensitive prodrug was composed of ortho ester-linked dasatinib (DAS-OE), which was further self-assembled with or without doxorubicin (DOX) to obtain two carrier-free nanoparticles (DOX/DAS-OE NPs or DAS-OE NPs). The prodrug-based nanoparticles united the superiorities of small molecules and nano-assemblies together and displayed well-defined structure, uniform spherical shape, high drug loading ratio and on-demand drug release behavior. The drug loading content of DAS and DOX was 61.6% and 21.9%, respectively, and more than 80.2% of DAS and 60.2% DOX were released from DOX/DAS-OE NPs within 20 h at pH 5.0. Both in vitro and in vivo studies demonstrated that the pH-sensitive ortho ester bonds in the prodrug underwent hydrolysis to release DAS and DOX simultaneously after cellular internalization, resulting in remarkable antitumor effect. Tumor growth inhibition rate was 19.9% (free DAS), 35.5% (free DOX), 66.3% (DAS-OE NPs) and 82.8% (DOX/DAS-OE NPs), respectively. Thus, the ortho ester-linked prodrug system shows great potentials in cancer therapy.

Vitamin E d-ɑ-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS) and indomethacin (IDM) can reverse multidrug resistance (MDR) via inhibiting P-glycoprotein (P-gp) and multidrug resistance associated protein 1 (MRP1) respectively, but their drawbacks in physicochemical properties limit their clinical application. To overcome these defects and enhance MDR reversal, the amphiphilic TPGS-IDM twin drug was successfully synthesized via esterification, and could self-assemble into free and paclitaxel-loaded (PTX-loaded) micelles. The micelles exhibited lower CMC values (5.2 × 10−5 mg/mL), long-term stability in PBS (pH 7.4) for 7 days and SDS solution (5 mg/mL) for 3 days, and effective drug release at esterase/pH 5.0. Moreover, the micelles could down-regulate ATP levels and promote ROS production in MCF-7/ADR via the mitochondrial impairment, therefore achieving MDR reversal and cell apoptosis. Additionally, the PTX-loaded micelles could significantly inhibit the cell proliferation and promote apoptosis for MCF-7/ADR via the synergistic chemosensitizing effect of TPGS and IDM, and synergistic cytotoxic effect of TPGS and PTX. Thus, the chemosensitizing micelles self-assembled from amphiphilic TPGS-indomethacin twin drug have the great potentials for reversing MDR in clinical cancer therapy.

For patients with intractable cancer-related pain, administration of strong opioid analgesics and adjuvant agents by the intrathecal (i.t.) route in close proximity to the target receptors/ion channels, may restore pain relief. Hence, the aim of this study was to use bioerodable polymers to encapsulate an opioid analgesic (hydromorphone) and an adjuvant drug (ketamine) to produce prolonged-release formulations for i.t. injection. A two-stage microfluidic method was used to fabricate nanoparticles (NPs). The physical properties were characterised using dynamic light scattering and transmission electron microscopy. A pilot in vivo study was conducted in a rat model of peripheral neuropathic pain. The in vitro release of encapsulated payload from NPs produced with a polymer mixture (CPP-SA/PLGA 50:50) was sustained for 28 days. In a pilot in vivo study, analgesia was maintained over a three day period following i.t. injection of hydromorphone-loaded NPs at 50 μg. Co-administration of ketamine-loaded NPs at 340 μg did not increase the duration of analgesia significantly. The two-stage microfluidic method allowed efficient production of analgesic/adjuvant drug-loaded NPs. Our proof-of-principle in vivo study shows prolonged hydromorphone analgesic for 78 h after single i.t. injection. At the i.t. dose administered, ketamine released from NPs was insufficient to augment hydromorphone analgesia.

To develop simple and effective nano-drug delivery systems remains a major challenge in cancer treatment. Herein, we synthesized an ortho ester-linked deoxycholic acid dimer (DCA-OE), which could effectively self-assemble with doxorubicin (DOX) to form stable nanoparticles (DCA-OE/DOX NPs) by a single emulsion method. DCA-based nanoparticles had a desirable size (∼200 nm), morphology (spherical shape), and high drug encapsulation (drug loading content of ∼18.0 %, drug loading efficiency of ∼77.6 %). DCA-OE could improve the stability and solubility of DOX in physiological environment, while pH-sensitive ortho ester linkage endowed the ability to release DOX quickly in cancer cells. In vitro cytotoxicity and apoptosis verified drug-loaded dimer nanoparticles had similar toxicity with free DOX. Besides, these particles could efficiently accumulate and penetrate into human liver carcinoma cell line (HepG2) multicellular spheroids, thus resulting in enhanced antitumor effect. In vivo tests further exhibited that DCA-OE/DOX NPs had lower systemic toxicity and higher tumor inhibition effect, and its tumor inhibition rate was 84.1 %, which was far more than free DOX (49.3 %). Therefore, the strategy to link functional small molecules with ortho ester has great potentials in specific delivery of anticancer drugs.

Herein pH-sensitive nanogels (NG1) and P-glycoprotein-repressive nanogels (NG2) were prepared by copolymerization between an ortho ester crosslinker (OEAM) and tocopheryl polyethylene glycol succinate (TPGS)-free or conjugated dextran. Nanogels with or without TPGS possessed a uniform diameter (∼180 nm) and excellent stability in various physiological environments. Doxorubicin (DOX) was successfully loaded into NG1 and NG2 to give NG1/DOX and NG2/DOX, both of them showed appropriate drug release profiles under mildly acidic conditions (pH 5.0). NG2/DOX possessed higher drug enrichment and lethality than NG1/DOX did on MCF-7/ADR cells. Analysis of corresponding index of efflux activity showed that NG2 could induce depolarization of mitochondrial membrane and interfere with ATP metabolism. NG2/DOX also displayed increased penetration and growth inhibition on MCF-7/ADR multicellular spheroids. These results demonstrated that pH-sensitive TPGS-functionalized nanogels (NG2) as drug carriers had great potential to suppress drug efflux in MCF-7/ADR cells and even overcome MDR on cancer cells.