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The nonselective membrane disruption of antimicrobial peptides (AMPs) helps in combating the antibacterial resistance. But their overall positive charges lead to undesirable hemolysis and toxicity toward normal living cells, as well as the rapid clearance from blood circulation. In consequence, developing smart AMPs to optimize the antimicrobial outcomes is highly urgent. Relying on the local acidity of microbial infection sites, in this work, we designed an acidity-triggered charge reversal nanotherapeutics with adaptable geometrical morphology for bacterial targeting and optimized therapy. C

The short lifetime of singlet oxygen reduces its accumulation in the endoplasmic reticulum, which limits the output of photodynamic therapy. A nanodevice with functions of singlet oxygen production, storage and release can improve the lifetime of singlet oxygen for enhancing phototherapeutic efficacy.

An "antibiotic-free strategy" provides a viable option to address bacterial infections, especially for the "superbug" challenge. However, the undesirable antibacterial activity of antibiotic-free agents hinders their practical applications. In this study, we developed a combination antibacterial strategy of coupling peptide-drug therapy with chemodynamic therapy (CDT) to achieve the effective bacterial inhibition. An amphiphilic oligopeptide (LAOOH-OPA) containing a therapeutic unit of

Recently, smart nanomaterials from peptide self-assembly have received extensive attention in the field of biological and medical applications. Through rationally designing the molecular structure, we constructed a borono-peptide that self-assembled into well-defined nanofibers. Relying on the specific recognition between the vicinal diol compound and boronic acid, a novel alizarin red S (ARS)-borono-peptide (BP) spherical nanoindicator was fabricated, accompanying with the emission of strong fluorescent signal. The fluorescent nanoindicator displayed an intense response to copper(II) ions and underwent the fluorescent "turn-off" due to the strong binding-induced displacement. Originating from the high selectivity toward copper(II) ions, good biocompatibility and cancer cell targeting, the nanoindicator offered the opportunity to image copper(II) ions in cancer cells via fluorescent change.

Meng-Xin Tian,1,2,* Liu-Ping Luo,3,4,* Wei-Ren Liu,1,2,* Wei Deng,5 Jia-Cheng Yin,1,2 Lei Jin,1,2 Xi-Fei Jiang,1,2 Yu-Fu Zhou,1,2 Wei-Feng Qu,1,2 Zheng Tang,1,2 Han Wang,1,2 Chen-Yang Tao,1,2 Yuan Fang,1,2 Shuang-Jian Qiu,1,2 Jian Zhou,1–2,6 Jing-Feng Liu,3,4 Jia Fan,1–2,6 Ying-Hong Shi1,21Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, People’s Republic of China; 3Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 4The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 5Department of Health Statistics and Social Medicine, Key Laboratory of Public Health Safety, Ministry of Education, School of Public Health, Fudan University, Shanghai, People‘s Republic of China; 6Institutes of Biomedical Sciences, Fudan University, Shanghai, People‘s Republic of China*These authors contributed equally to this work Purpose: To develop and validate a decision aid to help make individualized estimates of tumor recurrence for patients with resected combined hepatocellular cholangiocarcinoma (CHC).Patients and methods: Risk factors of recurrence were identified in the derivation cohort of 208 patients who underwent liver resection between 1995 and 2014 at Zhongshan Hospital to develop a prediction score. The model was subsequently validated in an external cohort of 101 CHC patients using the C concordance statistic and net reclassification index (NRI).Results: On multivariate analysis, five independent predictors associated with tumor recurrence were identified, including sex, γ-glutamyl transferase, macrovascular invasion, hilar lymphoid metastasis and adjuvant transcatheter arterial chemoembolization. The prediction score was constructed using these 5 variables, with scores ranging from 0 to 5. A patient with a score of 0 had a predicted 1- and 5-year recurrence risk of 11.1% and 22.2%, respectively. In the validation cohort, the NRIs of prediction score vs American Joint Committee on Cancer 7th, TNM staging system at 1-year and 5-year were 0.185 (95% CI, 0.090–0.279, P

A multifunctional nanoplatform based on mesoporous silica nanoparticles (MSNs) was developed for combinational tumor therapy. Doxorubicin (DOX) was chosen as an antitumor drug and loaded into mesopores of MSNs via physical absorption. Then, a tumor-targeted fusion peptide conjugated with 2,3-dimethylmaleic anhydride (DTCPP) and a therapeutic peptide conjugated with 2,3-dimethylmaleic anhydride (DTPP) were introduced to the surface of MSNs as super-pH-sensitive nanovalves through disulfide linkages. The BSA adsorption assay confirmed the charge-reversal property of MSN-ss-DTPP&DTCPP nanoparticles at slightly acidic condition (pH 6.8) and superior stability in physiological environment (pH 7.4). According to the drug release research, both glutathione (GSH) and acidic condition are required for the accelerated drug release from DOX@MSN-ss-DTPP&DTCPP nanoparticles. Moreover, in vitro studies demonstrated the significantly reinforced tumor cellular uptake efficiency and mitochondrial disruption ability of DOX@MSN-ss-DTPP&DTCPP nanoparticles in tumor environment, in which DOX@MSN-ss-DTPP&DTCPP nanoparticles exhibited the preferred cytotoxicity toward αvβ3-positive human cervical carcinoma (HeLa) cells. We believe that the multifunctional dual-stimuli-sensitive MSN could provide an effective strategy for combinational tumor therapy.

A luminescent Zn(II)-based MOF, [Zn(dptz)(BDC)(H2O)]n [1, dptz = 3,6-di(1H-pyrazol-4-yl)-1,2,4,5-tetrazine, H2BDC = terephthalic acid], with Lewis basic nitrogen sites has been synthesized by a solvothermal method. Using ligands with higher pK a value, complex 1 exhibits excellent solvent and pH stabilities in the pH range 2–12. 1 can serve as a highly sensitive and efficient luminescent probe for detecting Fe3+ and Cr2O7 2− ions in aqueous systems. The values of K SV toward Fe3+ and Cr2O7 2− were estimated to be 1.61 × 103 M−1 and 1.26 × 104 M−1, respectively. The possible sensing mechanism has been discussed. All these results suggest 1 is a promising dual-functional luminescent sensor for the detection of Fe3+ and Cr2O7 2− ions in aqueous solution.

A luminescent Zn(II)-based MOF, [Zn(dptz)(BDC)(H2O)]n [1, dptz = 3,6-di(1H-pyrazol-4-yl)-1,2,4,5-tetrazine, H2BDC = terephthalic acid], with Lewis basic nitrogen sites has been synthesized by a solvothermal method. Using ligands with higher pKa value, complex 1 exhibits excellent solvent and pH stabilities in the pH range 2–12. 1 can serve as a highly sensitive and efficient luminescent probe for detecting Fe3+ and Cr2O72− ions in aqueous systems. The values of KSV toward Fe3+ and Cr2O72− were estimated to be 1.61 × 103 M−1 and 1.26 × 104 M−1, respectively. The possible sensing mechanism has been discussed. All these results suggest 1 is a promising dual-functional luminescent sensor for the detection of Fe3+ and Cr2O72− ions in aqueous solution.

During the past decades, functionalized nano-systems were believed in holding the bright future of the nanomaterials in biomedical applications. Due to their excellent biocompatibility, biodegradation capability, and biological activity, functional peptides have been vastly used solitary or employed as functional components in nano-systems for disease treatments. This review focuses on the recent advances on the use of functional peptides as a toolbox to construct various delivery nano-systems for tumor treatments. Arising from the special function contributed to the nano-systems, the functional peptides are mainly divided into three groups, cell-targeting peptides (CTPs), cell-penetrating peptides (CPPs), and environment-sensitive peptides. Within each group, their usage in both organic and inorganic systems is discussed. In particular, strategies used to generate promising therapeutic nano-systems for efficient tumor treatment are also highlighted.

The morphology of nanomedicines has a large influence on the anticancer efficiency of therapeutic agents in biological systems. In this study, camptothecin (CPT)-based nanodrugs with helical and spherical shapes were simply built without the need of any additional carriers. Self-deliverable spherical nanodrug represented a therapeutic advantage over the helical one, which was uncovered from the in vitro toxicity assay. Confocal imaging study indicated that the better outcome of spherical nanodrug was ascribed to the faster cellular uptake. With the aid of sonication treatment, helical nanodrugs with different lengths (HD-1, HD-2, HD-3, HD-4) were created. In comparing with the longest HD-1, the drug release kinetics indicated that the shortest HD-4 exhibited a 20% elevation in cumulative drug release at the first 10 h. The internalized drug amount of HD-4 was three-fold higher than that of HD-1 after the cultivation with 4T1 cells for 2 h. These results demonstrated that the anticancer efficacy of helical nanodrugs was inversely proportional to their lengths. The strategy demonstrated here presents great promise for the preparation of nanodrugs with suitable morphology for cancer therapy.

Designing and constructing favorable water-dispersible fullerenes and their derivatives are of huge importance for biological applications addressing DNA-cleavage and photodynamic therapy (PDT). In the present work, a mild, green and facile synthetic approach for the preparation of C60 nanoparticles was developed for the first time via the combination of mussel-inspired chemistry and the Michael addition reaction. The resultant C60–PDA–PEI nanoparticles were characterized by transmission electron microscopy (TEM), dynamic laser scattering (DLS), Fourier-transform infrared spectroscopy (FT-IR), Raman spectra, X-ray photoelectron spectra (XPS) and thermogravimetric analysis (TGA), demonstrating that the above two-step strategy allows easy access to the preparation of highly water-dispersible fullerene derivatives. Benefiting from their unique nanostructure, the versatile C60–PDA–PEI nanoparticles display a uniform hydrodynamic size of 160 nm in water and efficient 1O2 generation under irradiation. Furthermore, the good ability of cleaving DNA under visible light at a mass concentration of 62.5 ng μL−1 gives them high potential as PDT agents. The universal approach described in this work is capable of introducing many other functional molecules onto PDA-modified fullerenes, thus extending the possible applications of fullerene-based species in many fields of biotechnology and pharmaceutical chemistry.

Here we designed and constructed a tryptophan-phenylalanine-phenylalanine-tryptophan (WFFW) tetrapeptide, which generated photostable and tunable fluorescence emission signals from 340 nm to 500 nm. The WFFW tetrapeptide could self-assemble into a spherical nanostructure with enhanced fluorescence intensity. Driven by π-π stacking and hydrogen bond interaction, WFFW co-assembled with arginine-glycine-aspartic acid (RGD) modified WFFW to form a cancer-targeted fluorescent nanoprobe, which could selectively image the cancer cells.

A tumor targeting redox-responsive drug delivery system (DDS) with bioactive surface was constructed by immobilizing peptide-based amphiphile C12-CGRKKRRQRRRPPQRGDS (defined as ADDA-TCPP) onto the mesoporous silica nanoparticles (MSNs) as an end-capping nanovalve, which consists of two main segments: a hydrophobic alkyl chain ADDA and a hydrophilic amino acid sequence containing a Tat48-60 peptide sequence with a thiol terminal group and an RGDS targeting ligand, via a disulfide linkage for redox-triggered intracellular drug delivery. A series of characterizations confirmed that the nanosystem had been successfully fabricated. The antitumor drug doxorubicin (DOX) was selected as a model drug and efficiently trapped in the pores of MSNs, and an in vitro release experiment demonstrated that the mesopores of the resulting DOX-loaded MSNs (DOX@MSN-ss-ADDA-TCPP) could be sealed tightly with ADDA-TCPP self-assemblies through hydrophobic interactions between the alkyl chains; the resulting DDS exhibited “zero pr...

Incorporation of poly(dopamine) (PDA) into the native oligopeptide hydrogel has been demonstrated to decrease the critical gel concentration (CGC), improve the rigidity of formed hybrid hydrogel, and especially endow the hydrogel with efficient free radical scavenging ability.

A novel hyperbranched polyphosphamide with abundant terminal groups of silane (HBPPA-Si) was synthesized from phosphorus oxychloride (POCl3), 4, 4′-diaminodiphenylmethane (DDM) and (3-aminopropyl) triethoxysilane (APTES), which had high thermal stability with a residual weight of 44.0 wt% at 800°C in nitrogen atmosphere. By incorporating 25 wt% of APP and HBPPA-Si with an optimum mass ratio of 1:1 into polypropylene (PP) composites, the PP/APP/HBPPA-Si composite reached V-0 rating at the UL-94 test and also obtained a maximum LOI value of 27.5%. Meanwhile, their peak heat release rates (PHRR), total heat release (THR), and total smoke production (TSP) reduced dramatically by 72.5%, 35.8%, and 62.7% respectively, when compared with virgin PP. The improved flame retardancy and smoke suppression of PP/APP/HBPPA-Si composite were ascribed to their excellent synergistic effect working efficiently in both condensed-phase and gas-phase actions. It is noticeable that the high-quality and high-quantity char residue possessing thermal-stable P- and Si-containing cross-linked structures can shield the underlying polymeric materials from further hydrolysis and simultaneously insulate the volatile fuel and heat transfer. Moreover, the weak polar silane shell of HBPPA-Si improved the interfacial compatibility of APP within the PP matrix, leading to enhanced mechanical properties with increasing HBPPA-Si concentration.

Synergistic therapy involving two or more therapeutic agents with different anticancer mechanisms represents a promising approach to eradicate chemotherapy-refractory cancers. However, the preparation of a synergistic therapy platform generally involves complicated procedures to encapsulate different therapeutic agents and thereby increases the purification difficulty. In this work, we reported a simple but robust strategy to prepare a highly controllable drug delivery system (DDS) for synergistic cancer therapy. To construct this robust DDS, mesoporous silica nanoparticles (MSNs) were employed as a nanoplatform to encapsulate anticancer drug doxorubicin (DOX). After using a tumor-targeting cellular membrane-penetrating peptide (TCPP) and a mitochondria-targeting therapeutic peptide (TPP) to seal the surface pores via disulfide bonds, these newly developed MSNs can target cancer cells, penetrate cell membrane and rapidly release anticancer drug and mitochondria-targeted peptide in cytoplasm, inducing a remarkable synergistic anticancer effect. The new design concept reported here will promote the development of targeted and smart DDSs for synergistic cancer therapy.

To integrate treatments of photothermal therapy, photodynamic therapy (PDT), and chemotherapy, this study reports on a multifunctional nanocomposite based on mesoporous silica-coated gold nanorod for high-performance oncotherapy. Gold nanorod core is used as the hyperthermal agent and mesoporous silica shell is used as the reservoir of photosensitizer (Al(III) phthalocyanine chloride tetrasulfonic acid, AlPcS4). The mesoporous silica shell is modified with β-cyclodextrin (β-CD) gatekeeper via redox-cleavable Pt(IV) complex for controlled drug release. Furthermore, tumor targeting ligand (lactobionic acid, LA) and long-circulating poly(ethylene glycol) chain are introduced via host–guest interaction. It is found that the nanocomposite can specifically target to hepatoma cells by virtue of the LA targeting moiety. Due to the abundant existence of reducing agents within tumor cells, β-CD can be removed by reducing the Pt(IV) complex to active cisplatin drug for chemotherapy, along with the releasing of entrapped AlPcS4 for effective PDT. As confirmed by in vitro and in vivo studies, the nanocomposite exhibits an obvious near-infrared induced thermal effect, which significantly improves the PDT and chemotherapy efficiency, resulting in a superadditive therapeutic effect. This collaborative strategy paves the way toward high-performance nanotherapeutics with a superior antitumor efficacy and much reduced side effects.

To overcome drug resistance, efficient cancer therapeutic strategies using a combination of small-molecule drugs and macromolecule drugs is highly desired. However, because of their significant differences in molecular weight and size, it is difficult to load them simultaneously in one vector and to release them individually. Here, a biodegradable organosilica-based core-shell-structured nanocapsule was designed and used as a dual stimuli-responsive drug vector to solve this problem. Biodegradable organosilica shell coated outside the macromolecule model drug "core" would be disrupted by high glutathione (GSH) levels inside tumor cells, resulting in the escape of the entrapped drugs. Small-molecule drugs capping on the surface of the organosilica shell via pH-responsive imine bonds can be cut and released in the acidic lysosomal environment. Transmission electron microscopy has shown that the framework of the organosilica shell was dissolved and degraded after 8 h incubation with 5 mM GSH. Confocal imaging confirmed that small-molecule and macromolecular drugs were individually released from the nanoparticles because of the pH or redox-triggered degradation under the tumor microenvironment and thus led to the strong fluorescence recovery in the cytoplasm. As expected, these biodegradable organosilica nanoparticles could not release drugs into normal cells but could specifically release them into tumor cells owing to their tumor-triggered targeting capability. This system will serve as an efficient shuttle for multidrug delivery and also provide a potential strategy to overcome drug resistance.

The clinical outcomes of conventional mono-chemotherapy of cancers are usually far from satisfactory due to some issues such as tumor heterogeneity and resistance to chemotherapeutic drugs. With the increasing knowledge of molecular signal pathways and pathological mechanisms involved in the initiation and progression of cancers, collaborative strategies have been elaborated to optimize therapeutic outcomes. This review surveys the most recent advances in combination therapy including combination chemotherapy, chemotherapy plus gene therapy, chemotherapy plus phototherapy, as well as chemotherapy plus immunotherapy. Additionally, chemotherapy-involved multiple therapy that merges various therapeutic modalities is also presented. We try to elicit the rationales of applying these combinational formulations for cancer chemotherapy, which might provide new guidelines for high-performance cancer treatments.

A versatile gold nanoparticle-based multifunctional nanocomposite AuNP@CD-AD-DOX/RGD was constructed flexibly via host-guest interaction for targeted cancer chemotherapy. The pH-sensitive anticancer prodrug AD-Hyd-DOX and the cancer-targeted peptide AD-PEG8-GRGDS were modified on the surface of AuNP@CD simultaneously, which endowed the resultant nanocomposite with the capability to selectively eliminate cancer cells. In vitro studies indicated that the AuNP@CD-AD-DOX/RGD nanocomposite was preferentially uptaken by cancer cells via receptor-mediated endocytosis. Subsequently, anticancer drug DOX was released rapidly upon the intracellular trigger of the acid microenvirenment of endo/lysosomes, inducing apoptosis in cancer cells. As the ideal drug nanocarrier, the multifunctional gold nanoparticles with the active targeting and controllable intracellular release ability hold the great potential in cancer therapy.

In this paper, an activable cell-penetrating peptide (CR8G3PK6, ACPP) with a shielding group of 2,3-dimethylmaleic anhydride (DMA) was conjugated with antitumor drug doxorubicin (DOX) to construct a novel prodrug (DOX-ACPP-DMA) for tumor targeted drug delivery. The shielding group of DMA linked to the primary amines of K6 through the amide bond was used to block the cell-penetrating function of the polycationic CPP (R8) through intramolecular electrostatic attraction at physiological pH 7.4. At tumor extracellular pH 6.8, the hydrolysis of DMA led to charge reversal, activating the pristine function of CPP for improved cellular uptake by tumor cells. Confocal laser scanning microscopy (CLSM) and flow cytometry studies revealed that the cellular uptake of DOX-ACPP-DMA was significantly enhanced after acid-triggered activation in both HeLa and COS7 cells. After cell internalization, the overexpressed intracellular proteases would further trigger drug release in cells. Both in vitro and in vivo investigations showed that the peptidic prodrug exhibited significant tumor growth inhibition and demonstrated great potential for tumor therapy.

Functional mesoporous silica particles have attracted growing research interest for controlled drug delivery in targeted cancer therapy. For the purpose of efficient targeting tumor cells and reducing the adverse effect of antitumor drug doxorubicin (DOX), biocompatible and enzyme-responsive mesoporous silica nanoparticles (MSNs) with tumor specificity were desired. To construct these functional MSNs, the classic rotaxane structure formed between alkoxysilane tether and α-cyclodextrin (α-CD) was employed to anchor onto the orifices of MSNs as gatekeeper in this work. After subsequent modification by multifunctional peptide (azido-GFLGR7RGDS with tumor-targeting, membrane-penetrating, and cathepsin B-responsive functions) to stabilize the gatekeeper, the resulting functional MSNs showed a strong ability to load and seal DOX in their nanopores. When incubating these DOX-loaded MSNs with tumor and normal cells, the nanoparticles could efficiently employ their surface-encoded RGDS and continuous seven arginine (R7) sequences to target tumor cells, penetrate the cell membrane, and enter tumor cells. Because cathepsin B overexpressed in late endosomes and lysosomes of tumor cells could specifically hydrolyze GFLG sequences of the nanovalves, the DOX-loaded MSNs showed an "off-on" drug release behavior that ∼80% loaded DOX could be released within 24 h and thus showed a high rate of apoptosis. Furthermore, in vitro cellular experiments indicated that DOX-loaded MSNs (DOX@MSN-GFLGR7RGDS/α-CD) had high growth inhibition toward αvβ3-positive HeLa cancerous cells. The research might offer a practical way for designing the tumor-targeted and enzyme-induced drug delivery system for cancer therapy.

We report a new tumor-targeting amphiphilic peptide that can form complementary hydrogen bonds with anti-tumor drug methotrexate (MTX), leading to reversible self-assembled morphology transition from loose micelles to densely packed nanorods or nanofibers. The MTX loaded nanorods can target tumor cells and show more than 2-fold higher cytotoxicity (IC50 = 0.38 mg L(-1)) than that towards normal cells (IC50 = 0.89 mg L(-1)).

A new multi-functional amphiphilic fusion (MFAF) peptide comprised of a multi-functional fusion peptide sequence (GFLGR8GDS) and a hydrophobic polycaprolactone (PCL) tail was designed and prepared. In aqueous solution, through the strong hydrophobic interaction among the PCL tails, this MFAF peptide can self-assemble into core–shell micelles at a low concentration with the anti-tumor drug doxorubicin (DOX) loaded in the core and the multi-functional fusion peptide sequence located on the shell. When incubating the DOX-loaded micelles with tumor and normal cells, the micelles can use the RGD and membrane-penetrating peptide (eight continuous arginine residues, R8) sequences to target tumor cells and penetrate cell membranes. Subsequently, cathepsin B, an enzyme over-expressed in late endosomes and lysosomes of tumor cells that can specifically hydrolyze the GFLG sequence, can break the micellar structure and lead to a rapid release and escape of loaded DOX from endosomes, resulting in the apoptosis of tumor cells. The MFAF peptide presents great potential as a new drug delivery platform for targeted cancer chemotherapy.

In this paper, four different kinds of mercaptan acids modified amphiphilic copolymers mPEG-b-PATMC-g-SRCOOH (R = CH2 , CH2CH2 , (CH2)10 and CH(COOH)CH2 ) were successfully synthesized by thiol-ene “click” reaction between pendent carbon-carbon double bonds of PEG-b-PATMC and thiol groups of thioglycolic acid, 3-mercaptopropionic acid, 11-mercaptoundecanoic acid or 2-mercaptosuccinic acid. DLS and TEM measurements showed that all the mPEG-b-PATMC-g-SRCOOH copolymers could self-assemble to form micelles which dispersed in spherical shape with nano-size before and after DOX loading. The positively-charged DOX could effectively load into copolymer micelles via synergistic hydrophobic and electrostatic interactions. All DOX-loaded mPEG-b-PATMC-g-SRCOOH micelles displayed sustained drug release behavior without an initial burst which could be further adjusted by the conditions of ionic strength and pH. Especially in the case of mPEG-b-PATMC-g-S(CH2)10COOH (P3) micelles, the suitable hydrophobility and charge density were not only beneficial to improve the DOX-loading efficiency, they were also good for obtaining smaller particle size, higher micelle stability and more timely drug delivery. Confocal laser scanning microscopy (CLSM) and MTT assays further demonstrated efficient cellular uptake of DOX delivered by mPEG-b-PATMC-g-SRCOOH micelles and potent cytotoxic activity against cancer cells.

Novel amphiphilic polycarbonates-graft-doxorubicin (mPEG-b-P(ATMC-co-DTC)-g-DOX) were successfully designed and synthesized for pH-triggered intercellular drug release in cancer cells. The amphiphilic block copolymer, mPEG-b-P(ATMC-co-DTC), was synthesized in bulk using immobilized porcine pancreas lipase (IPPL) as the catalyst. After allyl epoxidation of ATMC units, DOX was covalently conjugated to the hydrophobic polycarbonates block through a hydrazone linkage. The resulting mPEG-b-P(ATMC-co-DTC)-g-DOX prodrugs could self-assemble to form nano-sized micelles in aqueous solution, while DOX contents in the hydrophobic core were 9.9 and 12.5 wt.%. DOX release rate from the prodrug micelles increased in acidic medium due to the acid-cleavable hydrazone linkage between the DOX and polycarbonates. MTT assays demonstrated that DOX prodrug micelles in this study showed effective cytotoxic effects to HeLa cells. Furthermore, confocal laser scanning microscopy (CLSM) observations also revealed that mPEG-b-P(ATMC-co-DTC)-g-DOX prodrugs could efficiently deliver and release DOX into the nuclei of HeLa cells.

Introducing drugs into gene delivery systems to fabricate co-delivery systems for synergy therapy has become a promising strategy for tumor therapy. In this study, a dual responsive co-delivery system RHD/p53 was fabricated to enhance the antitumor efficacy with a low dose of doxorubicin (DOX). The reducible branched cationic polypeptide (RBCP), which was cross-linked via the thiol groups of two three-armed cationic peptides (CRR)2KRRC and (CHH)2KHHC, was designated as RH. Then, DOX was immobilized on RH via pH-sensitive hydrazone bonds to obtain RHD. The positively charged RHD could compress p53 plasmid to form RHD/p53 complexes. After RHD/p53 complexes accumulated in tumor sites, the ability of cell penetrating by cationic peptide (CRR)2KRRC would facilitate the cellular internalization of complexes. Then, the complexes would be trapped in endosome, and the cleavage of hydrazone bonds in the intracellular acidic endosome could lead to pH-induced release of DOX. Additionally, the ability of protonation by (CHH)2KHHC could promote the escape of complexes from endosome to cytoplasm. Due to the cleavage of disulfide bonds triggered by the high-content GSH in cytoplasm, the complexes would be degraded and released p53 for co-therapy to improve antitumor efficacy. Both in vitro and in vivo studies indicated that dual responsive co-delivery system RHD/p53 could enhance antitumor efficacy, which provides a useful strategy for co-delivery of different therapeutic agents in tumor treatment.

In this study, a novel thymine-functionalized six-membered cyclic carbonate monomer (TAC) was synthesized by the Michael-addition reaction between thymine and acryloyl carbonate (AC). The corresponding functional amphiphilic block copolymer mPEG- b -PTAC was further successfully synthesized by ring-opening polymerization using immobilized porcine pancreas lipase (IPPL) as the catalyst and mPEG as the macroinitiator. Meanwhile, mPEG- b -P(TAC-co-DTC) and mPEG- b -PDTC were also synthesized by the same enzymatic methods for comparison on different TAC contents. The structures of monomer and copolymers were characterized by 1 H-NMR, 13 C-NMR and FTIR. All the amphiphilic block copolymers could self-assemble to form nano-sized micelles in aqueous solution. Transmission electron microscopy (TEM) observation showed that the micelles dispersed in spherical shape with nano-size before and after MTX loading. 1 H-NMR and FTIR results confirmed the successful formation of multiple hydrogen-bonding interactions between exposed thymine groups of hydrophobic PTAC segments and 2,6-diaminopyridine (DAP) groups of MTX molecules, which resulting in the higher drug loading capacity and the pH-sensitive drug release behavior. MTT assays also indicated lower toxicity of copolymer but higher potent cytotoxic activity of MTX-loaded copolymer against HeLa cells.