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.

A dual-Förster resonance energy transfer (FRET)-based versatile prodrug (V-prodrug), in which the fluorescence of both 5(6)-carboxylfluorescein (FAM) and doxorubicin (DOX) can be quenched by 4-(dimethylaminoazo)benzene-4-carboxylic acid (Dabcyl) with high quenching efficiency, is developed in this paper. The V-prodrug can selectively bind to the α_vβ₃ integrin overexpressed cancer cells through the Arg-Gly-Asp (RGD) targeting moiety. After that, the acid-mediated DOX release of the V-prodrug can be real-time monitored by the increase of the red fluorescence from DOX. Thereafter, DOX-induced cell apoptosis can also be in situ assessed by the fluorescence recovery of the FAM, due to the caspase-3-mediated Asp-Glu-Val-Asp (DEVD) peptide sequence cleavage. This novel prodrug provides a cascaded imaging of real-time drug release and subsequent cell apoptosis, which enables the in situ detection of the cancer response and the therapeutic efficacy evaluation of the prodrug.

In this study, a pH sensitive chimeric peptide is developed to codeliver a photosensitizer, protoporphyrin IX (PpIX), and plasmid DNA simultaneously. In the presence of matrix metalloproteinase-2 (MMP-2), the chimeric peptide undergoes the process of hydrolysis of PLGVR peptide sequence, exfoliation of PEG, and increase of positive charges. As a result, the chimeric peptide can be preferentially uptaken by MMP-2 rich tumor cells. To realize synergistic effect of drug and gene delivery, a dual-stage light irradiation strategy is developed, i.e., the short time light irradiation can efficiently enhance the endosomal escape of the chimeric peptide/PpIX/DNA complexes by the formation the reactive oxygen species (ROS), resulting in synergistic endosomal escape and improved DNA expression. In addition, due to the screened phototoxicity of PpIX, short time light irradiation does not lead to detectable changes in the cell viability. After the gene transfection, the screened phototoxicity of PpIX is subsequently stimulated by long time irradiation to achieve high synergistic efficacy of photodynamic and gene therapies. Both in vitro and in vivo studies confirm the chimeric peptide-based nanocarrier with a good synergistic effect is a promising nanoplatform for tumor treatments.

In this paper, a self-delivery system PpIX-PEG-(KLAKLAK)₂ (designated as PPK) is fabricated to realize mitochondria-targeted photodynamic tumor therapy. It is found that the PPK self-delivery system exhibited high drug loading efficacy as well as novel capacity in generation of intracellular reactive oxygen species (ROS). This study also indicated that the photochemical internalization effect of the photosensitizer protoporphyrin IX (PpIX) under a short time light irradiation improved the cellular internalization of PPK. On the contrary, PPK could target to the subcellular organelle mitochondria due to the presence of proapoptosis (KLAKLAK)₂ peptide. Importantly, the in situ generation of ROS in mitochondria enhanced the photodynamic therapy efficacy under another long time irradiation, leading to significant cell death with decreased mitochondrial membrane potential. Besides, relative high tumor accumulation, minimal systemic cytotoxicity and efficacious long-term tumor inhibition in vivo are also confirmed by using a murine model. All these results demonstrated the self-delivery system PPK with a dual-stage light irradiation strategy is a promising nanoplatform for tumor treatment.

Nanomaterials that integrate diagnostic and therapeutic functions within a single nanoplatform promise great advances in revolutionizing cancer therapy. A smart multifunctional theranostic drug-delivery system (DDS) based on gold nanorods (abbreviated as GNR/TSDOX) is designed for cancer-targeted imaging and imaging-guided therapy. In this intelligent theranostic DDS, the active targeting ligand biotin is introduced to track cancer sites in vivo. With the aid of photothermal/photoacoustic imaging, GNR/TSDOX can ablate cancer specifically and effectively. When stimulated with a single near-infrared (NIR) light source, this NIR light energy is effectively absorbed and converted into heat by GNR/TSDOX for localized photothermal therapy and the increase in temperature also further triggers the cascaded release of the anticancer drug for combined thermo-chemotherapy. More importantly, the in vivo cure effect can be well guided by regulating the irradiation time and intensity of the NIR light.

Thermoresponsive amphiphilic copolymer, poly[N-isopropyl acrylamide-co-3-(trimethoxysilyl)propylmethacrylate]-b-poly{N-[3-(dimethylamino)propyl]methacrylamide} with a branched structure was designed and synthesized by consecutive reversible addition–fragmentation chain-transfer polymerization. The further hydrolysis of trimethoxysilyl functions in 3-(trimethoxysilyl) propyl methacrylate units led to the fabrication of core-crosslinked (CCL) micelles with silica crosslinks at temperatures above the lower critical solution temperature of the poly(N-isopropyl acrylamide) block. The thermally induced structural and morphological changes of the CCL micelles in aqueous solution were investigated by transmission electron microscopy and ¹H-NMR analyses. The resulting CCL micelles were further explored as nanocarriers for the codelivery of an anticancer drug and nucleic acid for enhanced therapeutic efficacy. The CCL micelles effectively condensed the nucleic acid and mediated higher gene transfer in the presence of serum than in serum-free transduction. A cytotoxicity study revealed that whereas the pure CCL micelles exhibited unapparent cytotoxicity, the codelivery of p53 and doxorubicin with the CCL micelle formulation resulted in better treatment efficiency than sole chemotherapy. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 41752.

A novel dicyclopeptide-based bolaamphiphile was synthesized. The hydrophilic cyclopeptide fragments were linked to an alkyl chain 1,6-bis(maleimido)hexane, which acted as a hydrophobic spacer. The transmission electron microscopy (TEM) observation indicated that the cyclopeptide bolaamphiphile (CPB) self-assembled into the nanotubes with a thickness of about 3 nm. Based on the optimized molecular conformation obtained via MM2 method, the length of CPB was demonstrated to be around 4 nm, implying that the nanotubes were single-walled. Fourier transform infrared spectroscopy (FT-IR) and circular dichroism (CD) analysis showed that the cyclopeptides in CPB mainly acted as the hydrophilic headgroups, rather than providing the well-ordered hydrogen bonding interaction responsible for β-sheet conformation. To investigate the special self-assembly behavior of CPB, the single cyclopeptide (CP) without the connection of the linker was synthesized. Further investigation indicated that the CP molecules can not form tubular structures but nanofibers.

To overcome the critical barriers in gene delivery, a series of reducible polycations (RPCs) based on low molecular weight (LMW) peptides, i.e. PolyHK₆H, PolyHK₆H-mPEG₁, PolyHK₆H-mPEG₂, and PolyHK₆H-mPEG₃, with different poly(ethylene glycol) (PEG) contents, are synthesized and evaluated as nonviral gene vectors. All the RPCs exhibit lower cytotoxicity compared with 25 kDa polyethyleneimine (PEI) and PEGylated PEI (PEI-mPEG: PEI-mPEG₁, PEI-mPEG₂, and PEI-mPEG₃). PolyHK₆H-mPEG₁ and PolyHK₆H-mPEG₂ can bind and condense plasmid deoxyribonucleic acid (pDNA) efficiently with a particle size of about 200 nm. Moreover, they display much higher transfection efficiency than that of 25 kDa PEI especially in serum-supplemented medium. Moreover, PolyHK₆H-mPEG₁ has equal transfection efficiency with PEI-mPEG₁ which is optimal in the PEI-mPEG, but PolyHK₆H-mPEG₁ exhibits significantly lower cytotoxicity than PEI-mPEG₁. This is attributed to the fact that inter-peptide disulfide bonds can increase the stability of RPCs/pDNA complexes in extracellular environment and thereafter cleave in cytoplasm to facilitate the release of pDNA in intracellular environment. The PEGylated RPCs demonstrate here improved intracellular gene transfer performance and will have great potential applications in vivo.

A novel intelligent “active defense” system that can specially respond to cancerous tissues for drug release was designed and prepared. The “active defense” system consists of a biodegradable dextran microgel core cross-linked by a Schiff's base and a surrounding layer formed by Layer-by-Layer (LbL) assembly. The loading and release of macromolecular model drug, dex-FITC, as well as antineoplastic drug, DOX, was investigated. The in vitro cell inhibition and drug release behavior of the drug delivery system were studied and the results showed that the entrapped drug could be explosively released from the microcapsules and thereafter taken up by cancer cells upon the trigger of the acidic environment around tumor tissues.

A glucose oxidase (GOx)-mediated glucose metabolism was in vitro mimicked and employed to regulate the self-assembly of peptide-based building blocks. In this new stimuli-responsive self-assembly system, two peptide-based building blocks, respectively, having aspartic acid (gelator 1) and lysine (gelator 2) residues were designed and prepared. When adding glucose and GOx to the aqueous solution of gelator 1 or the self-assembled fibrillar hydrogel of gelator 2 to construct glucose metabolism system, the metabolic product (gluconic acid) can trigger the protonation of the peptide molecules and induce the phase transitions of gelators 1 (sol-gel) and 2 (gel-sol). Because this glucose metabolism regulated peptide self-assembly is built on the oxidation of glucose, it can be used as a simple visual biosensor for glucose detection.

A new “plug and play” polymeric template with the driving force of host–guest interaction between β-CD and naphthalene-modified functional groups was designed and studied. Multiple functional groups can be loaded into the template directly and conveniently. Importantly, the “plug and play” effect of the polymeric template is reversible and the functional groups could be removed from the polymeric template conveniently by adding AD-HCl. The studies on the cell viability and phagocytosis proved that the loading and unloading process of this template could be realized in vitro. © 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2012.

A graphene oxide hydrogel (GOH) is fabricated via suspending the graphene oxide (GO) in water without any additional processing steps. At the hydrogel/air interface, a well-defined hydrogel membrane forms once the solvent is removed by vacuum drying. The microstructure of the resulting GOH film can be tailored by different dehydration approaches, as well as by varying the GO concentration in the hydrogel. This GOH exhibited pH-responsiveness and good mechanical properties. Meanwhile, the GOH presented good adsorption capacity to the organic dye rhodamine B and anionic chromate Cr₂O₇²⁻. This GOH may find great potential in many fields, such as wastewater treatment, biodetection, etc.

Two thermo- and pH-sensitive polypeptide-based copolymers, poly(N-isopropylacrylamide-co-N-hydroxymethylacrylamide)-b-poly(L-lysine) (P(NIPAAm-co-HMAAm)-b-PLL, P1) and poly(N-isopropylacrylamide-co-N-hydroxymethylacrylamide)-b-poly(glutamic acid) (P(NIPAAm-co-HMAAm)-b-PGA, P2), have been designed and synthesized by the ring-opening anionic polymerization of N-carboxyanhydrides (NCA) with amino-terminated P(NIPAAm-co-HMAAm). It was found that the block copolymers exhibit good biocompatibility and low toxicity. As a result of electrostatic interactions between the positively charged PLL and negatively charged PGA, P1 and P2 formed polyion complex (PIC) micelles consisting of polyelectrolyte complex cores and P(NIPAAm-co-HMAAm) shells in aqueous solution. The thermo- and pH-sensitivity of the PIC micelles were studied by UV/Vis spectrophotometry, dynamic light scattering (DLS), and transmission electron microscopy (TEM). Moreover, fluorescent PIC micelles were achieved by introducing two fluorescent molecules with different colors. Photographs and confocal laser scanning microscopy (CLSM) showed that the fluorescence-labeled PIC micelles exhibit thermo- and pH-dependent fluorescence, which may find wide applications in bioimaging in complicated microenvironments.

A series of amphiphilic diblock copolypeptides (ADCs), 5-(4-aminophenyl)-10,15,20-triphenyl-porphyrin (APP) conjugated poly(L-leucine)-block-polylysine (APP-L_nK_m) with different molar ratios of L-leucine unit and lysine unit were designed and synthesized. The optimized composition of the polypeptide was determined to be APP-L₁₀₉K₁₈₆, which has high fluorescence quantum yield and could self-assemble into micelles in an aqueous medium with mean particle size <30 nm. The in vitro study indicates that APP-L₁₀₉K₁₈₆ shows no significant dark cytotoxicity when the concentration is below 200 mg L⁻¹ for HepG2 and HeLa cells. In contrast, the polymer exhibits apparent phototoxicity with low IC₅₀ values toward HepG2 and HeLa cells, implying that the potential high photodynamic therapy efficacy of the polymer. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010

A peptide containing a RGD (arginine-glycine-aspartic acid) sequence as well as a hydrophobic N-fluorenyl-9-methoxycarbonyl (FMOC) tail was prepared via a standard FMOC solid-phase peptide synthesis technique. The supramolecular self-assembly of such peptide through π–π stacking from FMOC tail can transfer the peptide aqueous solution into a three-dimensional hydrogel. The biocompatibility of the peptide hydrogel was evaluated via clinical follow-up and histological analysis. The data obtained demonstrated that the peptide hydrogel exhibited good biocompatibility when injected to the subconjunctival space and anterior chamber of rabbit, indicating a potential application in ophthalmology as an implantable drug delivery system for the treatment to ocular anterior segment diseases such as glaucoma, iridocyclitis, and keratopathy. © 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2010

The strategy for in situ chemical gelation of poly(N-isopropylacrylamide-co-hydroxylethyl methacrylate) [P(NIPAAm-co-HEMA)]-based polymers was demonstrated. Two types of new P(NIPAAm-co-HEMA) derivatives with alkyne and azide pendant groups, respectively, were prepared. When the solutions of the two derivatives were mixed together, a crosslinking reaction, a type of Huisgen's 1,3-dipolar azide-alkyne cycloaddition, in the presence of Cu(I) catalyst occurs. The morphology, equilibrium swelling ratio, swelling kinetics, and temperature response kinetics of the in situ gelated hydrogels were studied. In comparison with the conventional PNIPAAm hydrogel, because of the spatial hindrance of polymeric chains, the resulted hydrogels had a macroporous structure as well as a fast shrinking rate. The strategy described here presents a potential alternative to the traditional synthesis techniques for the in situ formation of thermoresponsive hydrogels. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 5263–5277, 2008