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In this study, a plasmon-semiconductor nanotheranostic system comprising Au nanostars/graphene quantum dots (AuS/QD) hybrid nanoparticles loaded with BNN6 and surface modified with PEG-pyrene was developed for the photo-triggered hyperthermia effect and NO production as the dual modality treatment against orthotopic triple-negative breast cancer. The structure and morphology of the hybrid nanodevice was characterized and the NIR-II induced thermal response and NO production was determined. The hybrid nanodevice has shown enhanced plasmonic energy transfer from localized surface plasmonic resonance of Au nanostars to QD semiconductor that activates the BNN6 species loaded on QD surfaces, leading to the effective NO production and the gas therapy in addition to the photothermal response. The increased accumulation of the NIR-II-responsive hybrid nanotheranostic in tumor via the enhanced permeation and retention effects was confirmed by both in vivo fluorescence and photoacoustic imaging. The prominent therapeutic efficacy of the photothermal/NO combination therapy from the BNN6-loaded AuS@QD nanodevice with the NIR-II laser irradiation at 1064 nm against 4T1 breast cancer was observed both in vitro and in vivo. The NO therapy for the cancer treatment was evidenced with the increased cellular nitrosative and oxidative stress, nitration of tyrosine residues of mitochondrial proteins, vessel eradication and cell apoptosis. The efficacy of the photothermal treatment was corroborated directly by severe tissue thermal ablation and tumor growth inhibition. The NIR-II triggered thermal/NO combination therapy along with the photoacoustic imaging-guided therapeutic accumulation in tumor shows prominent effect to fully inhibit tumor growth and validates the promising strategy developed in this study.

Curcumin is proven to have potent anti-inflammatory activity, but its low water solubility and rapid degradation in physiological conditions limit its clinical use, particularly in intravenous drug delivery. In this study, we fabricated rod-shaped, acid-labile nanogels, using high biosafe and biocompatible polymers, for intravenous application in systemic inflammation treatment. The constituent polymers of the nanogels were prepared via the conjugation of vitamin B

Currently, research on cancer therapy is focused on cancer stem cell therapy to overcome drug resistance and tumor recurrence. Although most studies thereof have focused on the effects of functional nanocarriers on cancer therapy, there is little discussion on the effect of nanocarriers on tumor-initiating cancer stem cells (TICSCs) and metastatic cancer stem cells (MCSCs). Therefore, a glutathione (GSH)-responsive micelle, a reactive oxygen species (ROS)-responsive micelle, and a dual GSH-/ROS-responsive micelle were prepared to evaluate the feasibility of using stimuli-responsive micelles to treat TICSCs and MCSCs. The experimental results demonstrate that ROS-responsive and dual ROS-/GSH-responsive micelles efficiently induce the death of both TICSCs and MCSCs because they could release drugs on both CSCs. However, GSH-responsive micelles were sensitive to TICSCs but not to MCSCs because the latter expressed a low GSH level. Relevant results suggest that the micelles with an ROS-responsive characteristic have great potential for delivering payloads efficiently to treat both TICSCs and MCSCs.

In the treatment of cancers, small interfering ribonucleic acids (siRNAs) are delivered into cells to inhibit the oncogenic protein’s expression, however, polyanions, hydrophilicity, and rapid degradations in blood, endosomal or secondary lysosomal degradation hamper clinal applications. In this study, we first synthesized and characterized two copolymers: methoxy poly(ethylene glycol)-b-poly(2-hydroxy methacrylate-ketal-pyridoxal) and methoxy poly(ethylene glycol)-b-poly(methacrylic acid-co-histidine). Afterwards, we assembled two polymers with the focal adhesion kinase (FAK) siRNA, forming polyplex-mixed micelles for the treatment of the human colon cancer cell line HCT116. In terms of the physiological condition, the cationic pyridoxal molecules that were conjugated on the copolymer with ketal bonds could electrostatically attract the siRNA. Additionally, the pyridoxal could form a hydrophobic core together with the hydrophobic deprotonated histidine molecules in the other copolymer and the hydrophilic polyethylene glycol (PEG) shell to protect the siRNA. In an acidic condition, the pyridoxal would be cleaved from the polymers due to the breakage of the ketal bonds and the histidine molecules can simultaneously be protonated, resulting in the endosome/lysosome escape effect. On the basis of our results, the two copolymers were successfully prepared and the pyridoxal derivatives were identified to be able to carry the siRNA and be cleavable by the copolymers in an acidic solution. Polyplex-mixed micelles were prepared, and the micellar structures were identified. The endosome escape behavior was observed using a confocal laser scanning microscopy (CLSM). The FAK expression was therefore reduced, and the cytotoxicity of siRNA toward human colon cancer cells was exhibited, rapidly in 24 h. This exceptional anticancer efficiency suggests the potential of the pH-sensitive polyplex-mixed micellar system in siRNA delivery.

Combination therapy through simultaneous delivery of two or more therapeutic agents using nanocarriers has emerged as an advanced tactic for cancer treatment. To ensure that two therapeutic agents can be co-delivered and rapidly release their cargo in tumor cells, a biocompatible pH-sensitive copolymer, methoxy poly(ethylene glycol)-b-poly(hydroxypropyl methacrylamide-g-α-tocopheryl succinate-g-histidine) (abbreviated as PTH), was designed and synthesized. The PTH copolymers spontaneously self-assembled into micellar-type nanoparticles in aqueous solutions and are used for co-delivery of therapeutic agents, doxorubicin (Dox) and α-TOS. During micellization, π-π stacking occurred between Dox/α-TOS and imidazole rings of PTH copolymers inducing a regular and tight arrangement of copolymers and drugs to form rod-like micelles, thus efficiently increasing the drug loading and encapsulation efficiency. The micelles enabled the rapid release of both Dox and α-TOS when the pH decreased from 7.4 to 4.5. The protein adsorption assay revealed that low amounts of IgG and BSA were adsorbed on the micelles. In vivo biodistribution demonstrated that the micelles could largely accumulate in the tumor tissues. Furthermore, drug-loaded micelles treated with HCT116 cancer cells exhibited higher cytotoxicity than normal cells, which confirmed that α-TOS exhibited a synergy effect with Dox towards cancer cells, while no recognizable side effects were observed during the treatment from organ function tests.

Radiotherapy is one of the general approaches to deal with malignant solid tumors in clinical treatment. To improve therapeutic efficacy, chemotherapy is frequently adopted as the adjuvant treatment in combination with radiotherapy. In this work, a reactive oxygen species (ROS)-responsive nanoparticle (NP) drug delivery system was developed to synergistically enhance the antitumor efficacy of radiotherapy by local ROS-activated chemotherapy, taking advantages of the enhanced concentration of reactive oxygen species (ROS) in tumor during X-ray irradiation and/or reoxygenation after X-ray irradiation. The ROS-responsive polymers, poly(thiodiethylene adipate) (PSDEA) and PEG-PSDEA-PEG, were synthesized and employed as the major components assembling in aqueous phase into polymer NPs in which an anticancer camptothecin analogue, SN38, was encapsulated. The drug-loaded NPs underwent structural change including swelling and partial dissociation in response to the ROS activation by virtue of the oxidation of the nonpolar sulfide residues in NPs into the polar sulfoxide units, thus leading to significant drug unloading. The in vitro performance of the chemotherapy from the X-ray irradiation preactivated NPs against BNL 1MEA.7R.1 murine carcinoma cells showed comparable cytotoxicity to free drug and appreciably enhanced effect on killing cancer cells while the X-ray irradiation being incorporated into the treatment. The in vivo tumor growth was fully inhibited with the mice receiving the local dual modality treatment of X-ray irradiation together with SN38-loaded NPs administered by intratumoral injection. The comparable efficacy of the local combinational treatment of X-ray irradiation with SN38-loaded NPs to free SN38/irradiation dual treatment corroborated the effectiveness of ROS-mediated drug release from the irradiated NPs at tumor site. The IHC examination of tumor tissues confirmed the significant reduction of VEGFA and CD31 expression with the tumor receiving the local dual treatment developed in this work, thus accounting for the absence of tumor regrowth compared to other single modality treatment.

Recent studies have indicated that cancer treatment based on immunotherapy alone is not viable. Combined treatment with other strategies is required to achieve the expected therapeutic effect. Reactive oxygen species (ROS) play an important role in regulating cancer cells and the tumor microenvironment, even in immune cells. However, rigorous regulation of the ROS level within the entire tumor tissue is difficult, limiting the application of ROS in cancer therapy. Therefore, we design an early phago-/endosome-escaping micelle that can release platinum-based drugs into the cytoplasm of macrophages and cancer cells, thereby enhancing the ROS levels of the entire tumor tissue; inducing apoptosis of cancer cells, down-regulation of CD47 expression of cancer cells, polarization of M1 macrophages, and phagocytosis of cancer cells by M1 macrophages; and achieving the dual effect of chemotherapy and macrophage-mediated immunotherapy.

To reduce the side effects of immune drugs and the sustainable release of immune drugs on local parts, we have designed an injectable thermal-sensitive hydrogel containing an imiquimod-loaded liposome system. In the extracellular environment of tumor tissues (pH 6.4), 50% of the drug was released from the carrier, which could be a result of the morphological changes of the liposomal microstructure in the acidic environment. According to the results in animals, the drug-containing liposomes combined with hydrogel can be effectively applied in breast cancer therapy to delay the growth of tumors as well as to dramatically reduce the death rate of mice.

Cytosolic drug delivery, a major route in cancer therapy, is limited by the lack of efficient and safe endosomal escape techniques. Herein, we demonstrate a reactive oxygen species (ROS)-responsive micelle composed of methoxy polyethylene glycol-b-poly(diethyl sulfide) (mPEG-PS) copolymers which can induce specific endosome escape in cancer cells by changes in the hydrophobicity of copolymers. Owing to the more ROS levels in cancer cells than normal cells, the copolymers can be converted into more hydrophilic and insert into and destabilize the cancer intracellular endosome membrane after cellular uptake. More importantly, we show that acid-intolerant drugs successfully maintain their bioactivity and cause selective cytotoxicity for cancer cells over normal cells. Our results suggest that the endosomal escape induced by hydrophobic-hydrophilic exchange of copolymers has great potential to locally and efficiently deliver biological agents (e.g., proteins and genes) in the cancer cell cytosol.

It has been demonstrated that by using doping and co-doping strategies the lifetimes as well as luminescence intensities of the doping species in the lanthanide oxysulfide nanoparticles (NPs) Ln2O2S:Ln’3+ (Ln=Gd, Tb, Eu; Ln׳=Tb, Eu, 1% and 5%) could be tuned. The lanthanide oxysulfide NPs, i.e., Gd2O2S, Tb2O2S and Gd2O2S:Tb3+(5%) were synthesized as matrices and doped with Eu3+(1% or 5%), by the thermal decomposition method and characterized by TEM, XRD, photoluminescence, cellular and in vivo animal imaging studies for potential luminescence bioimaging applications. Of these materials, Gd2O2S:Eu3+(5%) NPs possess the highest photo-stability and strongest luminescent intensity at 625 nm with a lifetime 853 μs in hexane. Surface modification of the Gd2O2S:Eu3+(5%) NPs with mPEG-APTES to increase its aqueous solubility resulted in almost complete luminescence quenching. Calcination of the host Gd2O2S:Eu3+(5%) NPs at 400 °C to increase their crystallinity and maintained some of their luminescence properties in aqueous solution. Further surface modification of the Gd2O2S:Eu3+(5%)-APTES NPs with mPEG and Alexa Fluor 660 allowed their effective cellular and in vivo animal luminescence imaging with low bio-toxicity. These novel imaging materials with tunable lifetimes would be potentially useful for luminescence bioimaging applications, particularly in the time-resolved, up-conversion, and/or multiplex modes.

The tumor-targeted delivery of near infrared (NIR)-triggered photothermal therapy (PTT) by varied nanocarriers has captured substantial attention. In order to boost the antitumor efficacy of PTT by promoting cellular uptake and tumor retention of PTT-carrying nanoparticles, the surface charge-changeable polymeric nanoparticles comprising poly(lactic-co-glycolic acid) (PLGA) cores covered with zwitterionic diblock copolymers, methoxypoly(ethylene glycol)-b-poly(methacrylic acid-co-histamine methacryamide), mPEG-b-P(MAA-co-HMA), were developed as vehicles of IR780. Due to the acid-triggered protonation of imidazole groups, the resulting positively charged HMA residues tend to form electrostatic complexes with negatively charged MAA residues, thus facilitating the embedding of outer PEG segments into the neutral and gel-like surfaces and thus the formation of inter-particle aggregation. Taking advantage of the weak acidity of tumor extracellular matrix, the IR780-loaded nanoparticles undergoing acidity-elicited dramatic structural transformation showed appreciably enhanced cellular uptake by TRAMP-C1 cells and prolonged tumor retention time.

A dual-sensitive polymeric drug conjugate (HA-SS-MP) was synthesized by conjugating hydrophobic 6-mercaptopurine (MP) to thiolated hyaluronic acid (HA) as the carrier and ligand to deliver doxorubicin (Dox) to parental colon cancer and colon cancer stem cells. Because of the amphiphilic nature of HA-SS-MP, it was self-assembled in the aqueous media, and Dox was physically encapsulated in the core of the micelles. The particle size and the zeta potential of the micelle were analyzed by dynamic light scattering (DLS), and the morphology of the micelle was investigated using transmission electron microscopy (TEM). Drug release study results revealed more drug release at pH 5.0 in the presence of GSH than that at the physiological pH value. The cytotoxicity of free Dox was slightly greater than that of Dox-loaded HA-SS-MP micelles. In vitro cytotoxicity of HA-SS-MP and Dox-loaded HA-SS-MP micelles was greater for cancer stem cells (HCT116-CSCs) than for parental HCT116 colon cancer cells and L929 normal fibroblast cells. The MTT and flow cytometry results confirmed that free HA competitively inhibited Dox-loaded HA-SS-MP uptake. Similarly, flow cytometry results revealed anti-CD44 antibody competitively inhibited cellular uptake of Rhodamine B isothiocyanate conjugated micelles, which confirms that the synthesized micelle is uptaken via CD44 receptor. Cell cycle analysis revealed that free drugs and Dox-loaded HA-SS-MP arrested parental HCT116 colon cancer cells at the S phase, while cell arrest was observed at the G0G1 phase in HCT116-CSCs. In addition, ex vivo biodistribution study showed that Dox-loaded HA-SS-MP micelles were accumulated more in the tumor region than in any other organ. Furthermore, the in vivo results revealed that Dox-loaded HA-SS-MP micelles exhibited more therapeutic efficacy than the free drugs in inhibiting tumor growth in BALB/C nude mice. Overall, the results suggested that the synthesized micelles could be promising as a stimuli carrier and ligand for delivering Dox to colon cancer cells and also to eradicate colon cancer stem cells.

An α-tocopheryl succinate (α-TOS) containing diblock copolymer micellar system was used to deliver doxorubicin (Dox), an anticancer drug, for HCT116 colon cancer therapy. The α-TOS containing diblock copolymers were synthesized by conjugation of α-TOS molecules and a mPEG-b-PHEMA hydrophilic diblock copolymer by ester bonds. The Dox-loaded polymeric micelles were then obtained by solvent exchange process. In acidic surroundings such as endosomes or secondary lysosomes, the structures of the Dox-loaded polymeric micelles deformed and released the drug loads. Additionally, Dox-loaded polymeric micelles enhanced the cytotoxicity of Dox and α-TOS to cancer cells in vitro. Dox-loaded polymeric micelles also showed an exceptional tumor inhibiting effect in vivo. This study indicates that the α-TOS containing polymeric micelle system can be used as a drug carrier for cancer therapy.

Multifunctional polymer nanoparticles have been developed for cancer treatment because they could be easily designed to target cancer cells and to enhance therapeutic efficacy according to cancer hallmarks. In this study, we synthesized a pH-sensitive polymer, poly(methacrylic acid-co-histidine/doxorubicin/biotin) (HBD) in which doxorubicin (DOX) was conjugated by a hydrazone bond to encapsulate an immunotherapy drug, imiquimod (IMQ), to form dual cancer-targeting and dual drug-loaded nanoparticles. At low pH, polymeric nanoparticles could disrupt and simultaneously release DOX and IMQ. Our experimental results show that the nanoparticles exhibited pH-dependent drug release behavior and had an ability to target cancer cells via biotin and protonated histidine.

This study presents a tumor-extracellular matrix pH-induced targeting liposome (ECM-targeting liposomes), crosslinked from methoxy-poly(ethylene glycol)-b-poly(N-2-hydroxypropyl methacrylamide-co-histidine)-cholesterol copolymers and biotin2-polyethylene glycol crosslinkers by hydrogen bonds to overcome the defects of liposomes. In this study, ECM-targeting liposomes were completely investigated their pH-responsibility, drug releasing behaviors, anticancer efficiencies and the time-dependent organ distribution and toxic effects. Experimental results indicate that ECM-targeting liposomes showed rapid drug releasing profiles in acidic conditions. Because the ECM-targeting liposomes accumulated preferentially in tumor, the ECM-targeting liposomes exhibited exceptional anticancer activity in vivo and lower hepatic and renal toxicity. The ECM-targeting liposomes which are switched on the targeting ability in tumor ECM possess potential for future application in anticancer therapy.

A novel drug delivery strategy featured with enhanced uptake of nanoparticles (NPs) by targeted tumor cells and subsequent intratumoral cellular hitchhiking of chemotherapy to deep tumor regions was described. The NP delivery system was obtained from assembly of poly(lactic acid-co-glycolic acid)-grafted hyaluronic acid (HA-g-PLGA) together with an anticancer drug, SN38, in aqueous phase, followed by implementing the NP surface with a layer of methoxypoly(ethylene glycol)-b-poly(histamine methacrylamide) (mPEG-b-PHMA) via hydrophobic association to improve the colloidal stability both in vitro and in vivo. Upon arrival of these PEGylated NPs at the acidic tumor site through the EPR effect, mPEG-b-PHMA became detached from the NP surface by the charge transition of the PHMA blocks from neutral (hydrophobic) to positively charged (hydrophilic) state via acid-induced protonation of their imidazole groups in tumor microenvironment. The exposure of HA shell on the naked NP thus resulted in enhanced uptake of NPs by CD44-expressed tumor cells, including cancer cells and tumor-associated macrophages (TAMs). Along with the TAMs being further chemotactically recruited by hypoxia cells, the engulfed nanotherapeutics was thus transported into the avascular area in which the anticancer action of chemotherapy occurred by virtue of the drug release alongside PLGA degradation, similar to those arising in other tumor nonhypoxia regions.

To solve biostability and organ distribution problems in polymer-coated liposomes, this study developed tumor–extracellular matrix pH-induced targeting polymer–liposome complexes (ECM-targeting liposomes) that are highly stable in a protein-rich environment and can trigger targeting ability in tumor ECM environment. Experimental results show that the ECM-targeting liposomes significantly reduced adsorption of various proteins (HSA, IgG, and fibrinogen) and leakage of encapsulated drug doxorubicin–hydrochloride from liposomes, significantly improved uptake efficiency in HCT116 colon cancer cells, improved HCT116 tumor accumulation, and reduced distribution in normal organs (e.g., liver, spleen, lung, etc.). We demonstrate that ECM-targeting liposomes overcome the limitations of conventional liposomes and stealth liposomes in cancer therapy.

Most anticancer drugs cause severe side effect due to the lack of selectivity for cancer cells. In recent years, new strategies of micellar systems, which design for specifically target anticancer drugs to tumors, are developed at the forefront of polymeric science. To improve efficiency of delivery and cancer specificity, considerable emphasis has been placed on the development of micellar systems with passive and active targeting. In this review article, we summarized various strategies of designing multifunctional micellar systems in the purpose of improving delivery efficiency. Micellar systems compose of a multifunctional copolymer or a mixture of two or more copolymers with different properties is a plausible approach to tuning the resulting properties and satisfied various requirements for anticancer drug delivery. It appears that multifunctional micellar systems hold great potential in cancer therapy.

Rapamycin has been developed as a potential anticancer drug for treatment in rapamycin-sensitive cancer models, but its poor water solubility greatly hampers the application to cancer therapy. This study investigated the preparation, release profiles, uptake and in vitro/in vivo study of a dual-responsive micellar formulation of rapamycin. Rapamycin-loaded micelles (rapa-micelles) measured approximately ca. 150 nm with narrow size distribution and high stability in bovine serum albumin solution. It was shown that rapamycin could be loaded efficiently in mixed micelles up to a concentration of 1.8 mg/mL by a hot shock protocol. Rapamycin release kinetic studies demonstrated that this type of micellar system could be applied in physiological conditions under varied pH environments. Confocal and pH-topography imaging revealed a clear distribution of rapa-micelles, and visible intracellular pH changes which induced encapsulated rapamycin to be released and then induced autophagolysosome formation. In vivo tumor growth inhibition showed that rapa-micelles exhibited excellent antitumor activity and a high rate of apoptosis in HCT116 cancer cells. These results indicated that dual-responsive mixed micelles provided a suitable delivery system for the parenteral administration of drugs with poor water solubility, such as rapamycin, in cancer therapy.

An optimized, biodegradable, dual temperature- and pH-responsive micelle system conjugated with functional group Cy5.5 was prepared in order to enhance tumor accumulation. The Dynamic light scattering (DLS) measurements showed that these diblock copolymers form micelle in PBS buffer with a size of around 50 nm by heating of an aqueous polymer solution from below to above the cloud point (CP). Anticancer drug, doxorubicin was incorporated into the inner core of micelle by hot shock protocol. The size and stability of the micelle were controlled by the copolymer composition and is fine tuned to extracellular pH of tumor. The mechanism then caused pH change and at body temperature which induce doxorubicin release from micelles and have strong effects on the viability of HeLa, ZR-75-1, MCF-7 and H661 cancer cells. Our in vivo results revealed a clear distribution of Doxorubicin-loaded mixed micelle (Dox-micelle) and efficiency targeting tumor site with particles increasing size in the tumor interstitial space, and the particles could not diffuse throughout the tumor matrix. In vivo tumor growth inhibition showed that Dox-micelle exhibited excellent antitumor activity and a high rate of anticancer drug in cancer cells by this strategy.

The sterically polymer-based liposomal complexes (SPLexes) were formed by cationic polymeric liposomes and pH-sensitive diblock copolymer were studied for their capabilities in improving the stability with high efficiency of siRNA delivery. The SPLexes were formed a dual-shelled structure and uniform size distribution. The PEGylated outer shell could mitigate the phagocytosis and reduce the cytotoxicity. Moreover, the folated SPLexes improved 42.9× accumulation in vitro and 1.7× tumor uptake in vivo in contrast with nonfolated SPLexes. The protonated copolymer at low pH would improve the siRNA released into cytoplasm following SPLexes fusion with the endo/lysosome membrane and inhibited the protein expression to 75.6 ± 4.5% efficiently. Results of this study significantly contribute to efforts to develop lipoplexes based siRNA delivery systems.

Multifunctional micelles for cancer cell targeting, distribution imaging, and anticancer drug delivery were prepared from an environmentally-sensitive graft copolymer, poly(N-isopropyl acrylamide-co-methacryl acid)-g-poly(D,L-lactide) (P(NIPAAm-co-MAAc)-g-PLA), a diblock copolymer, methoxy poly(ethylene glycol)-b-poly(D,L-lactide) (mPEG-PLA) and two functionalized diblock copolymers, galactosamine-PEG-PLA (Gal-PEG-PLA) and fluorescein isothiocyanate-PEG-PLA (FITC-PEG-PLA). Anticancer drug, free base doxorubicin (Dox) was incorporated into the inner core of multifunctional micelles by dialysis. From the drug release study, a change in pH (from pH 7.4 to 5.0) deformed the structure of the inner core from that of aggregated P(NIPAAm-co-MAAc), causing the release of a significant quantity of doxorubicin (Dox) from multifunctional micelles. Multifunctional micelles target specific tumors by an asialoglycoprotein (HepG2 cells)-Gal (multifunctional micelle) receptor-mediated tumor targeting mechanism. This mechanism then causes intracellular pH changes which induce Dox release from multifunctional micelles and that micelles have strong effects on the viability of HepG2 cells and are abolished by galactose. Confocal laser scanning microscopy (CLSM) reveals a clear distribution of multifunctional micelles. With careful design and sophisticated manipulation, polymeric micelles can be widely used in cancer diagnosis, cancer targeting, and cancer therapy simultaneously.

This study developed reactive oxygen species (ROS) and glutathione (GSH) dual redox-responsive micelles, which encapsulate anticancer drug camptothecin (CPT), protect CPT activity, and trigger CPT release in cancer cell H2O2- or GSH-rich surroundings. Experimental results show that CPT-loaded dual redox-responsive micelles remain stable at low levels of ROS and GSH in blood circulation, have high redox sensitivities needed to CPT release in cancer cells with high ROS or GSH (e.g., lung, gastric, and colon cancer cells), and prevent undersigned CPT toxicity in ROS/GSH balanced normal cells (e.g., fibroblast cells, etc.) or normal organs (e.g., liver, kidney, etc.). The CPT-loaded dual redox-responsive micelles also had high in vivo antitumor efficacy. This study demonstrates that ROS and GSH dual redox-responsive micelles have potential use as anticancer therapeutic nanomedicine in various cancer therapies.

A novel mixed micelle with a multifunctional core and shell is successfully prepared from a graft copolymer, poly(N-isopropyl acrylamide-co-methacrylic acid)-g-poly(d,l-lactide) (P(NIPAAm-co-MAAc)-g-PLA) and two diblock copolymers, poly(ethylene glycol)-b-poly(d,l-lactide) and poly (2-ethyl-2-oxazoline)-b-poly(d,l-lactide). This nanostructure completely screens the highly negative charges of the graft copolymer and exhibits multifunctionality because it has a specialized core/shell structure. An example of this micelle structure used in intracellular drug delivery demonstrates a strong relationship between drug release and the functionality of the mixed micelle. Additionally, the efficiency of the screening feature is also displayed in the cytotoxicities; mixed micelles exhibit higher drug activity and lower material cytotoxicity than micelles from P(NIPAAm-co-MAAc)-g-PLA ([NIPAAm]/[MAAc]/[PLA] = 84:5.9:2.5 mol/mol) copolymer. This study not only presents a new micelle structure generated using a graft–diblock copolymer system, but also elucidates concepts upon which the preparation of a multifunctional micelle from a graft copolymer with a single (or many) diblock copolymer(s) can be based for applications in drug delivery.

Nanomaterials have attracted lots of recent research attention as they possess unique photophysical, magnetic, and thermal properties with the potential of being engineered for various biomedical theranostic applications. The objective of this book chapter is to provide a timely overview on the synthetic methodology, surface engineering, physiological itinerary, and theranostic applications for the nanophases and nanostructures consisting of inorganic and/or organic materials. This chapter starts with an introduction, followed by a brief review of the applications and preparative methods of the inorganic nanomaterials with surface plasmon resonance, photoluminescence, magnetic, and bioactive properties. The effects of surface modification with polymers and morphology on the physiological itinerary and toxicity of the nanomaterials are then discussed to help the design of vehicles for targeted tissue imaging and drug delivery. Finally, examples of several promising nanotechnologies and theranostic applications are given including biosensors, magnetic hyperthermia, and photodynamic therapy (PDT) for tumor treatment. This chapter ends with a conclusion and future perspective section. To make use of all the innovative ideas and demonstrative prove-of-principles of nanomaterials for practical biomedical applications, it is absolutely necessary to emphasize and expand efforts on their translational research and development, including clinical studies and large-scale manufacturing of these novel engineered nanomaterials.

Correction for ‘Preparation and characterization of potential doxorubicin-loaded mixed micelles formed from vitamin E containing graft copolymers and PEG-b-PLA diblock copolymers’ by Kuan-Yi Lee et al., RSC Adv., 2015, 5, 83825–83836.

PEG-modified gold nanoparticles (PEG-modified GNs) with diameters of 40 nm and 70 nm were prepared to elucidate the effect of extent of PEG (M.W. 5000) grafting and particle size on tumor accumulation and cellular uptake. Flow cytometry reveals that cellular uptake is strongly related to the size of PEG-modified GNs, rather than the extent of PEG-5K grafting level. Cytotoxicity analysis based on the intracellular release of drugs showed that the 70 nm PEG-modified GNs have the higher cytotoxicity, beccause of their greater cellular uptake. Also, particle size, rather than PEG-5K grafting level affects tumor accumulation. However, PEG-5K grafting level significantly affects the accumulation of particles in the liver and spleen. This finding is important in determining the proper PEG-5K grafting level and particle size for designing nano-medicines.

Most anticancer drugs cause severe side effect due to the lack of selectivity for cancer cells. In recent years, new strategies of micellar systems, which design for specifically target anticancer drugs to tumors, are developed at the forefront of polymeric science. To improve efficiency of delivery and cancer specificity, considerable emphasis has been placed on the development of micellar systems with passive and active targeting. In this review article, we summarized various strategies of designing multifunctional micellar systems in the purpose of improving delivery efficiency. Micellar systems compose of a multifunctional copolymer or a mixture of two or more copolymers with different properties is a plausible approach to tuning the resulting properties and satisfied various requirements for anticancer drug delivery. It appears that multifunctional micellar systems hold great potential in cancer therapy.

This article reports a flexible hollow nanoparticles, self-assembling from poly(N-vinylimidazole-co-N-vinylpyrrolidone)-g-poly(d,l-lactide) graft copolymers and methoxyl/functionalized-PEG-PLA diblock copolymers, as an anticancer drug doxorubicin (Dox) carrier for cancer targeting, imaging, and cancer therapy. This multifunctional hollow nanoparticle exhibited a specific on-off switch drug release behavior, owning to the pH-sensitive structure of imidazole, to release Dox in acidic surroundings (intracellular endosomes) and to capsulate Dox in neutral surroundings (blood circulation or extracellular matrix). Imaging by SPECT/CT shows that nanoparticle conjugated with folic acids ensures a high intratumoral accumulation due to the folate-binding protein (FBP)-binding effect. In vivo tumor growth inhibition shows that nanoparticles exhibited excellent antitumor activity and a high rate of apoptosis in cancer cells. After 80-day treatment course of nanoparticles, it did not appreciably cause heart, liver and kidney damage by inactive Dox or polymeric materials. The results indicate that the flexible carriers with an on-off switched drug release may be allowed to accurately deliver to targeted tumors for cancer therapy.

Multifunctional mixed micelles that constructed from poly(HEMA-co-histidine)-g-PLA and diblock copolymer PEG-PLA with functional moiety was developed in this study. The mixed micelles had well defined core shell structure which was evaluated by TEM. The functional inner core of poly(HEMA-co-histidine)-g-PLA exhibited pH stimulate to enable intracellular drug delivery and outer shell of PEG-b-PLA with functional moiety Cy5.5 for biodistribution diagnosis and folate for cancer specific targeting were synthesized at the end of the polymer chain. The graft and diblock copolymer self assembled to nanospheres against water with an average diameter below 120 nm without doxorubicin, and an average diameter of around 200 nm when loaded with drug. From drug released study, a change in pH destroy the inner core to lead a significant doxorubicin(Dox) release from mixed micelles. Cellular uptake of folate-micelles was found to be higher than that of non-folate-micelles due to the folate-binding effect on the cell membrane, thereby providing a similar cytotoxic effect to drug only against the HeLa cell line. In vivo study revealed that specific targeting of folate-micelles exhibited cancer targeting and efficiency expression on tumor growth, indicating that multifunctional micelles prepared from poly(HEA-co-histidine)-g-PLA and folate-PEG-PLA have great potential in cancer chemotherapy and diagnosis.

Mixed micelles formed by critical micelle concentration (Cmc) character's diblock copolymer, and temperature-sensitive character's diblock copolymer were studied for their capabilities in improving stability with and without drug. Experimental results showed that this type of mixed micellar systems possessed complementary effects in adjusting external temperature shift (storage vs. body temperature) and concentration change (dilution after intravenous injection). Therefore, they provided excellent stability as drug carriers. Further results obtained from physicochemical property and drug release kinetics studies demonstrated such systems could also be applied to physiological conditions, in compliance with varied pH environments. We concluded that the newly developed mixed micelles can serve as a potential injectable drug delivery system for anticancer drugs, such as doxorubicin and many others.

A novel mixed micelle that comprised of poly(N-isopropylacrylamide-co-methacrylic acid)-graft-poly(D,L-lactide) (P(NIPAAm-co-MAAc)-g-PLA) with methoxy poly(ethylene glycol)-b-poly(D,L-lactide) (mPEG-b-PLA) was developed for application in cancer therapy. The mixed micelle had an multi-functional inner core of P(NIPAAm-co-MAAc)-g-PLA to enable intracellular drug delivery and an extended hydrophilic outer shell of mPEG to hide the inner core. Stability analysis of the mixed micelles in bovine serum albumin (BSA) solution indicates that the diblock copolymer mPEG efficiently protected the BSA adsorption on the mixed micelles because the hydrophobic groups of graft copolymer were efficiently screened by mPEG. From the drug release study, the mPEG-PLA diblock copolymer in mixed micelles slightly affected the functionalities of the P(NIPAAm-co-MAAc)-g-PLA graft copolymer; the graft copolymer still exhibited pH- and thermo-sensitivities in this core-shell structure. A change in pH deformed the structure of the inner core from that of aggregated P(NIPAAm-co-MAAc), causing the release of a significant quantity of doxorubicin (Dox) from mixed micelles. Clear differences between free Dox and Dox-mixed micelles were observed using confocal laser scanning microscopy (CLSM). This study presents not only a new micelle structure for a graft-diblock copolymer system, but also a method for overcoming some of the limitations on biomaterials used in intravenous injection.

Anticancer drug doxorubicin (DOX) was physically loaded into the micelles prepared from poly(2-ethyl-2-oxazoline)-b-poly(L-lactide) diblock copolymers (PEOz-PLLA). PEOz-PLLA consists of hydrophilic segment PEOz and hydrophobic segment PLLA showed pH-sensitivity in the aqueous solution. The DOX-loaded micelle exhibited a narrow size distribution with a mean diameter around 170 nm. The micellar structure can preserve hydrophobic drug DOX under the physiological condition (pH 7.4) and selectively release DOX by sensing the intracellular pH change in late endosomes and secondary lysosomes (pH 4-5). At 37 degrees C, the cumulated released rate of DOX from micelles was about 65% at pH 5.0 in the initial 24 h. Additionally, polymeric micelles had low cytotoxicity in human normal fibroblast HFW cells for 72 h by using MTT assay. Moreover, DOX-loaded micelles could slowly and efficiency decrease cell viability of non-small-cell lung carcinoma CL3 cells. Taken together, PEOz-b-PLLA diblock polymeric micelles may act as useful drug carriers for cancer therapy.

New thermo-responsive, pH-responsive, and biodegradable nanoparticles comprised of poly(D,L-lactide)-graft-poly(N-isopropyl acrylamide-co-methacrylic acid) (PLA-g-P(NIPAm-co-MAA)) were developed by grafting biodegradable poly(D,L-lactide) onto N-isopropyl acrylamide and methacrylic acid. A core-shell type nano-structure was formed with a hydrophilic outer shell and a hydrophobic inner core, which exhibited a phase transition temperature above 37 degrees C suitable for biomedical application. Upon heating above the phase transition temperature, PLA-g-P(NIPAm-co-MAA) nanoparticle showed a polarity increase of pyrene in either buffer solution or intra-hepato-carcinoma cells as determined by fluorescence measurement, indicating that the structure of nanoparticles caused leakages from outer shell copolymers aggregation and collapsed. The drug loading level of 5-fluorouracil (5-FU) encapsulated in the PLA-g-P(NIPAm-co-MAA) nanoparticles can be as high as 20%. The release of 5-FU from nanoparticles was strongly controlled by the pH in the aqueous solution. Based on these results, PLA-g-P(NIPAm-co-MAA) nanoparticles can be used as a drug carrier for intracellular delivery of anti-cancer drug.