Patterned Manipulated Surface Based on Femtosecond Laser with Adjustable Wetting Speed and Directional Fluid Delivery.

Recently, due to the crucial roles of multifunctional liquid manipulation surfaces in biomedical transportation, microfluidics, and chemical engineering, the demand for controllable and functional aspects of directed liquid transportation has increased significantly. However, designing an intelligent manipulation surface that is easy to manufacture and fully functional remains an immense challenge. To address this challenge, a smart surface that can regulate the rate of liquid transport within a patterned channel by temperature is reported. A synergistically controlled approach of poly(N-isopropylacrylamide) and micropillar shape-memory polymers (SMPs) was used to modulate the wetting rate of liquids on surfaces. By femtosecond laser direct writing, temperature-responsive composite surfaces are embedded in the microstructure of shape-memory polymers (SMPs) in a patterned manner, resulting in the preparation of novel programmable liquid manipulation surfaces incorporating boundaries possessing asymmetric wettability. Since the smart surface is based on SMP, the superhydrophobic part in the superhydrophobic/controllable wettability patterning platform is also programmed for droplet directional transport, which takes advantage of the difference in wettability between the rewritable indentation track and the periphery to allow droplets to flow into the temperature-controlled velocity track, enriching the functionality of the surface. In addition, based on its excellent controllability and patterning, the surface has been shown to be used in microfluidic circuit chips with self-cleaning properties, which provides new ideas for circuit timing control. This study provides promising prospects for the effective development of multifunctional liquid steering surfaces, lab-on-a-chip, and microfluidic devices.

The Effect of Block Ratio and Structure on the Thermosensitivity of Double and Triple Betaine Block Copolymers.

AB-type and BAB-type betaine block copolymers composed of a carboxybetaine methacrylate and a sulfobetaine methacrylate, PGLBT-b-PSPE and PSPE-b-PGLBT-b-PSPE, respectively, were synthesized by one-pot RAFT polymerization. By optimizing the concentration of the monomer, initiator, and chain transfer agent, block extension with precise ratio control was enabled and a full conversion (~99%) of betaine monomers was achieved at each step. Two sets (total degree of polymerization: ~300 and ~600) of diblock copolymers having four different PGLBT:PSPE ratios were prepared to compare the influence of block ratio and molecular weight on the temperature-responsive behavior in aqueous solution. A turbidimetry and dynamic light scattering study revealed a shift to higher temperatures of the cloud point and micelle formation by increasing the ratio of PSPE, which exhibit upper critical solution temperature (UCST) behavior. PSPE-dominant diblocks created spherical micelles stabilized by PGLBT motifs, and the transition behavior diminished by decreasing the PSPE ratio. No particular change was found in the diblocks that had an identical AB ratio. This trend reappeared in the other set whose entire molecular weight approximately doubled, and each transition point was not recognizably impacted by the total molecular weight. For triblocks, the PSPE double ends provided a higher probability of interchain attractions and resulted in a more turbid solution at higher temperatures, compared to the diblocks which had similar block ratios and molecular weights. The intermediates assumed as network-like soft aggregates eventually rearranged to monodisperse flowerlike micelles. It is expected that the method for obtaining well-defined betaine block copolymers, as well as the relationship of the block ratio and the chain conformation to the temperature-responsive behavior, will be helpful for designing betaine-based polymeric applications.

All-Atom Molecular Dynamics Simulations of the Temperature Response of Poly(glycidyl ether)s with Oligooxyethylene Side Chains Terminated with Alkyl Groups.

Recently, experimental investigations of a class of temperature-responsive polymers tethered to oligooxyethylene side chains terminated with alkyl groups have been conducted. In this study, aqueous solutions of poly(glycidyl ether)s (PGE) with varying numbers of oxyethylene units, poly(methyl(oligooxyethylene)n glycidyl ether) (poly(Me(EO)nGE)), and poly(ethyl(oligooxyethylene)n glycidyl ether) (poly(Et(EO)nGE) (n = 0, 1, and 2) were investigated by all-atom molecular dynamics simulations, focusing on the thermal responses of their chain extensions, the recombination of intrapolymer and polymer-water hydrogen bonds, and water-solvation shells around the alkyl groups. No clear relationship was established between the phase-transition temperature and the polymer-chain extensions unlike the case for the coil-globule transition of poly(N-isopropylacrylamide). However, the temperature response of the first water-solvation shell around the alkyl group exhibited a notable correlation with the phase-transition temperature. In addition, the temperature at which the hydrophobic hydration shell strength around the terminal alkyl group equals the bulk water density (TCRP) was slightly lower than the cloud point temperature (TCLP) for the methyl-terminated poly(Me(EO)nGE) and slightly higher for the ethyl-terminated poly(Et(EO)nGE). It was concluded that the polymer-chain fluctuation affects the relationship between TCRP and TCLP.

Highly Sensitive Temperature Sensor Based on Vernier Effect Using a Sturdy Double-cavity Fiber Fabry-Perot Interferometer.

Temperature measuring is a daily procedure carried out worldwide in practically all environments of human activity, but it takes particular relevance in industrial, scientific, medical, and food processing and production areas. The characteristics and performance of the temperature sensors required for such a large universe of applications have opened the opportunity for a comprehensive range of technologies and architectures capable of fulfilling the sensitivity, resolution, dynamic range, and response time demanded. In this work, a highly sensitive fiber optic temperature sensor based on a double-cavity Fabry-Perot interferometer (DCFPI) is proposed and demonstrated. Taking advantage of the Vernier effect, we demonstrate that it is possible to improve the temperature sensitivity exhibited by the polymer-capped fiber Fabry-Perot interferometer (PCFPI) up to 39.8 nm/°C. The DCFPI is sturdy, reconfigured, and simple to fabricate, consisting of a semi-spherical polymer cap added to the surface of the ferrule of a commercial single-mode fiber connector (SMF FC/PC) placed in front of a mirror at a proper distance. The length of the air cavity (Lair) was adjusted to equal the thickness of the polymer cap (Lpol) plus a distance δ to generate the most convenient Vernier effect spectrum. The DCFPI was packaged in a machined, movable mount that allows the adjustment of the air cavity length easily but also protects the polymer cap and simplifies the manipulation of the sensor head.

An injectable hyperthermic nanofiber mesh with switchable drug release to stimulate chemotherapy potency.

We developed a smart nanofiber mesh (SNM) with anticancer abilities as well as injectability and fast recovery from irregular to non-compressible shapes. The mesh can be injected at the tumor site to modulate and control anticancer effects by loading the chemotherapeutic drug, paclitaxel (PTX), as well as magnetic nanoparticles (MNPs). The storage modulus of the mesh decreases when applied with a certain shear strain, and the mesh can pass through a 14-gauge needle. Moreover, the fibrous morphology is maintained even after injection. In heat-generation measurements, the mesh achieved an effective temperature of mild hyperthermia (41-43°C) within 5 min of exposure to alternating magnetic field (AMF) irradiation. An electrospinning method was employed to fabricate the mesh using a copolymer of N-isopropylacrylamide (NIPAAm) and N-hydroxyethyl acrylamide (HMAAm), whose phase transition temperature was adjusted to a mildly hyperthermic temperature range. Pplyvinyl alcohol (PVA) was also incorporated to add shear-thinning property to the interactions between polymer chains derived from hydrogen bonding, The "on-off" switchable release of PTX from the mesh was detected by the drug release test. Approximately 73% of loaded PTX was released from the mesh after eight cycles, whereas only a tiny amount of PTX was released during the cooling phase. Furthermore, hyperthermia combined with chemotherapy after exposure to an AMF showed significantly reduced cancer cell survival compared to the control group. Subsequent investigations have proven that a new injectable local hyperthermia chemotherapy platform could be developed for cancer treatment using this SNM.

Temperature-Responsive Polymer Brush Coatings for Advanced Biomedical Applications.

Modern biomedical technologies predict the application of materials and devices that not only can comply effectively with specific requirements, but also enable remote control of their functions. One of the most prospective materials for these advanced biomedical applications are materials based on temperature-responsive polymer brush coatings (TRPBCs). In this review, methods for the fabrication and characterization of TRPBCs are summarized, and possibilities for their application, as well as the advantages and disadvantages of the TRPBCs, are presented in detail. Special attention is paid to the mechanisms of thermo-responsibility of the TRPBCs. Applications of TRPBCs for temperature-switchable bacteria killing, temperature-controlled protein adsorption, cell culture, and temperature-controlled adhesion/detachment of cells and tissues are considered. The specific criteria required for the desired biomedical applications of TRPBCs are presented and discussed.

Hyphenating temperature gradient elution with refractive index detection through temperature-responsive liquid chromatography.

Refractive index detection (RID) is attractive because it allows approaching the benefits of universal detection with liquid chromatography, by which ideally standard independent calibration and hence compound independent quantification becomes possible. Nevertheless, the implementation of RID has remained limited as it offers poor detection sensitivity while only being compatible with isocratic mobile phases. The implementation of compositional solvent gradients has remained prohibitively challenging in commercial HPLC-RID systems due to the resulting drastic alterations in refractive index and extreme baseline drift. While the refractive index is also highly dependent on temperature, more leeway appears possible to mitigate the problem, particularly when the used temperature gradients can be limited. Temperature-responsive liquid chromatography (TRLC) allows obtaining isocratic reversed phase type of separations, whereby retention is modulated via temperature changes âˆ¼ 15 °C-20 °C above and below the polymer conversion temperature. Elution profiles, reminiscent of what can be obtained with solvent gradients in conventional RPLC, can then be obtained by enacting downwards temperature gradients on the columns. This work comprises a proof-of-principle to illustrate the possibilities of combining thermal gradient TRLC with RID. The observed baseline drift appeared thereby very minor (<5 nRIU min-1), and hence easily controllable. Short chain fatty acids are used as representative compounds to assess this new approach. Overlapping calibration lines are accordingly obtained for all fatty acids between butyric and decanoic acid.

Stimuli-Responsive Thiomorpholine Oxide-Derived Polymers with Tailored Hydrophilicity and Hemocompatible Properties.

Thermo-responsive hydrophilic polymers, including those showing tuneable lower critical solution temperature (LCST), represent a continuous subject of exploration for a variety of applications, but particularly in nanomedicine. Since biological pH changes can inform the organism about the presence of disequilibrium or diseases, the development of dual LCST/pH-responsive hydrophilic polymers with biological potential is an attractive subject in polymer science. Here, we present a novel polymer featuring LCST/pH double responsiveness. The monomer ethylthiomorpholine oxide methacrylate (THOXMA) can be polymerised via the RAFT process to obtain well-defined polymers. Copolymers with hydroxyethyl methacrylate (HEMA) were prepared, which allowed the tuning of the LCST behaviour of the polymers. Both, the LCST behaviour and pH responsiveness of hydrophilic PTHOXMA were tested by following the evolution of particle size by dynamic light scattering (DLS). In weak and strong alkaline conditions, cloud points ranged between 40-60 °C, while in acidic medium no LCST was found due to the protonation of the amine of the THOX moieties. Additional cytotoxicity assays confirmed a high biocompatibility of PTHOXMA and haemolysis and aggregation assays proved that the thiomorpholine oxide-derived polymers did not cause aggregation or lysis of red blood cells. These preliminary results bode well for the use of PTHOXMA as smart material in biological applications.

Macromolecular crowding transforms regenerative medicine by enabling the accelerated development of functional and truly three-dimensional cell assembled micro tissues.

Scaffold-free in vitro organogenesis exploits the innate ability of cells to synthesise and deposit their own extracellular matrix to fabricate tissue-like assemblies. Unfortunately, cell-assembled tissue engineered concepts require prolonged ex vivo culture periods of very high cell numbers for the development of a borderline three-dimensional implantable device, which are associated with phenotypic drift and high manufacturing costs, thus, hindering their clinical translation and commercialisation. Herein, we report the accelerated (10 days) development of a truly three-dimensional (338.1 ± 42.9 µm) scaffold-free tissue equivalent that promotes fast wound healing and induces formation of neotissue composed of mature collagen fibres, using human adipose derived stem cells seeded at only 50,000 cells/cm2 on an poly (N-isopropylacrylamide-co-N-tert-butylacrylamide (PNIPAM86-NTBA14) temperature-responsive electrospun scaffold and grown under macromolecular crowding conditions (50 µg/ml carrageenan). Our data pave the path for a new era in scaffold-free regenerative medicine.

Synthesis of Temperature-Responsive Polymers Containing Piperidine Carboxamide and N,N-diethylcarbamoly Piperidine Moiety via RAFT Polymerization.

In this study, poly(N-acryloyl-nipecotamide) (PNANAm), poly(N-acryloyl-isonipecotamide) (PNAiNAm), and poly(N-acryloyl-N,N-diethylnipecotamide) (PNADNAm) are synthesized as novel temperature-responsive polymers using reversible addition-fragmentation chain-transfer polymerization. Aqueous solutions of these three polymers are examined via temperature-dependent optical transmittance measurements. The PNANAm sample with a hydrophilic terminal group shows an upper critical solution temperature (UCST) in phosphate-buffered saline (PBS) when its molecular weight (Mn ) is 7600 or higher, whereas PNANAm (Mn < 7600) is soluble. The UCST is influenced by molecular weight and the polymer concentration. In contrast, PNANAm sample with nonionic terminal group shows UCST, when Mn is below 7600, suggesting that the terminal nonionic group possibly increases UCST of PNANAm. The urea addition experiment suggests that the driving force for expression of UCST of PNANAm is the formation of inter-and intramolecular hydrogen bonds among the polymer chains. PNAiNAm is soluble in PBS but exhibits an UCST in an appropriate concentration of ammonium sulfate. In contrast, PNADNAm exhibits a lower critical solution temperature. Comparing the chemical structure of these polymers and their phase transition behaviors suggests that the carboxamide group position in the piperidine ring could determine the UCST expression. These results could help design temperature-responsive polymers with a desired the cloud point temperature.

Understanding the temperature induced aggregation of silica nanoparticles decorated with temperature-responsive polymers: Can a small step in the chemical structure make a giant leap for a phase transition?

Temperature-responsive nanomaterials have gained increasing interest over the past decade due their ability to undergo conformational changes in situ, in response to a change in temperature. One class of temperature-responsive polymers are those with lower critical solution temperature, which phase separate in aqueous solution above a critical temperature. When these temperature-responsive polymers are grafted to a solid nanoparticle, a change in their surface properties occurs above this critical temperature, from hydrophilic to more hydrophobic, giving them a propensity to aggregate. This study explores the temperature induced aggregation of silica nanoparticles functionalised with two isomeric temperature-responsive polymers with lower critical solution temperature (LCST) behavior, namely poly(N-isopropyl acrylamide) (PNIPAM), and poly(2-n-propyl-2-oxazoline) (PNPOZ) with similar molecular weights (5000 Da) and grafting density. These nanoparticles exhibited striking differences in the temperature of aggregation, which is consistent with LCST of each polymer. Using a combination of small-angle neutron scattering (SANS) and dynamic light scattering (DLS), we probed subtle differences in the aggregation mechanism for PNIPAM- and PNPOZ-decorated silica nanoparticles. The nanoparticles decorated with PNIPAM and PNPOZ show similar aggregation mechanism that was independent of polymer structure, whereby aggregation starts by the formation of small aggregates. A further increase in temperature leads to interaction between these aggregates and results in full-scale aggregation and subsequent phase separation.

Responsive polymer-assisted 3D cryogel supports Huh7.5 as in vitro hepatitis C virus model and ectopic human hepatic tissue in athymic mice.

The three-dimensional (3D) cell culture models serve as the interface between conventional two-dimensional (2D) monolayer culture and animal models. 3D culture offers the best possible model system to understand the pathophysiology of human pathogens such as hepatitis C virus (HCV), which lacks a small animal model, due to narrow host tropism and non-permissiveness of murine hepatocytes. In this study, functionally robust spheroids of HCV permissive Huh7.5 cells were generated, assisted by the temperature or pH-responsive polymers PNIPAAm and Eudragit respectively, followed by the long-term growth of the multilayered 3D aggregates in poly(ethylene glycol) (PEG)-alginate-gelatin (PAG) cryogel. The human serum albumin (HSA), marker of hepatic viability was detected up to 600 ng/ml on 24th day of culture. The 3D spheroid culture exhibited a distinct morphology and transcript levels with the upregulation of hepato-specific transcripts, nuclear factor 4α (HNF4α), transthyretin (TTr), albumin (Alb), phase I and phase II drug-metabolizing genes. The two most important phase I enzymes CYP3A4 and CYP2D6, together responsible for 90% metabolism of drugs exhibited up to 9- and 12-fold increment, respectively in transcripts. The 3D culture was highly permissive to HCV infection and supported higher multiplicity of infection compared to monolayer Huh7.5 culture. Quantitation of high levels of HSA (500-200 ng/ml) in circulation in mice for 32 days asserted integration with host vasculature and in vivo establishment of 3D culture implants as an ectopic human hepatic tissue in mice. The study demonstrates the 3D spheroid Huh7.5 culture as a model for HCV studies and screening potential for anti-HCV drug candidates.

Smart Polymeric Systems: A Biomedical Viewpoint.

Stimuli-responsive polymers (SRPs) are a recent innovative approach that has numerous biomedical applications. These smart polymers can be used in various industrial and medical areas. Smart polymeric hydrogels are a new class of biomedical materials that have attracted much attention in recent years. These hydrogels change their properties in response to alterations in the chemical, physical, or biochemical properties of their environment, and can be used for many biomedical applications. In this review, we discuss these novel materials with a focus on temperature-responsive polymers as the most applicable type of SRPs. Different types of these polymeric systems and their thermodynamics, as well as challenges for their clinical translation, their combination with other biosystems such as liposomes, and their applications are presented.

Converting Poly(Methyl Methacrylate) into a Triple-Responsive Polymer.

Multiresponsive polymers that can respond to several external stimuli are promising materials for a manifold of applications. Herein, a facile method for the synthesis of triple-responsive (pH, temperature, CO2 ) poly(N,N-diethylaminoethyl methacrylamide) by a post-polymerization amidation of poly(methyl methacrylate) (PMMA) is presented. Combined with trivalent counterions ([Fe(CN)6 ]3- ) both an upper and lower critical solution temperature (UCST/LCST)-type phase behavior can be realized at pH 8 and 9. PMMA and PMMA-based block copolymers are readily accessible by living anionic and controlled radical polymerization techniques, which opens access to various responsive polymer architectures based on the developed functionalization method. This method can also be applied on melt-processed bulk PMMA samples to introduce functional, responsive moieties at the PMMA surface.

Star-Shaped Poly(2-ethyl-2-oxazoline) and Poly(2-isopropyl-2-oxazoline) with Central Thiacalix[4]Arene Fragments: Reduction and Stabilization of Silver Nanoparticles.

The interaction of silver nitrate with star-shaped poly(2-ethyl-2-oxazoline) and poly(2-isopropyl-2-oxazoline) containing central thiacalix[4]arene cores, which proceeds under visible light in aqueous solutions at ambient temperature, was studied. It was found that this process led to the formation of stable colloidal solutions of silver nanoparticles. The kinetics of the formation of the nanoparticles was investigated by the observation of a time-dependent increase in the intensity of the plasmon resonance peak that is related to the nanoparticles and appears in the range of 400 to 700 nm. According to the data of electron and X-ray spectroscopy, scanning and transmission electron microscopy, X-ray diffraction analysis, and dynamic light scattering, the radius of the obtained silver nanoparticles is equal to 30 nm. In addition, the flow birefringence experiments showed that solutions of nanoparticles have high optical shear coefficients.

Preparation of injectable hydrogels from temperature and pH responsive grafted chitosan with tuned gelation temperature suitable for tumor acidic environment.

In this present work, stimuli responsive polymers that can respond to the temperature and pH of the environment were prepared. A series of temperature responsive diblock copolymers based on poly(ethylene glycol) methyl ether (mPEG) and ε-caprolactone (CL) were synthesized. Subsequently, the diblock copolymers were grafted onto chitosan, a pH responsive biopolymer. These chitosan-graft-(mPEG-block-PCL) (chitosan-g-(mPEG-b-PCL)) graft copolymers were structurally characterized by 1H NMR and FTIR and their sol-gel phase transitions were analyzed by the test tube inversion method as well as dynamic rheological measurements. These chitosan-g-(mPEG-b-PCL) graft copolymers demonstrated tunable temperature and pH responsive sol-gel phase transitions that correspond well with body temperature and pH of acidic tumor microenvironments. Gelation temperature (Tgel) decreased with increasing pH of the system, increasing PCL composition in the diblock copolymers, increasing solution concentration and decreasing grafting content of the diblock copolymers on chitosan. The graft copolymer hydrogels successfully showed the sustained release of both doxorubicin and curcumin for up to 2 weeks. The designed system was based on chitosan-g-(mPEG-b-PCL) graft copolymers, of which chitosan showed pH responsive properties and mPEG-b-PCL acted as a temperature sensitive moiety. In addition, mPEG and PCL are recognized as biocompatible polymers and chitosan has been engaged in various pharmaceutical research. Thus, this system could be considered an alternative choice for drug delivery applications.

Norfloxacin and Bisphenol-A Removal Using Temperature-Switchable Graphene Oxide.

Graphene oxide (GO) is a competitive candidate used for adsorption of emerging organic contaminants (EOCs) from water. To overcome GO's spontaneous aggregation tendency in adsorption and to ease contaminant desorption from the adsorbent for adsorbent regeneration, a modified GO (P-GO), with temperature-switchable hydrophilicity/hydrophobicity, obtained by grafting temperature-responsive poly( N- n-propylacrylamide) was proposed. Two model EOCs, norfloxacin (NOR) and bisphenol A (BPA), with distinct hydrophilicity/hydrophobicity were employed. P-GO showed significant temperature-responsive adsorption behaviors: P-GO was more hydrophilic at a lower temperature and was beneficial for the adsorption of hydrophilic NOR, whereas it turned more hydrophobic at a higher temperature and was preferred for the adsorption of hydrophobic BPA. Compared with GO, P-GO under corresponding optimal conditions had comparable large adsorption amounts for NOR because of an "adsorption site replacement" strategy and notably enhanced adsorption for BPA because of strengthened hydrophobic association. Main interfacial binding interactions were π-π electron donor-acceptor effect and H-bonding for NOR adsorption and hydrophobic association and H-bonding for BPA uptake. On the basis of the temperature-responsive adsorption behaviors and studied interfacial interactions, regeneration of the adsorbent at designed temperatures using water (without additional chemicals) as an eluent is realized. This achievement is important for reducing risks of secondary environmental pollution during regeneration and easing further recovery of organic contaminants if needed.

Recent Progress and Advances in Stimuli-Responsive Polymers for Cancer Therapy.

The conventional chemotherapeutic agents, used for cancer chemotherapy, have major limitations including non-specificity, ubiquitous biodistribution, low concentration in tumor tissue, and systemic toxicity. In recent years, owing to their unique features, polymeric nanoparticles have been widely used for the target-specific delivery of drugs in the body. Although polymeric nanoparticles have addressed a number of important issues, the bioavailability of drugs at the disease site, and especially upon cellular internalization, remains a challenge. A polymer nanocarrier system with a stimuli-responsive property (e.g., pH, temperature, or redox potential), for example, would be amenable to address the intracellular delivery barriers by taking advantage of pH, temperature, or redox potentials. With a greater understanding of the difference between normal and pathological tissues, there is a highly promising role of stimuli-responsive nanocarriers for drug delivery in the future. In this review, we highlighted the recent advances in different types of stimuli-responsive polymers for drug delivery.

Segmental Mobility Studies of Poly(N-isopropyl acrylamide) Interactions with Gold Nanoparticles and Its Use as a Thermally Driven Trapping System.

Thermal desolvation of poly(N-isopropylacrylamide) (PNIPAM) in the presence of a low concentration of gold nanoparticles incorporates the nanoparticles resulting in suspended aggregates. By covalently incorporating <1% acenaphthylene into the polymerization feed this copolymer is enabled to be used as a model to study the segmental mobility of the PNIPAM backbone in response to gold nanoparticles both below and above the desolvation temperature, showing that there is a physical conformational rearrangement of the soluble polymer at ultralow nanoparticle loadings, indicating low affinity interactions with the nanoparticles. Thermal desolvation is capable of extracting >99.9% of the nanoparticles from their solutions and hence demonstrates that poly(N-isopropylacrylamide) can act as an excellent scrubbing system to remove metallic nanomaterial pollutants from solution.

Construction and application of a liver cancer-targeting drug delivery system based on core-shell gold nanocages.

BACKGROUND: In order to achieve drug targeting and controlled release, we have successfully developed a novel drug release system DOX/AuNCs-PM-HA with gold nanocages (AuNCs) as photothermal cores, thermally responsive copolymer P(NIPAM-co-Am) (PM) as the near-infrared (NIR) stimuli gatekeeper and hyaluronic acid as a targeting ligand as well as a capping agent. METHODS: Cell uptake and cell viability were investigated. In vivo photoacoustic tomography imaging in H22 tumor bearing mice was analyzed for the tumor targeting effect of the nanocomplexes. Antitumor efficacy and the tissue distribution in vivo were investigated. RESULTS: In vitro results demonstrated that the DOX/AuNCs-PM-HA had significant anticancer activity against SMMC-7721 cells under NIR irradiation. Furthermore, in vivo photoacoustic tomography imaging of the nanocomplexes in H22 tumor bearing mice could indicate effective tumor targeting. Our studies on antitumor efficacy and the tissue distribution in vivo showed that many DOX/AuNCs-PM-HA nanocomplexes could efficiently accumulate at the tumor site so that they could inhibit the tumor growth effectively with limited side effects. The in vitro and in vivo results confirmed that the tumor-targeting and controlled-release drug system DOX/AuNCs-PM-HA with the combination of chemotherapy and photothermal therapy showed strong anti-tumor effect and would have great potential for future cancer therapy. CONCLUSION: This tumor targeting DOX/AuNCs-PM-HA nanocomplex responded not only to the external stimuli of NIR, but also the internal stimuli of hyaluronidase, providing the potential for pinpointed and multi-stimuli responsive intracellular drug release.