As the most important and common treatment in cancer therapy, chemotherapy still faces many challenges such as poor tumor selectivity and multidrug resistance. In recent years, nanomedicine delivery systems have provided the new strategies to many limitations of conventional chemotherapy [1]. Nano-drug delivery systems have greater potential for multiple targeting functionalization, in vivo imaging, combined drug delivery, and other aspects compared to the traditional drug delivery systems [2]. Targeting drug delivery systems are driven by the incorporation of stimuli-responsive materials, enabling them to bypass the biological barrier and achieve targeted intracellular drug delivery [1]. Stimuli-responsive nano-drug delivery systems typically have two constructional approaches: one is that the nanocarrier material itself has a stimulus-responsive property and the other is stimuli-responsive group or molecule to modify the surface of the nanomaterial. A large variety of nanomaterials could respond to physical stimuli, chemical stimuli or biological stimuli. Herein we select several common response factors combined with specific examples to make a review and outlook of nano-drug delivery system in cancer therapy.

Responsive nano-drug delivery systems

      Among these response materials, the pH-responsive materials are widely designed for use in nanomedicine delivery systems in cancer therapy. It is well known that many chemical bonds are not stable in strong acid or base systems. Based on this feature, pH-responsive polymers with acid-labile chemical bonds are usually designed to remain stable at physiological pH, but they will quickly degrade in the weak acid environment of tumor tissue resulting in drug targeting release. And these polymers ensure to retain their pH responsiveness after incorporation into nanostructures [2].

      Tu et al. developed a pH-responsive drug delivery system by PEGylating commercially available aliphatic dendritic polyester Boltorn H40. Based on its amphiphilic structure, the resulting star copolymer (H40-star-mPEG) with a hydrophobic H40 core and multiple hydrophilic mPEG arms self-assembles into a stable micelle in aqueous solution. The experimental results show that the drug release rate of DOX loaded micelles is greatly increased in acidic environment [3]. Heffernan et al. used a novel hydrophobic polymer-poly (1, 4-phenyleneacetone dimethylene ketal) (PPADK), which contains ketal bonds in its backbone to make polyketal nanoparticles. Under acidic conditions, the nanoparticles are hydrolyzed to low molecular weight hydrophilic compounds and the encapsulated therapeutic agent is released at an accelerated rate [4]. In addition, there is an interesting strategy for drug delivery under acidic condition [4]. Ke et al. incorporated sodium bicarbonate and anticancer drug (DOX) into PLGA hollow microspheres (HMs) by a double emulsion method. In an acidic environment, NaHCO3 reacts with hydrogen ions to form CO₂ bubbles. The enlargement of the volume leads to the rupture of the microsphere wall and the rapid release of anticancer drugs [5].

      When light strikes the material, it transfers some of the energy to the irradiated material, which can be used to change the polarity, structure, and configuration of the chemical bond, triggering the drug release mechanism. The general design idea is to passivate the target molecule with a photoactive protecting group, and the material undergoes photolysis reaction after light irradiation to activate the target molecule to complete the drug release. Karthik and coworkers constructed light-responsive nano-drug delivery systems using two new components: fluorescent carbon dots and a quinoline based photo trigger. They have developed fluorescent carbon dots tethered to a quinoline based photo trigger for regulated delivery of anticancer drugs. The photo regulated drug release ability of Qucbl-Cdots has been established by means of periodic exposure to light and dark conditions. Furthermore, Qucbl-Cdots were readily internalized inside the HeLa cells and showed precise control over the drug release to kill the cancer cells upon irradiation. However, the use of Qucbl-Cdots in in vivo studies is limited due to their absorbance below 500 nm [6].

      When the temperature of the system changes, it can cause varieties in the volume, solubility and configuration of the temperature-sensitive material to trigger drug release. Temperature-responsive microgels were synthesized with poly N-isopropylmeth acrylamide (PNIPMAM; transition temperature=44^o C) as shell and with poly N-isopropylacrylamide (PNIPAM; transition temperature=34^o C) as core by Berndt and his copartners, and the response temperature can be adjusted by changing the shell /core mass ratio. The effect of mass ratio on the thermal behavior of spherical core-shell microgels was investigated [7].

      Of course, it is also possible to control the targeted release of magnetic nanoparticles in the tissues of the patient through an external magnetic field. Magnetic drug delivery materials are usually made of metal or metal oxide nanoparticles, with organic substances such as fatty acids, polysaccharides or polymers wrapped to improve colloidal stability [8]. Ye et al. encapsulated inorganic imaging agents of super paramagnetic iron oxide nanoparticles (SPION), manganese-doped zinc sulfide (Mn: ZnS) quantum dots (QDs) and the anticancer drug busulfan in PLGA nanoparticles by an emulsion-evaporation method. Then the PLGA nanovesicles were prepared and the vesicles were used as nano-drug systems for anticancer drug delivery. Also, the degradation property of PLGA vesicles was investigated in vitro researches and the vesicle delivery ability to anticancer drugs was evaluated by in vivo animal experiments. The delivery system has high entrapment efficiency and sustained drug release capacity for lipophilic drug busulfan. Preliminary conclusions have been drawn that the delivery system has high encapsulation efficiency and sustained drug release capacity for lipophilic drug busulfan [9].

      Enzyme response is the most common in biological stimulation. Enzyme-responsive nano-drug delivery systems are catalyzed and degraded by enzymes of specific tissues or cells (Eg tumor cells) upon entry into the human body, thereby triggering the release of the entrained drug. It can also serve to enhance the efficiency of drug delivery and reduce side effects. Thornton et al. attached the oppositely charged peptide chains to the polyethylene acrylamide gel particles. Enzymes can cleave peptide chains from gel particles on gel particles when the gel encounters thermophilic protease. The negatively charged portion of the peptide chain is cut off, leaving the cationic portion of the gel particles make a positive charge on the whole. The role of the same type of charge repulsion makes the gel burst to release the drug loaded [10]

      Recent studies on dual-response nano-drug delivery systems have been increasingly available. Synergy between the two response stimuli allows for more precise regulation of the site and dose of drug release. Jaber and coworkers reduced the particle size of the nanometer drug H₃PMo₁₂O₄0 to 15 nmby solvothermal method and synthesized Fe3O4 @SiO2 /poly (N-isopropylacrylamide) as a magneto caloric nanocarrier for the H₃PMo₁₂O₄0 nano-drug. Then the release behavior of H₃PMo₁₂O₄0 nano-drug on the thermal response carrier was investigated in the AC magnetic field. The effects of drug particle size, loading and release medium temperature on the drug release were investigated. It can be concluded with the magnetic field strength, temperature and drug loading increased, the drug release rate would increase [11].

Challenges and Future Prospects

      With the deepening of research on cancer therapy of nanodrug delivery system, it has been possible to achieve the targeted control of anticancer drugs, combined administration and prolongation of circulation time. This effectively reduces the damage caused by chemotherapy and traditional modes of administration to the human body and has broad application prospects in the field of biomedicine. However, most of the delivery systems still remain in the experimental phase. Such as the biocompatibility of nanocarrier materials, the toxicity of degradation products to human beings and the irreversibility of response process are all the problems to be solved. Thus, there is still a long way to go from the experimental stage to the clinical testing to the final popularization and application. Even so, nanomedicine delivery systems will certainly make even more major breakthroughs with the development of nanotechnology and biomedical technologies and the cross-cutting assistance in various academic fields.

      This work was supported by was supported by the National Key R&D Program of China (2016YFC1000902), the National Science Foundation of China (51503093) and the Shenyang Science and Technology Bureau (F16-205-1-37).