6.5.4 The application of polymer nano-drug carrier...
The functions of polymer nano-drug carriers mainly include improving the watersolubility of hydrophobic drugs，reducing the toxic and side effects of drugs，and enhancing the enrichment of drugs in tumors.Besides，enhancing the tumor accumulation of the polymer nano-drug carriers，maintaining the stability of the polymer nano-drug carriers before it reaches the tumor，reducing or preventing the early release of the drugs，and fast releasing drug in the tumor area can all improve the therapeutic effect.The methods to maintain the blood stability of polymer nano-drug carriers include using polymer prodrugs instead of small molecular drugs，designing cross-linked nano-drug carriers and reducing critical micelle concentration of polymers.The factor of the motility of the polymer chains，the effect of serum protein adsorption and blood shear force，can destabilize the polymer nano-drug carriers，resulting in the early release of drugs from carriers.In addition，the drug itself may be separated from the carriers in advance by diffusion.All of these factors can reduce the bioavailability of drugs（see extended reading 5）.
Polymer prodrug method is to conjugate chemotherapeutic drugs to the polymers through the responsive covalent bond，which were used to make nano-drug carriers.Because the drugs conjugated on polymer chains have slower diffusion rates，which reduce the diffusion-driven premature drug release.The covalent bonds of responsive groups can break in the tumor microenvironment.The commonly used tumor microenvironment includes acidic pH，high reactive oxygen species concentration，certain enzymes，and high glutathione concentration.For example，Luan et al.prepared two amphiphilic polymer prodrugs by linking PEG and DOX or PTX via disulfide bonds，respectively.Their co-assembly can form polymer micelles with precisely regulated PTX/DOX loading ratios.The drug release rate from the micelles in the reductive tumor microenvironment was faster than that under normal conditions.
Cross-linking the polymer nano-drug carriers is a method to enhance the stability of the carriers and reduce the premature release of drugs from the carriers.Among them，the covalent bonds required for cross-linking can usually break by responding to certain characters in the tumor microenvironment.Hennink et al.constructed a small molecule prodrug that could break under acidic pH condition by bonding DOX to methylacrylamide via a hydrazone bond.The copolymerization of DOX prodrug and the polymer containing the side chains of methacrylic acid generated the cross-linked polymer nano-drug delivery system.The system released only 5％of the drug in the normal blood pH（pH=7.4），while it could release 100％of the drug in the acidic environment in the same time period.The results of animal experiments showed that the drug delivery system has a good inhibitory effect on melanoma.(https://www.daowen.com)
After entering the blood，the polymer nano-drug carriers will be gradually cleared in vivo，and its blood concentration will decrease continuously in a certain period of time.When the concentration is lower than the critical micelle concentration of the polymers，the stability of the polymer nano-drug carrier decreases，which easily leads to the destruction of the structure of the carrier and the premature release of the drug.Therefore，reducing the critical micelle concentration of the polymers can improve the stability of the nano-drug carriers.Cao et al.synthesized amphiphilic polymer molecules by combining the superhydrophilic zwitterionic polymers with the super-hydrophobic lipid molecules.The amphiphilic polymers could be used to prepare micelles with strong contrast polarity between their hydrophobic and hydrophilic components，which were used to deliver chemotherapy drugs（Figure 6-10（a））.The results showed that the critical micelle concentration of the micelle could be as low as 2.7×10-6 mmol/L，which is 1/106 of sodium dodecyl sulfonate，a commonly used small molecule surfactant，and 1/104 of polysorbate 80，a large molecule surfactant.The results of animal experiments showed that docetaxel delivered by the polymer micelles with strong contrast polarity showed significant better treatment effect than drugs delivered by nano-drug carriers prepared from polysorbate 80 and commercial docetaxel nano-formulation.
The drug release rate of the polymer nano-drug carriers in tumors is also a key factor to obtain a good therapeutic effect.If the drug release rate is low，the effective drug concentration will be reduced.If the drug is released too fast，it may quickly leave tumors and become ineffective.Therefore，a suitable drug release rate has an important impact on the treatment of melanoma.The mechanism of drug release includes drug diffusion from the carriers，drug release due to the destructions of nano-drug carriers by responding to acidic pH or certain enzymes，and drug release due to interruption of covalent or non-covalent interactions between the drug and the carrier.How to achieve controlled drug release is one of the key problems of the polymer nano-drug delivery system in the field of tumor treatment.