6.5.3 The principle of designing polymer nano-drug...
Polymer nano-drug carriers can prolong the time of some water-soluble small molecule drugs in blood circulation，solve the problem of poor water-solubility of hydrophobic anticancer drugs，and improve the stability of drugs.According to the traditional theory，the enrichment of polymer nano-drug carriers in the tumor is based on the enhanced permeability and retention（EPR）effect，which refers to the presence of the wide fenestrations on tumor vessel walls and the defective lymphatic drainage（Figure 6-9）.But the polymer nano-drug carriers need to overcome a number of physiological barriers before they can act on cancer cells.These barriers include the adsorption of serum proteins，the removal of nano-drugs by liver and spleen，and the passage of nano-drugs through tumor vessel walls and their internalization into tumor cells.To overcome these physiological barriers，polymer nanodrug carriers must have specific physical and chemical properties，so that they can adapt to the mechanism of action with various parts of bodies.However，because of the complexity of the in vivo environment and physiological barriers，the design of most current polymer nanodrug carriers is still unable to fully meet the needs of overcoming these physiological barriers.In addition，different physiological barriers have contradictory requirements for the physicochemical properties of nano-drug.For example，in order to avoid the removal of the polymer nano-drug carrier in the blood by the protective mononuclear phagocytic system as a foreign body，the size of the polymer nano-drug carrier is generally required to be small，but in order to achieve a longer tumor residence time and drug action time，the size of the polymer nano-drug carrier is generally required to be large.These conflicting demands greatly increase the difficulty of designing polymer nano-drug carriers.Although the design to promote tumor enrichment of nanomaterials remains to be optimized，based on a large number of research results，we can summarize some basic laws of carrier design，including the size and surface chemical properties of nanomaterials.
The size of polymer nano-drug carrier is an important factor affecting its pharmacokinetic dynamics and in vivo distribution.In general，nanomaterials larger than 100 nm are easier to be removed from the blood by macrophages and other mononuclear phagocytes than nanomaterials of smaller size，which negatively impacts their tumor accumulation.When the size of NPs is less than 5 nm，NPs will rapidly eliminate from bodies via the kidney，reducing their blood circulation time.When the size of NPs is between 5 nm and 100 nm，smaller NPs generally exhibit better intratumor diffusion.However，NPs with good diffusion ability do not necessarily bring higher tumor enrichment，because the interstitial fluid pressure existing between the tumor periphery and core can push the nanodrug carriers back to the blood vessels from the tumor tissues.Therefore，nanomaterials of small size have shorter tumor retention time.Studies have shown that the interstitial fluid pressure in some melanoma tissues can be as high as 50 mmHg.Because of the complex microenvironment of the tumor，the best sizes of the polymer nano-drug carriers for tumor accumulation should be determined by experiments.For example，Kataoka et al.prepared drug-carrying polymer micelles with an average particle size of 30 nm using PEG-b-P（Glu）block copolymer.At the same time，they also prepared drug-carrying polymer micelles with an average particle size of 70 nm by co-assembly of PEG-b-P（Glu）and P（Glu）homopolymer.By comparing the tumor accumulation of 30 nm，70 nm of polymer micelles with the 80 nm the US FDA-approved liposome formulation（doxil）in melanoma lymphatic metastatic tumor model，they found that polymer micelles with an average particle size of 30 nm had the deepest tumor penetration depth，the highest tumor accumulation，and the best chemotherapeutic effect.This example shows that the regulation of particle size is of great significance for the treatment of melanoma with polymer nano-drug delivery system.However，the mechanism of different polymer materials interact with in vivo system may differ，so it is necessary to study and discuss different materials in distinct tumor models.
The surface chemical property of the polymer nano-drug carriers is also an important factor affecting its tumor accumulation.Compared with nanomaterials with positive or negative surface charges，nanomaterials with neutral surface can effectively reduce the adsorption of serum proteins，which can improve their blood circulation time and tumor accumulation effect.Therefore，PEG is commonly used to protect the surface of polymer nano-drug carriers.It has been shown that the density of PEG on the surface of polymer nano-drug carriers can influence their blood circulation time and tumor accumulation.Wang et al.used PEG-b-PCL block copolymers to co-assemble with PCL homopolymers to prepare a series of polymer micelles with tunable sizes and surface PEG densities by adjusting the PCL chain length and the ratios of PCL homopolymer in the assemblies.Subsequently，polymer micelles with an average size of about 100 nm and different PEG densities（0.19-0.86 PEG chains/nm2）were selected to study the influence of surface PEG densities on the in vivo distribution and tumor accumulation of the polymer nano-drug carriers.The results showed that the polymer micelles with high PEG density had the least adsorption and the longest blood retention time.After loading docetaxel，the polymer micelles with the highest PEG density showed the best therapeutic effect on melanoma and the longest survival in mice.In addition to PEG，the zwitterionic small molecule and polymer ligands are also frequently used to modify the surface of polymer nano-drug carriers.The so-called zwitterionic ligands refer to ligands with equal positive and negative charges，resulting in a neutral charge（see extended reading 4）.(https://www.daowen.com)
Although PEG and zwitterionic ligands can reduce the adsorption of serum proteins，they also reduce the interaction between nanomaterials and tumor cells.To selectively enhance the interaction between the nano-drug carriers and tumor cells，we can add tumor targeting groups or introduce stimulus response groups to nano-drug carriers that specifically change the surface physicochemical properties at the tumor site.The target groups promote the accumulation of nanomaterials in tumors by enhancing the interaction between polymer nano-drug carriers and receptors on tumor cells and tissues.Commonly used target groups include small molecules，saccharides，peptides，proteins and other categories.The receptors highly expressed on the surface of melanoma cells include transferrin receptor（TfR），folic acid receptor（FR），fibroblast growth factor receptor（FGFR），laminin receptor（LR），somatostatin receptor（SSTR），sigma receptor，MC1R，CD44，etc.Tu et al.prepared a nano-drug delivery system loaded with cisplatin by using ethylenediamine modified hyaluronic acid.The nano-drug delivery system enhances the targeting ability by using the interaction between hyaluronic acid and CD44 expressed on melanoma cells，and can achieve responsive drug release in acidic or reductive environments.In addition，integrins，which are highly expressed on melanoma neovascular endothelial cells can also be used as targets for polymer nano-drug carriers.Common targeting groups include Arg-gly-Asp（RGD），circular Arg-Gly-Asp-D-Tyr-Lys（cRGDyK），etc.Tu et al.prepared block copolymers by conjugation Dα-tocopherol polyethylene glycol succinate with PLA through disulfide bonds，which were cleavable by GSH in tumor cells（TPGS-b-PLA）.The co-assembly of TPGS-b-PLA and PEGb-PLA can produce PTX-loaded polymer nano-micelles with or without RGD on the surfaces.The cleavage of disulfide bonds in polymer micelles by GSH in tumor cells triggered the release of PTX.The experiment results showed that polymer nano-micelles with RGD targeting groups have better tumor inhibition effect than those without RGD and commercial PTX nanoformulations，which confirmed that RGD can improve the melanoma targeting ability of polymer nano-drug carriers.Changing the physical and chemical properties of polymer nano-drug carriers specifically in tumor is the use of the stimuli-responsive groups on nano-drug carriers that can have physical or chemical reactions in the tumor microenvironment to change their surface physical and chemical properties，which prevents polymer nano-drug carriers from serum protein absorption before entering tumors，and promotes the interaction between polymer nano-drug carriers and tumor tissues or tumor cells after they enter tumors，leading to their enhanced tumor accumulation.Cai et al.successfully delivered nucleic acid drugs and photosensitizer to melanoma by using the pHresponsive polymer nano-drug carriers that can detach PEG on the surface in tumor acidic microenvironment.After the removal of PEG，the zeta potential of the polymer nano-drug carrier was increased to 20 mV，enhancing the interaction between polymer nano-drug carrier and the negatively charged cell membrane.At present，there are still some problems in the research of melanoma targeting polymer nano-drug carriers，such as insufficient targeting ability of ligands，and the shelter of targeting groups by serum proteins causing the loss of the targeting ability.Therefore，further research is still needed for the targeting ability of polymer nano-drug carriers.