Translatable High Drug-Loading Drug Delivery Systems Based on

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Translatable High Drug Loading Drug Delivery Systems Based on Biocompatible Polymer Nanocarriers Weizhi Chen, Sensen Zhou, Lei Ge, Wei Wu, and Xiqun Jiang* MOE Key Laboratory of High Performance Polymer Materials and Technology, Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, and Jiangsu Key Laboratory for Nanotechnology, Nanjing University, Nanjing 210093, P. R. China. ABSTRACT: Most nanocarriers possess low drug loading, resulting in frequently repeated administration and thereby high cost and increased side effects. Furthermore, the characteristics of nanocarrier materials, especially the drug loading capacity, plays a vital role in the drug delivery efficacy. In this review, we focus on the readily translatable polymeric drug delivery systems with high drug loading, which are comprised of biocompatible polymers such as poly(ethylene glycol), poly(N-vinylpyrrolidone), polyoxazoline, natural proteins like albumin and casein, non-natural proteins such as recombinant elastin-like polypeptides, as well as nucleic acids. At the end of this review, applications of these polymeric nanocarriers on the delivery of proteins and gene drugs are also briefly discussed.

1. INTRODUCTION Chemotherapy plays a vital role in cancer treatment. However, most chemotherapeutic drugs are hydrophobic and not suitable for in vivo usage. The small molecular weight of most chemotherapeutic drugs is also an obstacle for prolonging blood circulation. For better therapeutic efficacy to be achieved, multiple injections with relatively high dose are needed. On the other hand, chemotherapy drugs have no selectivity and can kill normal cells as well, which means that the side effect is systematic. In turn, the side effects severely limit the injection dose of drugs. Therefore, numerous works have attempted to improve anticancer efficiency and reduce the side effects of chemotherapeutic drugs. With the development of medical technology and the improving understanding of tumor pathology, drugs based on proteins, peptides, as well as nucleic acids have been developed. However, rapid enzymatic degradation, low stability, and undesirable pharmacokinetics hinder the application of these biological medicines in the clinic. Nanomaterials are very helpful in cancer treatment for improving the drug accumulation within tumors and decreasing the systemic toxicity of most drugs.1−4 Most solid tumors have special pathophysiology characteristic such as rich blood vessels, increased permeability of the blood vessels, and ineffective lymphatic drainage. Nanosized drug carriers can extravasate via leaky blood vessels and accumulate at the tumor site, which is known as “enhanced permeability and retention (EPR) effect”.5 The EPR effect is also called passive targeting. On the other hand, various targeting agents based on characteristics of the tumor microenvironment have been investigated and widely applied for selectively targeting tumors.6 For both passive and active targeting approaches, the carrier materials play a crucial role in improving drug delivery efficacy. For a satisfactory drug delivery efficacy to be © XXXX American Chemical Society

obtained, the materials should be deliberately designed. Materials used for drug delivery, in our opinion, should (1) be biocompatible and nontoxic, (2) allow for loading or conjugating diverse drugs with high drug loading, (3) show favorable release behavior, (4) have good pharmacokinetics and an extended circulating half-life, (5) allow for modifications and functionalization, and 6) be easy to obtain or synthesize in a few steps with high yield. Biocompatibility is the primary requirement for materials used for drug delivery. Second, high drug content is necessary. High drug content means low frequency of drug administration, which ultimately reduces clinical costs and side effects and improves the quality of life of the patient. In this review, we discuss the merits and demerits of the most frequently used biocompatible drug nanocarriers with high drug loading that are either natural or synthetic. In the first part of this review, we discuss the synthetic material-based nanocarriers, for example, poly(ethylene glycol) (PEG), poly(Nvinylpyrrolidone) (PVP), and polyoxazoline (POx), as shown in Figure 1. Then, natural biopolymer materials including proteins, peptides, and nucleic acids are introduced. We also briefly discuss gene therapeutic drug delivery at the end of this review. Special Issue: Biomacromolecules Asian Special Issue Received: February 8, 2018 Revised: April 4, 2018 Published: April 24, 2018 A

DOI: 10.1021/acs.biomac.8b00218 Biomacromolecules XXXX, XXX, XXX−XXX

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Figure 1. Biocompatible materials applied for drug delivery systems that we are discussed in this review. Figure 2. Application of biocompatible polymers in drug delivery systems. (a) Drugs are directly conjugated to the ends of polymers. and then the conjugates self-assemble into nanoparticles. (b) Amphipathic polymers self-assemble into micelles, and hydrophobic drugs are loaded into the cores. (c) Biocompatible polymers are used for coating the surface of nanoparticles to improve biocompatibility.

2. SYNTHETIC POLYMER-BASED NANO DRUG DELIVERY SYSTEMS 2.1. PEGylated Nanomedicines. Targeted delivery of drug to tumor sites needs a prolonged blood circulation time, slow clearance from the body, and low nonspecific interaction with proteins in the blood. However, not all hydrophilic polymers can provide a long circulation time. Poly(ethylene glycol) (PEG) is an FDA-approved synthetic polymer that has been widely applied for drug delivery systems due to its great biocompatibility and stealth property. PEGylation can enhance the water solubility of hydrophobic drugs and prolong the body-residence time of drugs, providing a lower kidney/liver clearance rate when compared to that of the unmodified drugs. Furthermore, PEGylated carriers are also characterized by reduced interaction with serum proteins. The longer blood circulation time gives drugs more opportunities to reach tumor sites before being expelled from body. On the other hand, the end groups of PEG can be easily modified for functionalization becaues it is also very soluble in organic solvents. Moreover, PEG with various molecular weights and low polydispersity index (PDI) are easily obtained through the anionic polymerization of ethylene oxide. As shown in Figure 2, PEG can be directly conjugated with drugs to develop a prodrug.7−9 Hu et al. synthesized polyprodrug amphiphiles with PEG and a reduction-cleavable CPT prodrug monomer.10 These polyprodrug amphiphiles provide >50 wt % CPT loading content with four different selfassembly nanostructures, spheres, large compound vesicles, smooth disks, and unprecedented staggered lamellae with spiked periphery. Shen et al. used short PEG with only eight repeating units as a hydrophilic block to conjugate with camptothecin (CPT). This amphiphile could self-assemble to a prodrug vesicle with high drug content as high as 58 wt %.11 As shown in Figure 3, the vesicle is not only a CPT prodrug but also can be used as a drug carrier to load other drugs such as doxorubicin (DOX) for synergy therapy. When free drug was loaded into the cavity of prodrug-based vesicles, the drug

loading could be further enhanced. Huang et al. prepared a PEG-acetal-paclitaxel (PTX) prodrug that can load free PTX when self-assembling into nanoparticles in water.12 This approach highly improved the drug loading to 60.3 wt %. Gu group designed a new graft copolymer that can form a polymeric nanocarrier in a protein folding-like manner with great loading capacity for two drugs (25.1 wt % for CPT and 30 wt % for DOX).13 Wu et al. developed fourth-generation dendrimers with different length PEG as end groups.14 On this basis, gemcitabine (GEM) was conjugated to the fourthgeneration dendrimers and obtained drug-conjugated dendrimers with 23−25 drug molecules attaching to one molecule of the dendrimers. In vivo examination in 4T1 tumor-bearing mice found that the GEM-conjugated dendrimers with the longest PEG end group showed the best tumor accumulation and penetration ability. Liu et al. prepared PEGylated unimolecular micelles serving as a novel theranostic platform that showed favorable CPT loading ability (>17.3 wt %).15 Alternately, PEG can be introduced as side chains for improving the hydrophilicity of the polymer backbones. For example, Yu et al. used PEG oligomer as the side chain of polyrotaxanes (PR) and then linked PTX with a high drug loading content of ∼29 wt %.16 The PR-PTX conjugate exhibited a unique in vivo fate, significant antitumor response, and deep intratumoral penetration. In addition, PEG can be used as a hydrophilic block to build nanocarriers with various hydrophobic blocks.17−20 During the self-assembly of amphiphilic copolymers, the premixed hydrophobic drugs can be loaded into the micellar cores. However, most drugs are highly hydrophobic and can self-aggregate when exposed to aqueous solutions, leading to a very low drug loading usually lower than 5 wt %. To overcome drug B


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Figure 3. Schematic diagram of the amphiphilic camptothecin (CPT) prodrugs (OEG-CPT and OEG-DiCPT) and their self-assembly into nanocapsules for loading other drugs. Reprinted with permission from ref 11. Copyright 2010, American Chemical Society.

based on PEG monomethylether-b-poly(methacrylamide tertbutyl carbazate) (MPEG-MABH).23 DOX was conjugated into MPEG-MABH through a pH-labile hydrazone bond with a high drug loading content of ∼40 wt %. Further, PEG can be coated onto the surface of nanocarriers, especially inorganic nanocarriers, to lower their interactions with serum proteins and achieve a better EPR effect.24−26 Although PEG has shown great advantages in prolonging circulation time in vivo and making nanoparticles more “stealthy”, some defects of PEG have also gradually been found. For example, the nonbiodegradability of PEG with high molecule weight is reminiscent of the use of relative low mass PEGs.27 On the other hand, paradoxically, PEGs with lower molecule weight are much easier to oxidize. 28 Most importantly, some studies demonstrated that PEG might trigger antibody-mediated clearance in animals and humans.29,30 When PEGylated nanoparticles are first injected into body, the pharmacokinetics are great. Nevertheless, these excellent pharmacokinetics go away, and the body eliminates the PEGylated nanoparticles more rapidly when PEGylated nanoparticles are injected into the body repeatedly. This is the so-called accelerated blood clearance (ABC) phenomenon.31−33 Thus, researchers are making efforts to reduce the ABC phenomenon by evaluating the effect factors34−36 and are focused on searching for alternatives to PEG. 2.2. Poly(N-vinylpyrrolidone) (PVP)-Based Nanomedicines. PVP is one alternative to PEG that has attracted increasing attention in drug delivery applications due to its good biocompatibility.37−41 In World War II, it was used as a plasma expander or a retarding agent for subcutaneous injection of hormone preparations such as vasopressin.42 PVP can be well-synthesized through controlled radical polymerization of vinylpyrrolidone43,44 and has a low PDI below 1.2. The functionalization of end groups is readily accessible.45,46 PVP is highly soluble in aqueous solution and can be used for improving the hydrophilicity and blood circulation time of drugs. The well-defined molecular structure provides PVP favorable biological properties. Similar to PEG, PVP also has a stealth property. A PVP-based shell is able to prolong the liposome circulation time in vivo.47 Kamada et al. found that PVP-modified tumor necrosis factor (TNF)-α had a longer plasma half-life than native TNF-α as well as PEGylated TNFα.48 Moreover, a distinct advantage of PVP is that PVP has no ABC phenomenon. When repeatedly injected into the body, the pharmacokinetics of PVP-coated nanoparticles remained

aggregation, the Cheng group prepared a dimeric prodrug of CPT (CPT-SS-CPT) through two carbonate linkages on the 2,6-bis(hydroxymethyl)-aniline whose amine group was protected by a disulfide bond.21 Then, they used methoxy poly(ethylene glycol)-block-polylactide (mPEG-PLA) to coprecipitate CPT-SS-CPT, as shown in Figure 4, and found that

Figure 4. Schematic illustration of encapsulating hydrophobic drugs into nanoparticles. (a) Hydrophobic drugs are encapsulated in a polymeric micelle with the undesired formation of large drug precipitates. (b) Illustration of drug dimer nanoaggregation followed by surface coating and particle stabilization by an amphiphilic polymer via hydrophobic interactions. Reprinted with permission from ref 21. Copyright 2015, American Chemical Society.

the drug loading of the CPT-SS-CPT dimeric drug can be up to 50 wt %. The high drug loading micelles showed great stability and could steadily release drug when the disulfide bond was cleaved. They also extended this strategy to DOX loading and achieved a similarly high drug payload, suggesting that the dimerization of drugs is a powerful method to acquire high drug loading. Instead of coprecipitation, dimeric drugs can be conjugated with PEG to form a liposome-like structure.22 The amphiphilic molecule can self-assemble into vesicles with drug loading as high as 60 wt %. Xu et al. reported a DOX prodrug C


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Figure 5. Schematic diagram of the preparation of PVP-PASP-CDDP nanoparticles. Reprinted with permission from ref 53. Copyright 2015, American Chemical Society.

particles showed great potential in the drug delivery field. Host−guest interactions and supermolecular chemistry provide a facile approach to synthesize a series of desired polymer structure under mild conditions.54−56 In addition, the supermolecular structure can be dissociated under certain conditions, which can be designed for stimulus-responsive dissociation and controlled release of drugs.57,58 The Leroux group prepared a poly(N-vinylpyrrolidone)-block-poly( D , L -lactide) (PVPPDLLA) with 37% DLLA content, which was less cytotoxic than Cremophor EL (CrmEL).59 When treated with water, PVP-PDLLA could self-assemble into polymeric micelles that could efficiently solubilize water-insoluble drugs such as PTX and docetaxel (DCTX). When PTX was loaded, the polymeric micelles showed equipotent cytotoxicity to Taxol. Moreover, compared to 20 mg/kg of Taxol, this PTX-loaded PVP-PDLLA possessed a higher maximum tolerated dose (MTD) even than 100 mg/kg, suggesting excellent biocompatibility of PVP. Comparing to Taxotere, PVP-PDLLA nanomedicine showed comparable in vitro cytotoxicity and in vivo toxicity,60 whereas blank vehicle PVP-PDLLA was more tolerable than polysorbate 80 even at a 4-fold higher dose. 2.3. Poly(2-oxazoline) (POx)-Based Nanomedicines. Besides PVP, poly(2-oxazoline)s (POx’s) are another class of potential substitutes for PEG. POx, also called peptide-like polymers, have been considered a potential biomedical material due to their good biocompatibility.61−64 POx with low PDI (20 wt % PTX, 15 wt % DOX, 50.6 molecules/HSA DOX, 11 molecules/ DHSA CDDP, 10 wt % DOX, 10.3 wt % taxol, 26.4 wt % DOX, 1200 molecules/particle DOX, 66.7 wt % DOX, 50 molecules/ nanotrain

14 15 16 21 22 23 50, 51 52 53 72 73 74−76

77 82 98 99 101 102 119 138 143 151 153 154

could be expelled from the body through the natural metabolism pathway. In contrast to peptides, the molecular weights of proteins are usually very large. Preparing high drug loaded nanocarriers with proteins is a challenge. Proteins usually have complicated secondary, tertiary, and quaternary structures. They are usually stabilized in water with hydrophilic parts outside and hydrophobic parts inside. Drugs can be loaded into the hydrophobic interior and conjugated on the surface. With rational design, a desired drug loading content can be achieved. In addition, proteins can be programmedly prepared with desired structure, molecular weight, and residues through genetic engineering technology. Further, protein-based nanocarriers are especially suitable for protein drug delivery. Nucleic acids are a class of incoming drug carriers. By virtue of DNA nanotechnology, diverse DNA origamis spring up. With precise control of sequences, drugs can effectively intercalate into the DNA nanostructures. From technology terms, it is easy to build various DNA nanostructures with high drug loading capacity. However, the biosafety of DNA I


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(10) Hu, X.; Hu, J.; Tian, J.; Ge, Z.; Zhang, G.; Luo, K.; Liu, S. Polyprodrug amphiphiles: hierarchical assemblies for shape-regulated cellular internalization, trafficking, and drug delivery. J. Am. Chem. Soc. 2013, 135, 17617−17629. (11) Shen, Y.; Jin, E.; Zhang, B.; Murphy, C. J.; Sui, M.; Zhao, J.; Wang, J.; Tang, J.; Fan, M.; VAn Kirk, E. V.; Murdoch, W. J. Prodrugs forming high drug loading multifunctional nanocapsules for intracellular cancer drug delivery. J. Am. Chem. Soc. 2010, 132, 4259−4265. (12) Huang, D.; Zhuang, Y.; Shen, H.; Yang, F.; Wang, X.; Wu, D. Acetal-linked PEGylated paclitaxel prodrugs forming free-paclitaxelloaded pH-responsive micelles with high drug loading capacity and improved drug delivery. Mater. Sci. Eng., C 2018, 82, 60−68. (13) Tai, W.; Mo, R.; Lu, Y.; Jiang, T.; Gu, Z. Folding graft copolymer with pendant drug segments for co-delivery of anticancer drugs. Biomaterials 2014, 35, 7194−7203. (14) Wu, W.; Driessen, W.; Jiang, X. Oligo(ethylene glycol)-based thermosensitive dendrimers and their tumor accumulation and penetration. J. Am. Chem. Soc. 2014, 136, 3145−3155. (15) Hu, X.; Liu, G.; Li, Y.; Wang, X.; Liu, S. Cell-penetrating hyperbranched polyprodrug amphiphiles for synergistic reductive milieu-triggered drug release and enhanced magnetic resonance signals. J. Am. Chem. Soc. 2015, 137, 362−368. (16) Yu, S.; Zhang, Y.; Wang, X.; Zhen, X.; Zhang, Z.; Wu, W.; Jiang, X. Synthesis of paclitaxel-conjugated β-cyclodextrin polyrotaxane and its antitumor activity. Angew. Chem., Int. Ed. 2013, 52, 7272−7277. (17) Chen, L.; Xie, Z.; Hu, J.; Chen, X.; Jing, X. Enantiomeric PLA− PEG block copolymers and their stereocomplex micelles used as rifampin delivery. J. Nanopart. Res. 2007, 9, 777−785. (18) Wei, J.; Shuai, X.; Wang, R.; He, X.; Li, Y.; Ding, M.; Li, J.; Tan, H.; Fu, Q. Clickable and imageable multiblock polymer micelles with magnetically guided and PEG-switched targeting and release property for precise tumor theranosis. Biomaterials 2017, 145, 138−153. (19) Feiner-Gracia, N.; Buzhor, M.; Fuentes, E.; Pujals, S.; Amir, R. J.; Albertazzi, L. Micellar stability in biological media dictates internalization in living cells. J. Am. Chem. Soc. 2017, 139, 16677− 16687. (20) Yoo, J.; Rejinold, N. S.; Lee, D.; Jon, S.; Kim, Y. C. Proteaseactivatable cell-penetrating peptide possessing ROS-triggered phase transition for enhanced cancer therapy. J. Controlled Release 2017, 264, 89−101. (21) Cai, K.; He, X.; Song, Z.; Yin, Q.; Zhang, Y.; Uckun, F. M.; Jiang, C.; Cheng, J. Dimeric drug polymeric nanoparticles with exceptionally high drug loading and quantitative loading efficiency. J. Am. Chem. Soc. 2015, 137, 3458−3461. (22) Wang, H.; Xu, M.; Xiong, M.; Cheng, J. Reduction-responsive dithiomaleimide-based nanomedicine with high drug loading and FRET-indicated drug release. Chem. Commun. 2015, 51, 4807−4810. (23) Xu, Z.; Zhang, K.; Hou, C.; Wang, D.; Liu, X.; Guan, X.; Zhang, X.; Zhang, H. A novel nanoassembled doxorubicin prodrug with a high drug loading for anticancer drug delivery. J. Mater. Chem. B 2014, 2, 3433−3437. (24) Qiu, F.; Tu, C.; Wang, R.; Zhu, L.; Chen, Y.; Tong, G.; Zhu, B.; He, L.; Yan, D.; Zhu, X. Emission enhancement of conjugated polymers through self-assembly of unimolecular micelles to multimicelle aggregates. Chem. Commun. 2011, 47, 9678−9680. (25) Chen, T.; Wu, W.; Xiao, H.; Chen, Y.; Chen, M.; Li, J. Intelligent drug delivery system based on mesoporous silica nanoparticles coated with an ultra-pH-sensitive gatekeeper and poly(ethylene glycol). ACS Macro Lett. 2016, 5, 55−58. (26) Gong, H.; Cheng, L.; Xiang, J.; Xu, H.; Feng, L.; Shi, X.; Liu, Z. Near-infrared absorbing polymeric nanoparticles as a versatile drug carrier for cancer combination therapy. Adv. Funct. Mater. 2013, 23, 6059−6067. (27) Yamaoka, T.; Tabata, Y.; Ikada, Y. Distribution and tissue uptake of poly(ethylene glycol) with different molecular weights after intravenous administration to mice. J. Pharm. Sci. 1994, 83, 601−606. (28) Aarthi, T.; Shaama, M. S.; Madras, G. Degradation of water soluble polymers under combined ultrasonic and ultraviolet radiation. Ind. Eng. Chem. Res. 2007, 46, 6204−6210.

nanostructures for long-term use still requires further investigation because DNA is an important component of genetic material and vital for the functionality of proteins. There is still a long way to go to obtain ideal drug carriers and delivery systems. Biocompatibility is the fundamental demand for drug delivery materials. For the therapeutic index of drugs to be improved, nanocarriers must be delicately designed with favorable in vivo behaviors. Meanwhile, high drug loading means less frequent injections, but every coin has two sides. High drug loading could affect the stability and drug release from nanocarriers. Thus, the question remains as for how to obtain a relatively high drug loading while maintaining acceptable stability and release kinetics. Structure optimization may be the solution. In the future, with the development of technology, different drugs with customized carriers that can maximize the therapeutic index of the drug will be realized.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Wei Wu: 0000-0003-1845-2809 Xiqun Jiang: 0000-0003-0483-0282 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by National Key R&D Program of China (2017YFA0205400), the Natural Science Foundation of China (Nos. 51690153, 21474045, 21720102005, and 51422303), and the Program for Changjiang Scholars and Innovative Research Team in University.

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REFERENCES

(1) Wicki, A.; Witzigmann, D.; Balasubramanian, V.; Huwyler, J. Nanomedicine in cancer therapy: challenges, opportunities, and clinical applications. J. Controlled Release 2015, 200, 138−157. (2) Sun, T.; Zhang, Y. S.; Pang, B.; Hyun, D. C.; Yang, M.; Xia, Y. Engineered nanoparticles for drug delivery in cancer therapy. Angew. Chem., Int. Ed. 2014, 53, 12320−12364. (3) MacEwan, S. R.; Chilkoti, A. From Composition to Cure: A Systems Engineering Approach to Anticancer Drug Carriers. Angew. Chem., Int. Ed. 2017, 56, 6712−6733. (4) Jiang, L.; Li, L.; He, X.; Yi, Q.; He, B.; Cao, J.; Pan, W.; Gu, Z. Overcoming drug-resistant lung cancer by paclitaxel loaded dualfunctional liposomes with mitochondria targeting and pH-response. Biomaterials 2015, 52, 126−139. (5) Davis, M. E.; Shin, D. M. Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat. Rev. Drug Discovery 2008, 7, 771− 782. (6) Peer, D.; Karp, J. M.; Hong, S.; Farokhzad, O. C.; Margalit, R.; Langer, R. Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotechnol. 2007, 2, 751−760. (7) Luo, T.; Loira-Pastoriza, C.; Patil, H. P.; Ucakar, B.; Muccioli, G. G.; Bosquillon, C.; Vanbever, R. PEGylation of paclitaxel largely improves its safety and anti-tumor efficacy following pulmonary delivery in a mouse model of lung carcinoma. J. Controlled Release 2016, 239, 62−71. (8) Lu, J.; Chuan, X.; Zhang, H.; Dai, W.; Wang, X.; Wang, X.; Zhang, Q. Free paclitaxel loaded PEGylated-paclitaxel nanoparticles: Preparation and comparison with other paclitaxel systems in vitro and in vivo. Int. J. Pharm. 2014, 471, 525−535. (9) Kang, Y.; Ha, W.; Zhang, S.; Li, B. J. Studies on pH-sensitive high drug loading prodrug micelles for anticancer drug delivery. J. Controlled Release 2013, 172, e81−e82. J


Review

Biomacromolecules (29) Ishida, T.; Ichihara, M.; Wang, X.; Yamamoto, K.; Kimura, J.; Majima, E.; Kiwada, H. Injection of PEGylated liposomes in rats elicits PEG-specific IgM, which is responsible for rapid elimination of a second dose of PEGylated liposomes. J. Controlled Release 2006, 112, 15−25. (30) Chang, C. J.; Chen, C. H.; Chen, B. M.; Su, Y. C.; Chen, Y. T.; Hershfield, M. S.; Lee, M. T.; Cheng, T. L.; Chen, Y. T.; Roffler, S. R.; Wu, J. Y. A genome-wide association study identifies a novel susceptibility locus for the immunogenicity of polyethylene glycol. Nat. Commun. 2017, 8, 522. (31) Ishihara, T.; Takeda, M.; Sakamoto, H.; Kimoto, A.; Kobayashi, C.; Takasaki, N.; Yuki, K.; Tanaka, K.; Takenaga, M.; Igarashi, R.; Maeda, T.; Yamakawa, N; Okamoto, Y.; Otsuka, M.; Ishida, T.; Kiwada, H.; Mizushima, Y.; Mizushima, T. Accelerated blood clearance phenomenon upon repeated injection of PEG-modified PLA-nanoparticles. Pharm. Res. 2009, 26, 2270−2279. (32) Ma, H.; Shiraishi, K.; Minowa, T.; Kawano, K.; Yokoyama, M.; Hattori, Y.; Maitani, Y. Accelerated blood clearance was not induced for a gadolinium-containing PEG-poly(L-lysine)-based polymeric micelle in mice. Pharm. Res. 2010, 27, 296−302. (33) Ishida, T.; Maeda, R.; Ichihara, M.; Irimura, K.; Kiwada, H. Accelerated clearance of PEGylated liposomes in rats after repeated injections. J. Controlled Release 2003, 88, 35−42. (34) Wang, X. Y.; Ishida, T.; Ichihara, M.; Kiwada, H. Influence of the physicochemical properties of liposomes on the accelerated blood clearance phenomenon in rats. J. Controlled Release 2005, 104, 91− 102. (35) Laverman, P.; Carstens, M. G.; Boerman, O. C.; Dams, E. T. M.; Oyen, W. J.; van Rooijen, N.; Corstens, F. H. M.; Storm, G. Factors affecting the accelerated blood clearance of polyethylene glycolliposomes upon repeated injection. J. Pharmacol. Exp. Ther. 2001, 298, 607−612. (36) Shiraishi, K.; Hamano, M.; Ma, H.; Kawano, K.; Maitani, Y.; Aoshi, T.; Ishii, K. J.; Yokoyama, M. Hydrophobic blocks of PEGconjugates play a significant role in the accelerated blood clearance (ABC) phenomenon. J. Controlled Release 2013, 165, 183−190. (37) Kaneda, Y.; Tsutsumi, Y.; Yoshioka, Y.; Kamada, H.; Yamamoto, Y.; Kodaira, H.; Tsunoda, S.; Okamoto, T.; Mukai, Y.; Shibata, H.; Nakagawa, S.; Mayumi, T. The use of PVP as a polymeric carrier to improve the plasma half-life of drugs. Biomaterials 2004, 25, 3259− 3266. (38) Bailly, N.; Thomas, M.; Klumperman, B. Poly(N-vinylpyrrolidone)-block-poly(vinyl acetate) as a drug delivery vehicle for hydrophobic drugs. Biomacromolecules 2012, 13, 4109−4117. (39) Handké, N.; Lahaye, V.; Bertin, D.; Delair, T.; Verrier, B.; Gigmes, D.; Trimaille, T. Elaboration of glycopolymer-functionalized micelles from an N-vinylpyrrolidone/lactide-based reactive copolymer platform. Macromol. Biosci. 2013, 13, 1213−1220. (40) Palao-Suay, R.; Aguilar, M. R.; Parra-Ruiz, F. J.; FernándezGutiérrez, M.; Parra, J.; Sánchez-Rodríguez, C.; Fernández, R.; Rodrigáñez, L.; Román, J. S. Anticancer and antiangiogenic activity of surfactant-free nanoparticles based on self-assembled polymeric derivatives of vitamin E: structure−activity relationship. Biomacromolecules 2015, 16, 1566−1581. (41) Kozlovskaya, V.; Liu, F.; Xue, B.; Ahmad, F.; Alford, A.; Saeed, M.; Kharlampieva, E. Polyphenolic polymersomes of temperaturesensitive poly(N-vinylcaprolactam)-block-Poly(N-vinylpyrrolidone) for anticancer therapy. Biomacromolecules 2017, 18, 2552−2563. (42) Ravin, H. A.; Seligman, A. M.; Fine, J. Polyvinyl pyrrolidone as a plasma expander. N. Engl. J. Med. 1952, 247, 921−929. (43) Pound, G.; McKenzie, J. M.; Lange, R. F.; Klumperman, B. Polymer-protein conjugates from [small omega]-aldehyde endfunctional poly(N-vinylpyrrolidone) synthesised via xanthate-mediated living radical polymerisation. Chem. Commun. 2008, 3193−3195. (44) Kang, H. U.; Yu, Y. C.; Shin, S. J.; Kim, J.; Youk, J. H. One-pot synthesis of poly(N-vinylpyrrolidone)-b-poly(ε-caprolactone) block copolymers using a dual initiator for RAFT polymerization and ROP. Macromolecules 2013, 46, 1291−1295.

(45) Aroua, S.; Tiu, E. G. V.; Ayer, M.; Ishikawa, T.; Yamakoshi, Y. RAFT synthesis of poly(vinylpyrrolidone) amine and preparation of a water-soluble C60-PVP conjugate. Polym. Chem. 2015, 6, 2616−2619. (46) Zheng, G.; Pan, C. Reversible addition−fragmentation transfer polymerization in nanosized micelles formed in situ. Macromolecules 2006, 39, 95−102. (47) Torchilin, V. P.; Shtilman, M. I.; Trubetskoy, V. S.; Whiteman, K.; Milstein, A. M. Amphiphilic vinyl polymers effectively prolong liposome circulation time in vivo. Biochim. Biophys. Acta, Biomembr. 1994, 1195, 181−184. (48) Kamada, H.; Tsutsumi, Y.; Yamamoto, Y.; Kihira, T.; Kaneda, Y.; Mu, Y.; Kodaira, H.; Tsunoda, S.; Nakagawa, S.; Mayumi, T. Antitumor activity of tumor necrosis factor-α conjugated with polyvinylpyrrolidone on solid tumors in mice. Cancer Res. 2000, 60, 6416−6420. (49) Ishihara, T.; Maeda, T.; Sakamoto, H.; Takasaki, N.; Shigyo, M.; Ishida, T.; Kiwada, H.; Mizushima, Y.; Mizushima, T. Evasion of the accelerated blood clearance phenomenon by coating of nanoparticles with various hydrophilic polymers. Biomacromolecules 2010, 11, 2700− 2706. (50) Zhu, Z.; Xie, C.; Liu, Q.; Zhen, X.; Zheng, X.; Wu, W.; Li, R.; Ding, Y.; Jiang, X.; Liu, B. The effect of hydrophilic chain length and iRGD on drug delivery from poly(epsilon-caprolactone)-poly(Nvinylpyrrolidone) nanoparticles. Biomaterials 2011, 32, 9525−9535. (51) Zhu, Z.; Li, Y.; Li, X.; Li, R.; Jia, Z.; Liu, B.; Guo, W.; Jiang, X. Paclitaxel-loaded poly(N-vinylpyrrolidone)-b-poly(ε-caprolactone) nanoparticles: Preparation and antitumor activity in vivo. J. Controlled Release 2010, 142, 438−446. (52) Xie, C.; Zhang, P.; Zhang, Z.; Yang, C.; Zhang, J.; Wu, W.; Jiang, X. Drug-loaded pseudo-block copolymer micelles with a multi-armed star polymer as the micellar exterior. Nanoscale 2015, 7, 12572−12580. (53) Yao, X.; Xie, C.; Chen, W.; Yang, C.; Wu, W.; Jiang, X. Platinum-incorporating poly(N-vinylpyrrolidone)-poly(aspartic acid) pseudoblock copolymer nanoparticles for drug delivery. Biomacromolecules 2015, 16, 2059−2071. (54) Yebeutchou, R. M.; Tancini, F.; Demitri, N.; Geremia, S.; Mendichi, R.; Dalcanale, E. Host−guest driven self-assembly of linear and star supramolecular polymers. Angew. Chem., Int. Ed. 2008, 47, 4504−4508. (55) Dreja, M.; Kim, I. T.; Yin, Y.; Xia, Y. Multilayered supermolecular structures self-assembled from polyelectrolytes and cyclodextrin host-guest complexes. J. Mater. Chem. 2000, 10, 603−605. (56) Harada, A.; Takashima, Y.; Yamaguchi, H. Cyclodextrin-based supramolecular polymers. Chem. Soc. Rev. 2009, 38, 875−882. (57) Ge, Z.; Hu, J.; Huang, F.; Liu, S. Responsive supramolecular gels constructed by crown ether based molecular recognition. Angew. Chem., Int. Ed. 2009, 48, 1798−1802. (58) Wei, H.; Yu, C. Cyclodextrin-functionalized polymers as drug carriers for cancer therapy. Biomater. Sci. 2015, 3, 1050−1060. (59) Le Garrec, D.; Gori, S.; Luo, L.; Lessard, D.; Smith, D. C.; Yessine, M. A.; Ranger, J. C.; Leroux, J. C. Poly(N-vinylpyrrolidone)block-poly(d,l-lactide) as a new polymeric solubilizer for hydrophobic anticancer drugs: in vitro and in vivo evaluation. J. Controlled Release 2004, 99, 83−101. (60) Le Garrec, D.; Gori, S.; Karkan, D.; Luo, L.; Lessard, D. G.; Smith, D.; Ranger, M.; Yessine, M. A.; Leroux, J. C. Preparation, characterization, cytotoxicity and biodistribution of docetaxel-loaded polymeric micelle formulations. J. Drug Delivery Sci. Technol. 2005, 15, 115−120. (61) Gaertner, F. C.; Luxenhofer, R.; Blechert, B.; Jordan, R.; Essler, M. Synthesis, biodistribution and excretion of radiolabeled poly(2alkyl-2-oxazoline)s. J. Controlled Release 2007, 119, 291−300. (62) Lübtow, M. M.; Hahn, L.; Haider, M. S.; Luxenhofer, R. Drug Specificity, Synergy and antagonism in ultrahigh capacity poly(2oxazoline)/poly(2-oxazine) based formulations. J. Am. Chem. Soc. 2017, 139, 10980−10983. (63) Platen, M.; Mathieu, E.; Lück, S.; Schubel, R.; Jordan, R.; Pautot, S. Poly(2-oxazoline)-based microgel particles for neuronal cell culture. Biomacromolecules 2015, 16, 1516−1524. K


Review

Biomacromolecules

Thermosensitive biodegradable and biocompatible bydrogel. Biomacromolecules 2012, 13, 40−48. (82) Chen, W.; Su, L.; Zhang, P.; Li, C.; Zhang, D.; Wu, W.; Jiang, X. Thermo and pH dual-responsive drug-linked pseudo-polypeptide micelles with a comb-shaped polymer as a micellar exterior. Polym. Chem. 2017, 8, 6886−6894. (83) Jeong, J. H.; Song, S. H.; Lim, D. W.; Lee, H.; Park, T. G. DNA transfection using linear poly(ethylenimine) prepared by controlled acid hydrolysis of poly(2-ethyl-2-oxazoline). J. Controlled Release 2001, 73, 391−399. (84) Wang, C. H.; Fan, K. R.; Hsiue, G. H. Enzymatic degradation of PLLA-PEOz-PLLA triblock copolymers. Biomaterials 2005, 26, 2803− 2811. (85) Elzoghby, A. O.; Samy, W. M.; Elgindy, N. A. Albumin-based nanoparticles as potential controlled release drug delivery systems. J. Controlled Release 2012, 157, 168−182. (86) Wang, J.; Wu, W.; Zhang, Y.; Wang, X.; Qian, H.; Liu, B.; Jiang, X. The combined effects of size and surface chemistry on the accumulation of boronic acid-rich protein nanoparticles in tumors. Biomaterials 2014, 35, 866−878. (87) Song, X.; Liang, C.; Gong, H.; Chen, Q.; Wang, C.; Liu, Z. Photosensitizer-conjugated albumin−polypyrrole nanoparticles for imaging-guided in vivo photodynamic/photothermal therapy. Small 2015, 11, 3932−3941. (88) Merlot, A. M.; Kalinowski, D. S.; Richardson, D. R. Unraveling the mysteries of serum albuminmore than just a serum protein. Front. Physiol. 2014, 5, 299. (89) Desai, N. Nanoparticle albumin bound (nab) technology: targeting tumors through the endothelial gp60 receptor and SPARC. Nanomedicine 2007, 3, 339. (90) Cortes, J.; Saura, C. Nanoparticle albumin-bound (nab)paclitaxel: improving efficacy and tolerability by targeted drug delivery in metastatic breast cancer. Eur. J. Cancer Suppl. 2010, 8, 1−10. (91) Langer, K.; Balthasar, S.; Vogel, V.; Dinauer, N.; Von Briesen, H.; Schubert, D. Optimization of the preparation process for human serum albumin (HSA) nanoparticles. Int. J. Pharm. 2003, 257, 169− 180. (92) Qi, J.; Yao, P.; He, F.; Yu, C.; Huang, C. Nanoparticles with dextran/chitosan shell and BSA/chitosan coreDoxorubicin loading and delivery. Int. J. Pharm. 2010, 393, 177−185. (93) Yu, S.; Yao, P.; Jiang, M.; Zhang, G. Nanogels prepared by selfassembly of oppositely charged globular proteins. Biopolymers 2006, 83, 148−158. (94) Yang, L.; Cui, F.; Cun, D.; Tao, A.; Shi, K.; Lin, W. Preparation, characterization and biodistribution of the lactone form of 10hydroxycamptothecin (HCPT)-loaded bovine serum albumin (BSA) nanoparticles. Int. J. Pharm. 2007, 340, 163−172. (95) Desai, N.; Trieu, V.; Yao, Z.; Louie, L.; Ci, S.; Yang, A.; Tao, C.; De, T.; Beals, B.; Dykes, D.; Noker, P.; Yao, R.; Labao, E.; Hawkins, M.; Shiong, P. S. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin. Cancer Res. 2006, 12, 1317−1324. (96) Gong, G.; Zhi, F.; Wang, K.; Tang, X.; Yuan, A.; Zhao, L.; Ding, D.; Hu, Y. Fabrication of a nanocarrier system through self-assembly of plasma protein and its tumor targeting. Nanotechnology 2011, 22, 295603. (97) Gong, G.; Xu, Y.; Zhou, Y.; Meng, Z.; Ren, G.; Zhao, Y.; Zhang, X.; Wu, J.; Hu, Y. Molecular switch for the assembly of lipophilic drug incorporated plasma protein nanoparticles and in vivo image. Biomacromolecules 2012, 13, 23−28. (98) Ding, D.; Tang, X.; Cao, X.; Wu, J.; Yuan, A.; Qiao, Q.; Pan, J.; Hu, Y. Novel self-assembly endows human serum albumin nanoparticles with an enhanced antitumor efficacy. AAPS PharmSciTech 2014, 15, 213−222. (99) Wu, J.; Song, C.; Jiang, C.; Shen, X.; Qiao, Q.; Hu, Y. Nucleolin targeting AS1411 modified protein nanoparticle for antitumor drugs delivery. Mol. Pharmaceutics 2013, 10, 3555−3563.

(64) Legros, C.; Wirotius, A. L.; De Pauw-Gillet, M. C.; Tam, K. C.; Taton, D.; Lecommandoux, S. Poly(2-oxazoline)-based nanogels as biocompatible pseudopolypeptide nanoparticles. Biomacromolecules 2015, 16, 183−191. (65) Wiesbrock, F.; Hoogenboom, R.; Leenen, M. A.; Meier, M. A.; Schubert, U. S. Investigation of the living cationicring-opening polymerization of 2-methyl-, 2-ethyl-, 2-nonyl-, and 2-phenyl-2oxazoline in a single-mode microwave reactor. Macromolecules 2005, 38, 5025−5034. (66) Kempe, K.; Ng, S. L.; Noi, K. F.; Müllner, M.; Gunawan, S. T.; Caruso, F. Clickable poly(2-oxazoline) architectures for the fabrication of low-fouling polymer capsules. ACS Macro Lett. 2013, 2, 1069−1072. (67) Adams, N.; Schubert, U. S. Poly(2-oxazolines) in biological and biomedical application contexts. Adv. Drug Delivery Rev. 2007, 59, 1504−1520. (68) Ulbricht, J.; Jordan, R.; Luxenhofer, R. On the biodegradability of polyethylene glycol, polypeptoids and poly(2-oxazoline)s. Biomaterials 2014, 35, 4848−4861. (69) Konradi, R.; Pidhatika, B.; Mühlebach, A.; Textor, M. Poly-2methyl-2-oxazoline: a peptide-like polymer for protein-repellent surfaces. Langmuir 2008, 24, 613−616. (70) Zalipsky, S.; Hansen, C. B.; Oaks, J. M.; Allen, T. M. Evaluation of blood clearance rates and biodistribution of poly(2-oxazoline)grafted liposomes. J. Pharm. Sci. 1996, 85, 133−137. (71) Viegas, T. X.; Bentley, M. D.; Harris, J. M.; Fang, Z.; Yoon, K.; Dizman, B.; Weimer, R.; Mero, A.; Pasut, G.; Veronese, F. M. Polyoxazoline: chemistry, properties, and applications in drug delivery. Bioconjugate Chem. 2011, 22, 976−986. (72) Zhang, P.; Qian, X.; Zhang, Z.; Li, C.; Xie, C.; Wu, W.; Jiang, X. Supramolecular amphiphilic polymer-based micelles with seven-armed polyoxazoline coating for drug delivery. ACS Appl. Mater. Interfaces 2017, 9, 5768−5777. (73) Zhang, P.; Yuan, K.; Li, C.; Zhang, X.; Wu, W.; Jiang, X. Cisplatin - rich polyoxazoline−poly (aspartic acid) supramolecular nanoparticles. Macromol. Biosci. 2017, 17, 1700206. (74) Luxenhofer, R.; Schulz, A.; Roques, C.; Li, S.; Bronich, T. K.; Batrakova, E. V.; Jordan, R.; Kabanov, A. V. Doubly amphiphilic poly(2-oxazoline)s as high-capacity delivery systems for hydrophobic drugs. Biomaterials 2010, 31, 4972−4979. (75) He, Z.; Schulz, A.; Wan, X.; Seitz, J.; Bludau, H.; Alakhova, D. Y.; Darr, D. B.; Perou, C. M.; Jordan, R.; Ojima, I.; Kabanov, A. V.; Luxenhofer, R. Poly(2-oxazoline) based micelles with high capacity for 3rd generation taxoids: Preparation, in vitro and in vivo evaluation. J. Controlled Release 2015, 208, 67−75. (76) He, Z.; Wan, X.; Schulz, A.; Bludau, H.; Dobrovolskaia, M. A.; Stern, S. T.; Montgomery, S. A.; Yuan, H.; Li, Z.; Alakhova, D.; Sokolsky, M.; Darr, D. B.; Perou, C. M.; Jordan, R.; Luxenhofer, R.; Kabanov, A. V. A high capacity polymeric micelle of paclitaxel: Implication of high dose drug therapy to safety and in vivo anti-cancer activity. Biomaterials 2016, 101, 296−309. (77) Han, Y.; He, Z.; Schulz, A.; Bronich, T. K.; Jordan, R.; Luxenhofer, R.; Kabanov, A. V. Synergistic combinations of multiple chemotherapeutic agents in high capacity poly(2-oxazoline) micelles. Mol. Pharmaceutics 2012, 9, 2302−2313. (78) Schulz, A.; Jaksch, S.; Schubel, R.; Wegener, E.; Di, Z.; Han, Y.; Meister, A.; Kressler, J.; Kabanov, A. V.; Luxenhofer, R.; Papadakis, C. M.; Jordan, R. Drug-Induced morphology switch in drug delivery systems based on poly(2-oxazoline)s. ACS Nano 2014, 8, 2686−2696. (79) Hoogenboom, R.; Thijs, H. M.; Jochems, M. J.; van Lankvelt, B. M.; Fijten, M. W.; Schubert, U. S. Tuning the LCST of poly(2oxazoline)s by varying composition and molecular weight: alternatives to poly(N-isopropylacrylamide)? Chem. Commun. 2008, 5758−5760. (80) Glassner, M.; Lava, K.; de la Rosa, V. R.; Hoogenboom, R. Tuning the LCST of poly(2-cyclopropyl-2-oxazoline) via gradient copolymerization with 2-ethyl-2-oxazoline. J. Polym. Sci., Part A: Polym. Chem. 2014, 52, 3118−3122. (81) Wang, C. H.; Hwang, Y. S.; Chiang, P. R.; Shen, C. R.; Hong, W. H.; Hsiue, G. H. Extended Release of Bevacizumab by L


Review

Biomacromolecules

(119) Zhen, X.; Wang, X.; Xie, C.; Wu, W.; Jiang, X. Cellular uptake, antitumor response and tumor penetration of cisplatin-loaded milk protein nanoparticles. Biomaterials 2013, 34, 1372−1382. (120) Elzoghby, A. O.; Samy, W. M.; Elgindy, N. A. Novel spraydried genipin-crosslinked casein nanoparticles for prolonged release of alfuzosin hydrochloride. Pharm. Res. 2013, 30, 512−522. (121) Song, F.; Zhang, L. M.; Yang, C.; Yan, L. Genipin-crosslinked casein hydrogels for controlled drug delivery. Int. J. Pharm. 2009, 373, 41−47. (122) Bini, E.; Foo, C. W. P.; Huang, J.; Karageorgiou, V.; Kitchel, B.; Kaplan, D. L. RGD-functionalized bioengineered spider dragline silk biomaterial. Biomacromolecules 2006, 7, 3139−3145. (123) Rombouts, W. H.; de Kort, D. W.; Pham, T. T.; van Mierlo, C. P.; Werten, M. W.; de Wolf, F. A.; van der Gucht, J. Reversible temperature-switching of hydrogel stiffness of coassembled, silkcollagen-like hydrogels. Biomacromolecules 2015, 16, 2506−2513. (124) Olsen, D.; Yang, C.; Bodo, M.; Chang, R.; Leigh, S.; Baez, J.; Polarek, J. Recombinant collagen and gelatin for drug delivery. Adv. Drug Delivery Rev. 2003, 55, 1547−1567. (125) Gupta, S. K.; Shukla, P. Microbial platform technology for recombinant antibody fragment production: A review. Crit. Rev. Microbiol. 2017, 43, 31−42. (126) Bracalello, A.; Santopietro, V.; Vassalli, M.; Marletta, G.; Del Gaudio, R.; Bochicchio, B.; Pepe, A. Design and production of a chimeric resilin-, elastin-, and collagen-like engineered polypeptide. Biomacromolecules 2011, 12, 2957−2965. (127) McDaniel, J. R.; Callahan, D. J.; Chilkoti, A. Drug delivery to solid tumors by elastin-like polypeptides. Adv. Drug Delivery Rev. 2010, 62, 1456−1467. (128) Liu, W.; Dreher, M. R.; Furgeson, D. Y.; Peixoto, K. V.; Yuan, H.; Zalutsky, M. R.; Chilkoti, A. Tumor accumulation, degradation and pharmacokinetics of elastin-like polypeptides in nude mice. J. Controlled Release 2006, 116, 170−178. (129) Betre, H.; Setton, L. A.; Meyer, D. E.; Chilkoti, A. Characterization of a genetically engineered elastin-like polypeptide for cartilaginous tissue repair. Biomacromolecules 2002, 3, 910−916. (130) Nuhn, H.; Klok, H. A. Secondary structure formation and LCST behavior of short elastin-like peptides. Biomacromolecules 2008, 9, 2755−2763. (131) Meyer, D. E.; Chilkoti, A. Quantification of the effects of chain length and concentration on the thermal behavior of elastin-like polypeptides. Biomacromolecules 2004, 5, 846−851. (132) MacKay, J. A.; Callahan, D. J.; FitzGerald, K. N.; Chilkoti, A. Quantitative model of the phase behavior of recombinant pHresponsive elastin-like polypeptides. Biomacromolecules 2010, 11, 2873−2879. (133) Chilkoti, A.; Dreher, M. R.; Meyer, D. E.; Raucher, D. Targeted drug delivery by thermally responsive polymers. Adv. Drug Delivery Rev. 2002, 54, 613−630. (134) Dreher, M. R.; Simnick, A. J.; Fischer, K.; Smith, R. J.; Patel, A.; Schmidt, M.; Chilkoti, A. Temperature triggered self-assembly of polypeptides into multivalent spherical micelles. J. Am. Chem. Soc. 2008, 130, 687−694. (135) Simnick, A. J.; Valencia, C. A.; Liu, R.; Chilkoti, A. Morphing low-affinity ligands into high-avidity nanoparticles by thermally triggered self-assembly of a genetically encoded polymer. ACS Nano 2010, 4, 2217−2227. (136) MacKay, J. A.; Chen, M.; McDaniel, J. R.; Liu, W.; Simnick, A. J.; Chilkoti, A. Self-assembling chimeric polypeptide−doxorubicin conjugate nanoparticles that abolish tumours after a single injection. Nat. Mater. 2009, 8, 993. (137) Bhattacharyya, J.; Bellucci, J. J.; Weitzhandler, I.; McDaniel, J. R.; Spasojevic, I.; Li, X.; Chilkoti, A. A paclitaxel-loaded recombinant polypeptide nanoparticle outperforms Abraxane in multiple murine cancer models. Nat. Commun. 2015, 6, 7939. (138) Chen, W.; Ji, S.; Qian, X.; Zhang, Y.; Li, C.; Wu, W.; Wang, F.; Jiang, X. Phenylboronic acid-incorporated elastin-like polypeptide nanoparticle drug delivery systems. Polym. Chem. 2017, 8, 2105−2114.

(100) Yuan, A.; Wu, J.; Song, C.; Tang, X.; Qiao, Q.; Zhao, L.; Gong, G.; Hu, Y. A Novel self-assembly albumin nanocarrier for reducing doxorubicin-mediated cardiotoxicity. J. Pharm. Sci. 2013, 102, 1626− 1635. (101) Xu, R.; Fisher, M.; Juliano, R. L. Targeted albumin-based nanoparticles for delivery of amphipathic drugs. Bioconjugate Chem. 2011, 22, 870−878. (102) Kuan, S. L.; Stöckle, B.; Reichenwallner, J.; Ng, D. Y.; Wu, Y.; Doroshenko, M.; Koynov, K.; Hinderberger, D.; Müllen, K.; Weil, T. Dendronized albumin core−shell transporters with high drug loading capacity. Biomacromolecules 2013, 14, 367−376. (103) Mansour, A. M.; Drevs, J.; Esser, N.; Hamada, F. M.; Badary, O. A.; Unger, C.; Fichtner, I.; Kratz, F. Development of proteinbinding bifunctional linkers for a new generation of dual-acting prodrugs. Cancer Res. 2003, 63, 4062−4066. (104) Ajaj, K. A.; Biniossek, M. L.; Kratz, F. Development of ProteinBinding Bifunctional Linkers for a New Generation of Dual-Acting Prodrugs. Bioconjugate Chem. 2009, 20, 390−396. (105) Hochdörffer, K.; Abu Ajaj, K.; Schäfer-Obodozie, C.; Kratz, F. Development of novel bisphosphonate prodrugs of doxorubicin for targeting bone metastases that are cleaved pH dependently or by cathepsin B: synthesis, cleavage properties, and binding properties to hydroxyapatite as well as bone matrix. J. Med. Chem. 2012, 55, 7502− 7515. (106) Kratz, F.; Drevs, J.; Bing, G.; Stockmar, C.; Scheuermann, K.; Lazar, P.; Unger, C. Development and in vitro efficacy of novel MMP2 and MMP9 specific doxorubicin albumin conjugates. Bioorg. Med. Chem. Lett. 2001, 11, 2001−2006. (107) Chung, D. E.; Kratz, F. Development of a novel albuminbinding prodrug that is cleaved by urokinase-type-plasminogen activator (uPA). Bioorg. Med. Chem. Lett. 2006, 16, 5157−5163. (108) Kratz, F.; Mansour, A.; Soltau, J.; Warnecke, A.; Fichtner, I.; Unger, C.; Drevs, J. Development of albumin-binding doxorubicin prodrugs that are cleaved by prostate-specific antigen. Arch. Pharm. 2005, 338, 462−472. (109) Elzoghby, A. O.; Abo El-Fotoh, W. S.; Elgindy, N. A. Caseinbased formulations as promising controlled release drug delivery systems. J. Controlled Release 2011, 153, 206−216. (110) Latha, M. S.; Lal, A. V.; Kumary, T. V.; Sreekumar, R.; Jayakrishnan, A. Progesterone release from glutaraldehyde cross-linked casein microspheres: in vitro studies and in vivo response in rabbits. Contraception 2000, 61, 329−334. (111) Latha, M. S.; Rathinam, K.; Mohanan, P. V.; Jayakrishnan, A. Bioavailability of theophylline from glutaraldehyde cross-linked casein microspheres in rabbits following oral administration. J. Controlled Release 1995, 34, 1−7. (112) Huang, J.; Shu, Q.; Wang, L.; Wu, H.; Wang, A. Y.; Mao, H. Layer-by-layer assembled milk protein coated magnetic nanoparticle enabled oral drug delivery with high stability in stomach and enzymeresponsive release in small intestine. Biomaterials 2015, 39, 105−113. (113) Kamiya, N.; Shiotari, Y.; Tokunaga, M.; Matsunaga, H.; Yamanouchi, H.; Nakano, K.; Goto, M. Stimuli-responsive nanoparticles composed of naturally occurring amphiphilic proteins. Chem. Commun. 2009, 35, 5287−5289. (114) Wang, W.; Lin, J. H.; Tsai, C. C.; Chuang, H. C.; Ho, C. Y.; Yao, C. H.; Chen, Y. S. Biodegradable glutaraldehyde-crosslinked casein conduit promotes regeneration after peripheral nerve injury in Adult Rats. Macromol. Biosci. 2011, 11, 914−926. (115) Romoscanu, A. I.; Mezzenga, R. Cross linking and rheological characterization of adsorbed protein layers at the oil−water interface. Langmuir 2005, 21, 9689−9697. (116) Huppertz, T.; Smiddy, M. A.; de Kruif, C. G. Biocompatible micro-gel particles from cross-linked casein micelles. Biomacromolecules 2007, 8, 1300−1305. (117) O’Connell, J. E.; de Kruif, C. G. β-Casein micelles; crosslinking with transglutaminase. Colloids Surf., A 2003, 216, 75−81. (118) Liu, C.; Yao, W.; Zhang, L.; Qian, H.; Wu, W.; Jiang, X. Cellpenetrating hollow spheres based on milk protein. Chem. Commun. 2010, 46, 7566−7568. M


Review

Biomacromolecules (139) Deshayes, S.; Cabral, H.; Ishii, T.; Miura, Y.; Kobayashi, S.; Yamashita, T.; Matsumoto, A.; Miyahara, Y.; Nishiyama, N.; Kataoka, K. Phenylboronic acid-installed polymeric micelles for targeting sialylated epitopes in solid tumors. J. Am. Chem. Soc. 2013, 135, 15501−15507. (140) Wang, J.; Zhang, Z.; Wang, X.; Wu, W.; Jiang, X. Size-and pathotropism-driven targeting and washout-resistant effects of boronic acid-rich protein nanoparticles for liver cancer regression. J. Controlled Release 2013, 168, 1−9. (141) Florczak, A.; Mackiewicz, A.; Dams-Kozlowska, H. Functionalized spider silk spheres as Drug carriers for targeted cancer therapy. Biomacromolecules 2014, 15, 2971−2981. (142) Elzoghby, A. O.; Samy, W. M.; Elgindy, N. A. Protein-based nanocarriers as promising drug and gene delivery systems. J. Controlled Release 2012, 161, 38−49. (143) Tian, R.; Wang, H.; Niu, R.; Ding, D. Drug delivery with nanospherical supramolecular cell penetrating peptide−taxol conjugates containing a high drug loading. J. Colloid Interface Sci. 2015, 453, 15−20. (144) Wu, D.; Wang, L.; Li, W.; Xu, X.; Jiang, W. DNA nanostructure-based drug delivery nanosystems in cancer therapy. Int. J. Pharm. 2017, 533, 169−178. (145) de Vries, J. W.; Zhang, F.; Herrmann, A. Drug delivery systems based on nucleic acid nanostructures. J. Controlled Release 2013, 172, 467−483. (146) Hu, Q.; Li, H.; Wang, L.; Gu, H.; Fan, C. DNA Nanotechnology-Enabled Drug Delivery Systems. Chem. Rev. 2018, DOI: 10.1021/acs.chemrev.7b00663. (147) Liu, X.; Wu, L.; Wang, L.; Jiang, W. A dual-targeting DNA tetrahedron nanocarrier for breast cancer cell imaging and drug delivery. Talanta 2018, 179, 356−363. (148) Liu, J.; Wei, T.; Zhao, J.; Huang, Y.; Deng, H.; Kumar, A.; Wang, C.; Liang, Z.; Ma, X.; Liang, X. J. Multifunctional aptamer-based nanoparticles for targeted drug delivery to circumvent cancer resistance. Biomaterials 2016, 91, 44−56. (149) Kim, K. R.; Kim, D. R.; Lee, T.; Yhee, J. Y.; Kim, B. S.; Kwon, I. C.; Ahn, D. R. Drug delivery by a self-assembled DNA tetrahedron for overcoming drug resistance in breast cancer cells. Chem. Commun. 2013, 49, 2010−2012. (150) Mou, Q.; Ma, Y.; Pan, G.; Xue, B.; Yan, D.; Zhang, C.; Zhu, X. DNA Trojan horses: self - assembled floxuridine - containing DNA polyhedra for cancer therapy. Angew. Chem. 2017, 129, 12702−12706. (151) Chang, M.; Yang, C. S.; Huang, D. M. Aptamer-conjugated DNA icosahedral nanoparticles as a carrier of doxorubicin for cancer therapy. ACS Nano 2011, 5, 6156−6163. (152) Jiang, Q.; Song, C.; Nangreave, J.; Liu, X.; Lin, L.; Qiu, D.; Wang, Z.; Zou, G.; Liang, X.; Yan, H.; Ding, B. DNA origami as a carrier for circumvention of drug resistance. J. Am. Chem. Soc. 2012, 134, 13396−13403. (153) Sun, W.; Jiang, T.; Lu, Y.; Reiff, M.; Mo, R.; Gu, Z. Cocoonlike self-degradable DNA nanoclew for anticancer drug delivery. J. Am. Chem. Soc. 2014, 136, 14722−14725. (154) Zhu, G.; Zheng, J.; Song, E.; Donovan, M.; Zhang, K.; Liu, C.; Tan, W. Self-assembled, aptamer-tethered DNA nanotrains for targeted transport of molecular drugs in cancer theranostics. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 7998−8003. (155) Zhu, G.; Hu, R.; Zhao, Z.; Chen, Z.; Zhang, X.; Tan, W. Noncanonical self-assembly of multifunctional DNA nanoflowers for biomedical applications. J. Am. Chem. Soc. 2013, 135, 16438−16445. (156) Yan, J.; Hu, C.; Wang, P.; Zhao, B.; Ouyang, X.; Zhou, J.; Liu, R.; He, D.; Fan, C.; Song, S. Growth and Origami Folding of DNA on Nanoparticles for High-Efficiency Molecular Transport in Cellular Imaging and Drug Delivery. Angew. Chem., Int. Ed. 2015, 54, 2431− 2435. (157) Kim, D. H.; Smith, J. T.; Chilkoti, A.; Reichert, W. M. The effect of covalently immobilized rhIL-1ra-ELP fusion protein on the inflammatory profile of LPS-stimulated human monocytes. Biomaterials 2007, 28, 3369−3377.

(158) Massodi, I.; Bidwell, G. L.; Raucher, D. Evaluation of cell penetrating peptides fused to elastin-like polypeptide for drug delivery. J. Controlled Release 2005, 108, 396−408. (159) Christensen, T.; Amiram, M.; Dagher, S.; Trabbic-Carlson, K.; Shamji, M. F.; Setton, L. A.; Chilkoti, A. Fusion order controls expression level and activity of elastin - like polypeptide fusion proteins. Protein Sci. 2009, 18, 1377−1387. (160) Qi, Y.; Simakova, A.; Ganson, N. J.; Li, X.; Luginbuhl, K. M.; Ozer, I.; Chilkoti, A. A brush-polymer/exendin-4 conjugate reduces blood glucose levels for up to five days and eliminates poly (ethylene glycol) antigenicity. Nature biomedical engineering 2018, 1, 0002. (161) Li, S.; Jiang, Q.; Liu, S.; Zhang, Y.; Tian, Y.; Song, C.; Wang, J.; Zou, Y.; Anderson, G.; Han, J.; Chang, Y.; Liu, Y.; Zhang, C.; Chen, L.; Zhou, G.; Nie, G.; Yan, H.; Ding, B.; Zhao, Y. A DNA nanorobot functions as a cancer therapeutic in response to a molecular trigger in vivo. Nat. Biotechnol. 2018, 36, 258−264. (162) Cao, H.; Zou, L.; He, B.; Zeng, L.; Huang, Y.; Yu, H.; Li, Y. Albumin biomimetic nanocorona improves tumor targeting and penetration for synergistic therapy of metastatic breast cancer. Adv. Funct. Mater. 2017, 27, 1605679. (163) Syga, M. I.; Nicolì, E.; Kohler, E.; Shastri, V. P. Albumin incorporation in polyethylenimine−DNA polyplexes influences transfection efficiency. Biomacromolecules 2016, 17, 200−207. (164) Ding, F.; Mou, Q.; Ma, Y.; Pan, G.; Guo, Y.; Tong, G.; Zhang, C. A crosslinked nucleic acid nanogel foreffective siRNA delivery and antitumor therapy. Angew. Chem. Int. Ed. 2018, 130, 3118−3122.

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