Qin Guo, Chen Jiangb. Delivery strategies for macromolecular drugs in cancer therapy[J]. Acta Pharmaceutica Sinica B, 2020, 10(6): 979-986

Delivery strategies for macromolecular drugs in cancer therapy
Qin Guo, Chen Jiangb
Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China
With the development of biotherapy, biomacromolecular drugs have gained tremendous attention recently, especially in drug development field due to the sophisticated functions in vivo. Over the past few years, a motley variety of drug delivery strategies have been developed for biomacromolecular drugs to overcome the difficulties in the druggability, e.g., the instability and easily restricted by physiologic barriers. The application of novel delivery systems to deliver biomacromolecular drugs can usually prolong the half-life, increase the bioavailability, or improve patient compliance, which greatly improves the efficacy and potentiality for clinical use of biomacromolecular drugs. In this review, recent studies regarding the drug delivery strategies for macromolecular drugs in cancer therapy are summarized, mainly drawing on the development over the last five years.
Key words:    Macromolecular drugs    Delivery strategies    Cancer therapy    Membrane-camouflage systems    Exosomes   
Received: 2019-08-06     Revised: 2019-09-23
DOI: 10.1016/j.apsb.2020.01.009
Funds: The work was supported by the grants from National Science Fund for Distinguished Young Scholars (81425023, China) and Program of Shanghai Academic Research Leader (18XD1400500, China).
Corresponding author: Chen Jiang
Author description:
PDF(KB) Free
Qin Guo
Chen Jiangb

1. Pagels RF, Prud'Homme RK. Polymeric nanoparticles and microparticles for the delivery of peptides, biologics, and soluble therapeutics. J Contr Release 2015;219:519-35.
2. Tyagi P, Santos JL. Macromolecule nanotherapeutics:approaches and challenges. Drug Discov Today 2018;23:1053-61.
3. Davis ME, Zuckerman JE, Choi CH, Seligson D, Tolcher A, Alabi CA, et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 2010;464:1067-70.
4. An S, Jiang X, Shi J, He X, Li J, Guo Y, et al. Single-component selfassembled RNAi nanoparticles functionalized with tumor-targeting iNGR delivering abundant siRNA for efficient glioma therapy. Biomaterials 2015;53:330-40.
5. Guo Q, Li C, Zhou W, Chen X, Zhang Y, Lu Y, et al. GLUT1-mediated effective anti-miRNA21 pompon for cancer therapy. Acta Pharm Sin B 2019;9:832-42.
6. Chauhan AS. Dendrimers for drug delivery. Molecules 2018;23. E938.
7. Palmerston Mendes L, Pan J, Torchilin VP. Dendrimers as nanocarriers for nucleic acid and drug delivery in cancer therapy. Molecules 2017;22. E1401.
8. Fan W, Wang X, Ding B, Cai H, Wang X, Fan Y, et al. Thioaptamerconjugated CD44-targeted delivery system for the treatment of breast cancer in vitro and in vivo. J Drug Target 2016;24:359-71.
9. Waite CL, Roth CM. PAMAM-RGD conjugates enhance siRNA delivery through a multicellular spheroid model of malignant glioma. Bioconjugate Chem 2009;20:1908-16.
10. Xu L, Yeudall WA, Yang H. Folic acid-decorated polyamidoamine dendrimer exhibits high tumor uptake and sustained highly localized retention in solid tumors:its utility for local siRNA delivery. Acta Biomater 2017;57:251-61.
11. Yim N, Ryu SW, Choi K, Lee KR, Lee S, Choi H, et al. Exosome engineering for efficient intracellular delivery of soluble proteins using optically reversible protein-protein interaction module. Nat Commun 2016;7:12277.
12. Erb U, Zhao K, Wang Z, Xiao L, Zoller M. Murine and human pancreatic tumor exosome recovery in mouse serum:diagnostic and prognostic potential and target cell delivery. Cancer Lett 2017;403:1-12.
13. Smyth T, Kullberg M, Malik N, Smith-Jones P, Graner MW, Anchordoquy TJ. Biodistribution and delivery efficiency of unmodified tumor-derived exosomes. J Contr Release 2015;199:145-55.
14. Whiteside TL. Tumor-derived exosomes and their role in cancer progression. Adv Clin Chem 2016;74:103-41.
15. Richards KE, Zeleniak AE, Fishel ML, Wu J, Littlepage LE, Hill R. Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells. Oncogene 2017;36:1770-8.
16. Zhang Z, Li X, Sun W, Yue S, Yang J, Li J, et al. Loss of exosomal miR-320a from cancer-associated fibroblasts contributes to HCC proliferation and metastasis. Cancer Lett 2017;397:33-42.
17. Lai RC, Yeo RW, Lim SK. Mesenchymal stem cell exosomes. Semin Cell Dev Biol 2015;40:82-8.
18. Bliss SA, Sinha G, Sandiford OA, Williams LM, Engelberth DJ, Guiro K, et al. Mesenchymal stem cell-derived exosomes stimulate cycling quiescence and early breast cancer dormancy in bone marrow. Cancer Res 2016;76:5832-44.
19. Rani S, Ryan AE, Griffin MD, Ritter T. Mesenchymal stem cellderived extracellular vesicles:toward cell-free therapeutic applications. Mol Ther 2015;23:812-23.
20. Zhang L, Zhang S, Yao J, Lowery FJ, Zhang Q, Huang WC, et al. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature 2015;527:100-4.
21. Kamerkar S, LeBleu VS, Sugimoto H, Yang S, Ruivo CF, Melo SA, et al. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature 2017;546:498-503.
22. Hood JL, San RS, Wickline SA. Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res 2011;71:3792-801.
23. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 2011;29:341-5.
24. Wahlgren J, de L Karlson T, Brisslert M, Vaziri Sani F, Telemo E, Sunnerhagen P, Valadi H. Plasma exosomes can deliver exogenous short interfering RNA to monocytes and lymphocytes. Nucleic Acids Res 2012;40:e130.
25. Didiot MC, Hall LM, Coles AH, Haraszti RA, Godinho BM, Chase K, et al. Exosome-mediated delivery of hydrophobically modified siRNA for Huntingtin mRNA silencing. Mol Ther 2016;24:1836-47.
26. Yang Z, Xie J, Zhu J, Kang C, Chiang C, Wang X, et al. Functional exosome-mimic for delivery of siRNA to cancer:in vitro and in vivo evaluation. J Contr Release 2016;243:160-71.
27. Ohno S, Takanashi M, Sudo K, Ueda S, Ishikawa A, Matsuyama N, et al. Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol Ther 2013;21:185-91.
28. Yang J, Zhang X, Chen X, Wang L, Yang G. Exosome mediated delivery of miR-124 promotes neurogenesis after ischemia. Mol Ther Nucleic Acids 2017;7:278-87.
29. Wen D, Peng Y, Liu D, Weizmann Y, Mahato RI. Mesenchymal stem cell and derived exosome as small RNA carrier and immunomodulator to improve islet transplantation. J Contr Release 2016;238:166-75.
30. El-Andaloussi S, Lee Y, Lakhal-Littleton S, Li J, Seow Y, Gardiner C, et al. Exosome-mediated delivery of siRNA in vitro and in vivo. Nat Protoc 2012;7:2112-26.
31. Lunavat TR, Jang SC, Nilsson L, Park HT, Repiska G, Lasser C, et al. RNAi delivery by exosome-mimetic nanovesicles-implications for targeting c-Myc in cancer. Biomaterials 2016;102:231-8.
32. Wang J, Li W, Lu Z, Zhang L, Hu Y, Li Q, et al. The use of RGD-engineered exosomes for enhanced targeting ability and synergistic therapy toward angiogenesis. Nanoscale 2017;9:15598-605.
33. Cheng H, Fan JH, Zhao LP, Fan GL, Zheng RR, Qiu XZ, et al. Chimeric peptide engineered exosomes for dual-stage light guided plasma membrane and nucleus targeted photodynamic therapy. Biomaterials 2019;211:14-24.
34. Hu CM, Zhang L, Aryal S, Cheung C, Fang RH, Zhang L. Erythrocyte membrane-camouflaged polymeric nanoparticles as a biomimetic delivery platform. Proc Natl Acad Sci U S A 2011;108:10980-5.
35. Li R, He Y, Zhang S, Qin J, Wang J. Cell membrane-based nanoparticles:a new biomimetic platform for tumor diagnosis and treatment. Acta Pharm Sin B 2018;8:14-22.
36. Pei Q, Hu X, Zheng X, Liu S, Li Y, Jing X, et al. Light-activatable red blood cell membrane-camouflaged dimeric prodrug nanoparticles for synergistic photodynamic/chemotherapy. ACS Nano 2018;12:1630-41.
37. Guo Y, Wang D, Song Q, Wu T, Zhuang X, Bao Y, et al. Erythrocyte membrane-enveloped polymeric nanoparticles as nanovaccine for induction of antitumor immunity against melanoma. ACS Nano 2015;9:6918-33.
38. Wang C, Ye Y, Sun W, Yu J, Wang J, Lawrence DS, et al. Red blood cells for glucose-responsive insulin delivery. Adv Mater 2017;29:1606617.
39. Luk BT, Hu CM, Fang RH, Dehaini D, Carpenter C, Gao W, et al. Interfacial interactions between natural RBC membranes and synthetic polymeric nanoparticles. Nanoscale 2014;6:2730-7.
40. Wang Q, Ren Y, Mu J, Egilmez NK, Zhuang X, Deng Z, et al. Grapefruit-derived nanovectors use an activated leukocyte trafficking pathway to deliver therapeutic agents to inflammatory tumor sites. Cancer Res 2015;75:2520-9.
41. Zhang Y, Zhang Y, Guo Q, Guo Z, Chen X, Liu L, et al. Trained macrophage bioreactor for penetrating delivery of fused antitumor protein. ACS Appl Mater Interfaces 2019;11:23018-25.
42. Li J, Ai Y, Wang L, Bu P, Sharkey CC, Wu Q, et al. Targeted drug delivery to circulating tumor cells via platelet membranefunctionalized particles. Biomaterials 2016;76:52-65.
43. Han X, Chen J, Chu J, Liang C, Ma Q, Fan Q, et al. Platelets as platforms for inhibition of tumor recurrence post-physical therapy by delivery of anti-PD-L1 checkpoint antibody. J Contr Release 2019; 304:233-41.
44. Hu CM, Fang RH, Wang KC, Luk BT, Thamphiwatana S, Dehaini D, et al. Nanoparticle biointerfacing by platelet membrane cloaking. Nature 2015;526:118-21.
45. Fang RH, Kroll AV, Gao W, Zhang L. Cell Membrane coating nanotechnology. Adv Mater 2018;30:e1706759.
46. Villa CH, Anselmo AC, Mitragotri S, Muzykantov V. Red blood cells:supercarriers for drugs, biologicals, and nanoparticles and inspiration for advanced delivery systems. Adv Drug Deliv Rev 2016;106:88-103.
47. Luk BT, Zhang L. Cell membrane-camouflaged nanoparticles for drug delivery. J Contr Release 2015;220:600-7.
48. Fu Q, Lv P, Chen Z, Ni D, Zhang L, Yue H, et al. Programmed codelivery of paclitaxel and doxorubicin boosted by camouflaging with erythrocyte membrane. Nanoscale 2015;7:4020-30.
49. Fang RH, Jiang Y, Fang JC, Zhang L. Cell membrane-derived nanomaterials for biomedical applications. Biomaterials 2017;128:69-83.
50. Xu XR, Yousef GM, Ni H. Cancer and platelet crosstalk:opportunities and challenges for aspirin and other antiplatelet agents. Blood 2018; 131:1777-89.
51. Lu Y, Hu Q, Jiang C, Gu Z. Platelet for drug delivery. Curr Opin Biotechnol 2018;58:81-91.
52. Li J, Sharkey CC, Wun B, Liesveld JL, King MR. Genetic engineering of platelets to neutralize circulating tumor cells. J Contr Release 2016; 228:38-47.
53. Sercombe L, Veerati T, Moheimani F, Wu SY, Sood AK, Hua S. Advances and challenges of liposome assisted drug delivery. Front Pharmacol 2015;6:286.
54. Wang P, Zhang L, Zheng W, Cong L, Guo Z, Xie Y, et al. Thermo-triggered release of CRISPR-Cas9 system by lipid-encapsulated gold nanoparticles for tumor therapy. Angew Chem Int Ed Engl 2018;57:1491-6.
55. Jiang W, Von Roemeling CA, Chen Y, Qie Y, Liu X, Chen J, et al. Designing nanomedicine for immuno-oncology. Nat Biomed Eng 2017;1:0029.
56. Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 2014;515:577-81.
57. Leone RD, Emens LA. Targeting adenosine for cancer immunotherapy. J Immunother Canc 2018;6:57.
58. Zheng B, Xu J, Chen G, Zhang S, Xiao Z, Lu W. Bacteriummimicking vector with enhanced adjuvanticity for cancer immunotherapy and minimized toxicity. Adv Funct Mater 2019:1901437.
59. Peer D, Karp JM, Hong S, Farokhzad OC, Margalit R, Langer R. Nanocarriers as an emerging platform for cancer therapy. Nat Nanotechnol 2007;2:751-60.
60. Yu J, Zhang Y, Ye Y, DiSanto R, Sun W, Ranson D, et al. Microneedlearray patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery. Proc Natl Acad Sci U S A 2015; 112:8260-5.
61. Wang C, Ye Y, Hochu GM, Sadeghifar H, Gu Z. Enhanced cancer immunotherapy by microneedle patch-assisted delivery of anti-PD1 antibody. Nano Lett 2016;16:2334-40.
62. Tahara Y, Akiyoshi K. Current advances in self-assembled nanogel delivery systems for immunotherapy. Adv Drug Deliv Rev 2015;95:65-76.
63. Song Q, Yin Y, Shang L, Wu T, Zhang D, Kong M, et al. Tumor microenvironment responsive nanogel for the combinatorial antitumor effect of chemotherapy and immunotherapy. Nano Lett 2017;17:6366-75.
64. Purwada A, Tian YF, Huang W, Rohrbach KM, Deol S, August A, et al. Self-assembly protein nanogels for safer cancer immunotherapy. Adv Healthc Mater 2016;5:1413-9.
Similar articles: