Дендримеры PAMAM и перспективы их применения в медицине

Разработка систем доставки лекарственных веществ на основе разветвленных биосовместимых полимеров — одно из наиболее перспективных направлений современной нанофармацевтики. Исследования в данной области ведут уже не одно десятилетие, а их результаты активно внедряют в производство. Дендримеры — новый класс универсальных синтетических полимеров с поверхностью высокой степени функциональности, — обладают уникальными свойствами: постоянством размера, высокой степенью разветвления, многовалентностью, растворимостью в воде, четко определенной молекулярной массой, наличием внутренних полостей. С выпуском первого коммерческого продукта на основе дендримера — геля VivaSol, «модельный ряд» дендримерных носителей существенно разросся. Поли(амид)аминовые дендримеры, состоящие из алкилдиаминового ядра и третичных аминовых ветвей, считают одними из наиболее перспективных соединений для разработки препаратов нового поколения. Однако их клиническая адаптация долгое время была ограничена вследствие их токсичности, неопределенности поведения в живых системах и фармакокинетического профиля, а также сложности в подборе терапевтической дозы. В обзоре представлены основные сведения о дендримерах PAMAM и сделана попытка оценить перспективы их применения в терапии различных заболеваний, в том числе COVID-19.

1. Kharwade R, More S, Warokar A, Agrawal P, Mahajan N. Starburst PAMAM dendrimers: Synthetic approaches, surface modifications, and biomedical applications. Arabian Journal of Chemistry. 2020; 13 (7): 6009–39.

2. Abedi-Gaballu F, Dehghan G, Ghaffari M, Yekta R, AbbaspourRavasjani S, et al. PAMAM dendrimers as efficient drug and gene delivery nanosystems for cancer therapy. Applied materials today, 2018; 12: 177–90.

3. Hannon G, Lysaght J, Liptrott NJ, Prina‐Mello A. Immunotoxicity considerations for next generation cancer nanomedicines. Advanced Science. 2019; 6 (19): 1900133.

4. Fox LJ, Richardson RM, Briscoe WH. PAMAM dendrimer — cell membrane interactions. Advances in Colloid and Interface Science. 2018; 257: 1–18.

5. Florendo M, Figacz A, Srinageshwar B, Sharma A, Swanson D, et al. Use of Polyamidoamine Dendrimers in Brain Diseases. Molecules. 2018; 23: 2238.

6. Igartúa DE, Martinez CS, Temprana CF, Alonso S del V, Jimena Prieto M. PAMAM dendrimers as a carbamazepine delivery system for neurodegenerative diseases: A biophysical and nanotoxicological characterization. International Journal of Pharmaceutics. 2018; 544 (1): 191–202.

7. Yan C, Gu J, Lv Y, Shi W, Wang Y, et al. Caproyl-Modified G2 PAMAM Dendrimer (G2-AC) Nanocomplexes Increases the Pulmonary Absorption of Insulin. AAPS PharmSciTech. 2019; 20: 298.

8. Xie H, Li L, Sun Y, Wang Y, Gao S, et al. An Available Strategy for Nasal Brain Transport of Nanocomposite Based on PAMAM Dendrimers via In Situ Gel. Nanomaterials. 2019; 9 (2): 147.

9. Alberto RFR, Martiniano B, Saúl RH, Jazmín GM, Mara GS, et al. In silico and in vivo studies of gp120-HIV-derived peptides in complex with G4-PAMAM dendrimers. RSC Advances. 2020; 10 (35): 20414–26.

10. Kheraldine H, Rachid O, Habib AM, Moustafa A-E, Benter IF, et al. Emerging innate biological properties of nano-drug delivery systems: A focus on PAMAM dendrimers and their clinical potential. Advanced Drug Delivery Reviews. 2021; 178: 113908.

11. Thiagarajan G, Sadekar S, Greish K, Ray A, Ghandehari H. Evidence of oral translocation of anionic G6.5 dendrimers in mice. Molecular pharmaceutics. 2013; 10 (3): 988–98.

12. Бахрушина Е. О., Анурова М. Н., Демина Н. Б., Лапик И. В., Тураева А. Р., и др. Системы доставки офтальмологических препаратов (обзор). Разработка и регистрация лекарственных средств. 2020; 10 (1): 57–66.

13. Prajapati SK, Jain A. Dendrimers for Advanced Drug Delivery. In Advanced Biopolymeric Systems for Drug Delivery. Eds: Springer, Cham. 2020; 339–60.

14. Wang J, Williamson GS, Lancina III MG, Yang H. Mildly crosslinked dendrimer hydrogel prepared via aza-Michael addition reaction for topical brimonidine delivery. Journal of biomedical nanotechnology. 2017; 13 (9): 1089–96.

15. Belamkar A, Harris A, Zukerman R, Siesky B, Oddone F, et al. Sustained release glaucoma therapies: Novel modalities for overcoming key treatment barriers associated with topical medications. Annals of Medicine. 2022; 54 (1); 343–58.

16. Liko F, Hindre F, Fernandez-Megia E. Dendrimers as innovative radiopharmaceuticals in cancer radionanotherapy. Biomacromolecules. 2016; 17 (10): 3103–14.

17. Jinhe Z, Ruimin W, Jianqiu Z, Yongming C, Wang X, et al. RGDyC peptide-Modified PAMAM Dendrimer Conjugates Labeled with Radionuclide131I for SPECT Imaging and Radiotherapy of Lung Carcinoma. Journal of Nuclear Medicine. 2019; 60 (1): 1056.

18. Marcinkowska M, Sobierajska E, Stanczyk M, Janaszewska A, Chworos A, et al. Conjugate of PAMAM Dendrimer, Doxorubicin and Monoclonal Antibody—Trastuzumab: The New Approach of a Well-Known Strategy. Polymers. 2018; 10: 187.

19. Araújo R, Santos S, Igne Ferreira E, Giarolla J. New Advances in General Biomedical Applications of PAMAM Dendrimers. Molecules. 2018; 23 (11): 2849–76.

20. Bhadra D, Bhadra S, Jain S, Jain NK. A PEGylated dendritic nanoparticulatecarrier of fluorouracil. Int J Pharm. 2003; 257 (1–2): 111–24.

21. Surekha B, Kommana NS, Dubey SK, Kumar AP, Shukla R, et al. PAMAM dendrimer as a talented multifunctional biomimetic nanocarrier for cancer diagnosis and therapy. Colloids and Surfaces B: Biointerfaces. 2021; 204: 111837.

22. Gupta L, Sharma AK, Gothwal A, Khan MS, Khinchi MP, et al. Dendrimer encapsulated and conjugated delivery of berberine: A novel approach mitigating toxicity and improving in vivo pharmacokinetics. International journal of pharmaceutics. 2017; 528 (1–2): 88–99.

23. Chen G, Jaskula–Sztul R, Harrison A, Dammalapati A, Xu W, et al. KE108-conjugated unimolecular micelles loaded with a novel HDAC inhibitor thailandepsin-A for targeted neuroendocrine cancer therapy. Biomaterials. 2016; 97: 22–33.

24. Srivastava A, Tripathi PK. PAMAM dendrimer-vitamin conjugate for delivery of paclitaxel as anticancer agent. International Journal of Green Pharmacy, 2020; 14 (4): 360–6.

25. Xu X, Li Y, Lu X, Sun Y, Luo J, et al. Glutaryl polyamidoamine dendrimer for overcoming cisplatin-resistance of breast cancer cells. Journal of Nanoscience and Nanotechnology. 2018; 18 (10): 6732–9.

26. Le PN, Pham DC, Nguyen DH, Tran NQ, Dimitrov V, et al. Poly (N-isopropylacrylamide)-functionalized dendrimer as a thermosensitive nanoplatform for delivering malloapelta B against HepG2 cancer cell proliferation. Advances in Natural Sciences: Nanoscience and Nanotechnology. 2017; 8 (2): 025014.

27. Parsian M, Mutlu P, Yalcin S, Tezcaner A, Gunduz U. Half generations magnetic PAMAM dendrimers as an effective system for targeted gemcitabine delivery. International Journal of Pharmaceutics. 2016; 515 (1–2): 104–13.

28. Majidzadeh H, Araj-Khodaei M, Ghaffari M, Torbati M, Dolatabadi JEN, et al. Nano-based delivery systems for berberine: A modern anticancer herbal medicine. Colloids and Surfaces B: Biointerfaces. 2020; 194: 111188.

29. Marcinkowska M, Stanczyk M, Janaszewska A, Gajek A, Ksiezak M, et al. Molecular Mechanisms of Antitumor Activity of PAMAM Dendrimer Conjugates with Anticancer Drugs and a Monoclonal Antibody. Polymers. 2019; 11 (9): 1422.

30. Yellepeddi VK, Kumar A, Maher DM, Chauhan SC, Vangara KK, et al. Biotinylated PAMAM dendrimers for intracellular delivery of cisplatin to ovarian cancer: role of SMVT. Anticancer research. 2011; 31 (3): 897–906.

31. Chanphai P, Tajmir-Riahi HA. Encapsulation of micronutrients resveratrol, genistein, and curcumin by folic acid-PAMAM nanoparticles. Molecular and Cellular Biochemistry. 2018; 449 (1): 157–66.

32. Tang Q, Liu D, Chen H, He D, Pan W, et al. Functionalized PAMAM-Based system for targeted delivery of miR-205 and 5-fluorouracil in breast cancer. Journal of Drug Delivery Science and Technology. 2022; 67: 102959.

33. Narmani A, Arani MAA, Mohammadnejad J, Vaziri AZ, Solymani S, et al. Breast tumor targeting with PAMAM-PEG-5FU-99mTc as a new therapeutic nanocomplex: in in-vitro and in-vivo studies. Biomedical Microdevices. 2020; 22 (2): 1–13.

34. Ren Y, Kang CS, Yuan XB, Zhou X, Xu P, et al. Co-delivery of as-miR-21 and 5-FU by poly (amidoamine) dendrimer attenuates human glioma cell growth in vitro. Journal of Biomaterials Science, Polymer Edition. 2010; 21 (3): 303–14.

35. Yoyen-Ermis D, Ozturk-Atar K, Kursunel MA, Aydin C, Ozkazanc D, et al. Tumor-induced myeloid cells are reduced by gemcitabineloaded PAMAM dendrimers decorated with anti-Flt1 antibody. Molecular pharmaceutics. 2018; 15 (4): 1526–33.

36. Bai CZ, Choi S, Nam K, An S, Park JS. Arginine modified PAMAM dendrimer for interferon beta gene delivery to malignant glioma. International journal of pharmaceutics. 2013; 445 (1–2): 79–87.

37. Chauhan AS. Dendrimers for drug delivery. Molecules. 2018; 23 (4): 938.

38. Bourne N, Stanberry LR, Kern ER, Holan G, Matthews B, et al. Dendrimers, a new class of candidate topical microbicides with activity against herpes simplex virus infection. Antimicrobial agents and chemotherapy. 2000; 44 (9): 2471–4.

39. Vahedifard F, Chakravarthy K. Nanomedicine for COVID-19: The role of nanotechnology in the treatment and diagnosis of COVID-19. Emergent materials. 2021; 4 (1): 75–99.

40. Günther SC, Maier JD, Vetter J, Podvalnyy N, Khanzhin N, et al. Antiviral potential of 3′-sialyllactose-and 6′-sialyllactoseconjugated dendritic polymers against human and avian influenza viruses. Scientific reports. 2020; 10 (1): 1–9.

41. Bohr A, Tsapis N, Foged C, Andreana I, Yang M, et al. Treatment of acute lung inflammation by pulmonary delivery of anti-TNF-α siRNA with PAMAM dendrimers in a murine model. European Journal of Pharmaceutics and Biopharmaceutics. 2020; 156: 114–120.

42. Jeon P, Choi M, Oh J, Lee M. Dexamethasone–Conjugated Polyamidoamine Dendrimer for Delivery of the Heme Oxygenase‐1 Gene into the Ischemic Brain. Macromolecular Bioscience. 2015; 15 (7): 1021–8.

43. Wang B, Navath RS, Romero R, Kannan S, Kannan R. Antiinflammatory and anti-oxidant activity of anionic dendrimer– N-acetyl cysteine conjugates in activated microglial cells. International journal of pharmaceutics. 2009; 377 (1–2): 159–68.

44. Kurtoglu YE, Navath RS, Wang B, Kannan S, Romero R, et al. Poly (amidoamine) dendrimer–drug conjugates with disulfide linkages for intracellular drug delivery. Biomaterials. 2009; 30 (11): 2112–21.

45. Inapagolla R, Guru BR, Kurtoglu YE, Gao X, Lieh-Lai M, et al. In vivo efficacy of dendrimer–methylprednisolone conjugate formulation for the treatment of lung inflammation. International journal of pharmaceutics. 2010; 399 (1–2): 140–7.

46. Vaidya A, Jain S, Pathak K, Pathak D. Dendrimers: Nanosized multifunctional platform for drug delivery. Drug Delivery Letters. 2018; 8 (1): 3–19.

47. Thanh VM, Nguyen TH, Tran TV, Ngoc UTP, Ho MN, et al. Low systemic toxicity nanocarriers fabricated from heparin-mPEG and PAMAM dendrimers for controlled drug release. Materials Science and Engineering: C. 2018; 82: 291–8.

48. Pandey P, Mehta M, Shukla S, Wadhwa R, Singhvi G, et al. Emerging nanotechnology in chronic respiratory diseases. Nanoformulations in Human Health. 2020: 449–68.

49. Paull JRA, Luscombe CA, Castellarnau A, Heery GP, Bobardt MD, Gallay PA. Protective Effects of Astodrimer Sodium 1% Nasal Spray Formulation against SARS-CoV-2 Nasal Challenge in K18hACE2 Mice. Viruses. 2021; 13: 1656.