We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

Selective targeting of cancer signaling pathways with nanomedicines: challenges and progress

    Harshita Abul Barkat

    Department of Pharmaceutics, College of Pharmacy, University of Hafr Al Batin, Al Jamiah, Hafr Al-Batin, 39524, Saudi Arabia

    ,
    Sabya Sachi Das

    Department of Pharmaceutical Sciences & Technology, BIT, Mesra, Ranchi, 835215, Jharkhand, India

    ,
    Md Abul Barkat

    *Author for correspondence:

    E-mail Address: abulbarkat05@gmail.com

    Department of Pharmaceutics, College of Pharmacy, University of Hafr Al Batin, Al Jamiah, Hafr Al-Batin, 39524, Saudi Arabia

    ,
    Sarwar Beg

    Department of Pharmaceutics, Nanomedicine Research Lab, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, India

    &
    Hazrina Ab Hadi

    Department of Pharmaceutical Technology, Faculty of Pharmacy, International Islamic University Malaysia, Kuantan, Pahang, 25200, Malaysia

    Published Online:https://doi.org/10.2217/fon-2020-0198

    Cancer is one of the leading causes of death worldwide. Regardless of advances in understanding the molecular mechanics of cancer, its treatment is still lacking and the death rates for many forms of the disease remain the same as six decades ago. Although a variety of therapeutic agents and strategies have been reported, these therapies often failed to provide efficient therapy to patients as a consequence of the inability to deliver right and adequate chemotherapeutic agents to the right place. However, the situation has started to revolutionize substantially with the advent of novel ‘targeted’ nanocarrier-based cancer therapies. Such therapies hold great potential in cancer management as they are biocompatible, tailored to specific needs, tolerated and deliver enough drugs at the targeted site. Their use also enhances the delivery of chemotherapeutics by improving biodistribution, lowering toxicity, inhibiting degradation and increasing cellular uptake. However, in some instances, nonselective targeting is not enough and the inclusion of a ligand moiety is required to achieve tumor targeting and enhanced drug accumulation at the tumor site. This contemporary review outlines the targeting potential of nanocarriers, highlighting the essentiality of nanoparticles, tumor-associated molecular signaling pathways, and various biological and pathophysiological barriers.

    Graphical abstract

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. Marte B. Tumor heterogeneity. Nature 501(7467), 327 (2013). • Provides a summary of cancer complications.
    • 2. Kircher M, Witten DM, Jain P, O'Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet. 46(3), 310–315 (2014).
    • 3. Suvà ML, Riggi N, Bernstein BE. Epigenetic reprogramming in cancer. Science 339(6127), 1567–1570 (2013).
    • 4. Seyfried TN, Flores RE, Poff AM, D'Agostino DP. Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis 35(3), 515–527 (2014).
    • 5. Sliwkowski MX, Mellman I. Antibody therapeutics in cancer. Science 341(6151), 1192–1198 (2013).
    • 6. Jabir NR, Tabrez S, Ashraf GM, Shakil S, Damanhouri GA, Kamal MA. Nanotechnology-based approaches in anticancer research. Int. J. Nanomed. 7, 4391–4408 (2012).
    • 7. Shiekh FA. Targeted nanotherapeutics in cancer. Int. J. Nanomed. 26(9), 1627–1628 (2014). •• Outlines the targeting potential of nanomedicine-based chemotherapeutics for cancer treatment.
    • 8. Bar-Zeev M, Livney YD, Assaraf YG. Targeted nanomedicine for cancer therapeutics: towards precision medicine overcoming drug resistance. Drug. Resist. Updat. 31, 15–30 (2017).
    • 9. Goldberg MS, Hook SS, Wang AZ et al. Biotargeted nanomedicines for cancer: six tenets before you begin. Nanomedicine 8(2), 299–308 (2013).
    • 10. Godwin A, Bolina K, Clochard M et al. New strategies for polymer development in pharmaceutical science – a short review. J. Pharm. Pharmacol. 53(9), 1175–1184 (2001).
    • 11. Rihova B. Immunomodulating activities of soluble synthetic polymer-bound drugs. Adv. Drug Deliv. Rev. 54(5), 653–674 (2002).
    • 12. Duncan R, Ringsdorf H, Satchi-Fainaro R. Polymer therapeutics–polymers as drugs, drug and protein conjugates and gene delivery systems: past, present and future opportunities. J. Drug Target. 14(6), 337–341 (2006).
    • 13. Segal E, Pan H, Ofek P et al. Targeting angiogenesis-dependent calcified neoplasms using combined polymer therapeutics. PLoS ONE 4(4), e5233 (2009).
    • 14. Miller K, Eldar-Boock A, Polyak D et al. Antiangiogenic antitumor activity of HPMA copolymer-paclitaxel-alendronate conjugate on breast cancer bone metastasis mouse model. Mol. Pharm. 8(4), 1052–1062 (2011).
    • 15. Miller K, Clementi C, Polyak D et al. Poly (ethylene glycol)-paclitaxel-alendronate self-assembled micelles for the targeted treatment of breast cancer bone metastases. Biomaterials 34(15), 3795–3806 (2013).
    • 16. Ringsdorf H. Structure and properties of pharmacologically active polymers. J. Polymer Sci. 51, 135–153 (1975).
    • 17. Mayer LD, Bally MB, Loughrey H, Masin D, Cullis PR. Liposomal vincristine preparations which exhibit decreased drug toxicity and increased activity against murine l1210 and p388 tumors. Cancer Res. 50(3), 575–579 (1990).
    • 18. Allen TM, Martin FJ. Advantages of liposomal delivery systems for anthracyclines. Semin. Oncol. 31(13 Suppl. 6), 5–15 (2004).
    • 19. Gabizon A, Shmeeda H, Barenholz Y. Pharmacokinetics of pegylated liposomal doxorubicin: review of animal and human studies. Clin. Pharmacokinet. 42(5), 419–436 (2003).
    • 20. Gabizon A, Meshorer A, Barenholz Y. Comparative long-term study of the toxicitiesof free and liposome-associated doxorubicin in mice after intravenous administration. J. Nat. Cancer Inst. 77(2), 459–469 (1986).
    • 21. Klibanov AL, Maruyama K, Torchilin VP, Huang L. Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes. FEBS Lett. 268(1), 235–237 (1990).
    • 22. Allen TM, Hansen C. Pharmacokinetics of stealth versus conventional liposomes: effect of dose. Biochim. Biophys. Acta 1068(2), 133–141 (1991). • Focuses on nonselective targeting of nanocarriers.
    • 23. Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 46(12 Pt 1), 6387–6392 (1986).
    • 24. Dvorak HF, Brown LF, Detmar M, Dvorak AM. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am. J. Pathol. 146(5), 1029–1039 (1995).
    • 25. Jain RK. Transport of molecules in the tumor interstitium: a review. Cancer Res. 47(12), 3039–3051 (1987).
    • 26. Maeda H, Matsumura Y. Tumoritropic and lymphotropic principles of macromolecular drugs. Crit. Rev. Ther. Drug Carrier Syst. 6(3), 193–210 (1989).
    • 27. Maeda H, Wu J, Sawa T, Matsumura Y, Hori K. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J. Control. Release 65(1–2), 271–284 (2000).
    • 28. Jang SH, Wientjes MG, Lu D, Au JL. Drug delivery and transport to solid tumors. Pharm. Res. 20(9), 1337–1350 (2003).
    • 29. Fang J, Nakamura H, Maeda H. The EPR effect: unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv. Drug Deliv. Rev. 63(3), 136–151 (2011).
    • 30. Torchilin V. Tumor delivery of macromolecular drugs based on the EPR effect. Adv. Drug Deliv. Rev. 63(3), 131–135 (2011).
    • 31. Maeda H, Nakamura H, Fang J. The EPR effect for macromolecular drug delivery to solid tumors: improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. Adv. Drug Deliv. Rev. 65, 71–79 (2013).
    • 32. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 407, 249–257 (2000).
    • 33. Hashizume H, Baluk P, Morikawa S et al. Openings between defective endothelial cells explain tumor vessel leakiness. Am. J. Pathol. 156(4), 1363–1380 (2000).
    • 34. Hobbs SK, Monsky WL, Yuan F et al. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc. Natl Acad. Sci. USA 95(8), 4607–4612 (1998).
    • 35. Jain RK, Stylianopoulos T. Delivering nanomedicine to solid tumors. Nat. Rev. Clin. Oncol. 7(11), 653–664 (2010).
    • 36. Chauhan VP, Jain RK. Strategies for advancing cancer nanomedicine. Nat. Mater. 12(11), 958–962 (2013).
    • 37. Padera TP, Stoll BR, Tooredman JB, Capen D, Tomaso ED, Jain RK. Pathology: cancer cells compress intratumor vessels. Nature 427(6976), 695 (2005).
    • 38. Adiseshaiah PP, Crist RM, Hook SS, McNeil SE. Nanomedicine strategies to overcome the pathophysiological barriers of pancreatic cancer. Nat. Rev. Clin. Oncol. 13(12), 750–765 (2016).
    • 39. Jiang W, Roemeling CAV, Chen Y et al. Designing nanomedicine for immuno-oncology. Nat. Biomed. Eng. 1(2), 1–11 (2017).
    • 40. Balkwill FR, Capasso M, Hagemann T. The tumor microenvironment at a glance. J. Cell Sci. 125(Pt 23), 5591–5596 (2012).
    • 41. Peer D, Karp JM, Hong S, Farokhzad OC, Margalit R, Langer R. Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotech. 2(12), 751–760 (2007).
    • 42. Allen TM. Ligand-targeted therapeutics in anticancer therapy. Nat. Rev. Cancer 2(10), 750–763 (2002).
    • 43. Kim BYS, Jiang W, Oreopoulos J, Yip CM, Rutka JT, Chan WCW. Biodegradable quantum dot nanocomposites enable live cell labeling and imaging of cytoplasmic targets. Nano Lett. 8(11), 3887–3892 (2008).
    • 44. Gao X, Cui Y, Levenson RM, Chung LWK, Nie S. In vivo cancer targeting and imaging with semiconductor quantum dots. Nat. Biotechnol. 22(8), 969–976 (2004).
    • 45. Choi HS, Liu W, Liu W et al. Design considerations for tumor-targeted nanoparticles. Nat. Nanotech. 5(1), 42–47 (2010).
    • 46. Peng L, Liu R, Marik J, Wang X, Takada Y, Lam KT. Combinatorial chemistry identifies high-affinity peptidomimetics against α4β1 integrin for in vivo tumor imaging. Nat. Chem. Biol. 2(7), 381–389 (2006).
    • 47. Jiang W, Kim BYS, Rutka JT, Chan WCW. Nanoparticle-mediated cellular response is size-dependent. Nat. Nanotech. 3(3), 145–150 (2008).
    • 48. Scott AM, Wolchok JD, Old LJ. Antibody therapy of cancer. Nat. Rev. Cancer 12(4), 278–287 (2012).
    • 49. Chan AC, Carter PJ. Therapeutic antibodies for autoimmunity and inflammation. Nat. Rev. Immunol. 10(5), 301–316 (2010).
    • 50. Van Cutsem E, Köhne CH, Hitre E et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N. Engl. J. Med. 360(14), 1408–1417 (2009).
    • 51. Hudis CA. Trastuzumab-mechanism of action and use in clinical practice. N. Engl. J. Med. 357(1), 39–51 (2007).
    • 52. Cheson BD, Leonard JP. Monoclonal antibody therapy for B-cell non-Hodgkin's lymphoma. N. Engl. J. Med. 359(6), 613–626 (2008).
    • 53. Verma S, Miles D, Gianni L et al. Trastuzumabemtansine for HER2-positive advanced breast cancer. N. Engl. J. Med. 367(19), 1783–1791 (2012).
    • 54. Tolcher AW, Sugarman S, Gelmon KA et al. Randomized Phase II study of BR96-doxorubicin conjugate in patients with metastatic breast cancer. J. Clin. Oncol. 17(2), 478–484 (1999).
    • 55. Wilhelm S, Tavares AJ, Dai Q et al. Analysis of nanoparticle delivery to tumors. Nat. Rev. Mater. 1, 16014 (2016).
    • 56. Kim BYS, Rutka JT, Chan WCW. Nanomedicine. N. Engl. J. Med. 363, 2434–2443 (2010).
    • 57. Joyce JA. Therapeutic targeting of the tumor microenvironment. Cancer Cell 7(6), 513–520 (2005).
    • 58. Arap W, Pasqualini R, Ruoslahti E. Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science 279(5349), 377–380 (1998).
    • 59. Sugahara KN, Teesalu T, Karmali PP et al. Tissue-penetrating delivery of compounds and nanoparticles into tumors. Cancer Cell 16(6), 510–520 (2009).
    • 60. Ruoslahti E, Bhatia SN, Sailor MJ. Targeting of drugs and nanoparticles to tumors. J. Cell Biol. 188(6), 759–768 (2010).
    • 61. Teesalu T, Sugahara KN, Kotamraju VR, Ruoslahti E. C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration. Proc. Natl Acad. Sci. USA 106(38), 16157–16162 (2009).
    • 62. Simberg D, Duza T, Park JH et al. Biomimetic amplification of nanoparticle homing to tumors. Proc. Natl Acad. Sci. USA 104(3), 932–936 (2007).
    • 63. Messerschmidt SK, Musyanovych A, Altvater M et al. Targeted lipid-coated nanoparticles: delivery of tumor necrosis factor-functionalized particles to tumor cells. J. Control. Release 137(1), 69–77 (2009).
    • 64. Weissleder R, Nahrendorf M, Pittet MJ. Imaging macrophages with nanoparticles. Nat. Mater. 13(2), 125–138 (2014).
    • 65. Zhang B, Shen S, Liao Z et al. Targeting fibronectins of glioma extracellular matrix by CLT1 peptide-conjugated nanoparticles. Biomaterials 35(13), 4088–4098 (2014).
    • 66. Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat. Rev. Drug Discov. 10(6), 417–427 (2011).
    • 67. Chauhan VP, Stylianopoulos T, Martin JD et al. Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner. Nat. Nanotechnol. 7(6), 383–388 (2012).
    • 68. Jiang W, Huang Y, An Y, Kim BY. Remodeling tumor vasculature to enhance delivery of intermediate-sized nanoparticles. ACS Nano 9(9), 8689–8696 (2015).
    • 69. Wong C, Stylianopoulos T, Cui J et al. Multistage nanoparticle delivery system for deep penetration into tumor tissue. Proc. Natl Acad. Sci. USA 108(6), 2426–2431 (2011).
    • 70. Cabral H, Matsumoto Y, Mizuno K et al. Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size. Nat. Nanotechnol. 6(12), 815–823 (2011).
    • 71. Das M, Mohanty C, Sahoo SK. Ligand-based targeted therapy for cancer tissue. Expert Opin. Drug Del. 6, 285–304 (2009).
    • 72. Das SS, Alkahtani S, Bharadwaj P et al. Molecular insights and novel approaches for targeting tumor metastasis. Int. J. Pharm. 585, 119556 (2020).
    • 73. Eldar-Boock A, Miller K, Sanchis J, Lupu R, Vicent MJ, Satchi-Fainaro R. Integrin-assisted drug delivery of nano-scaled polymer therapeutics bearing paclitaxel. Biomaterials 32(15), 3862–3874 (2011).
    • 74. Sjoblom T, Jones S, Wood LD et al. The consensus coding sequences of human breast and colorectal cancers. Science 314(5797), 268–274 (2006).
    • 75. Wood LD, Parsons DW, Jones S et al. The genomic landscapes of human breast and colorectal cancers. Science 318(5853), 1108–1113 (2007).
    • 76. Sellers WR. A blueprint for advancing genetics-based cancer therapy. Cell 147(1), 26–31 (2011). • Overview of different limitations associated with conventional chemotherapy.
    • 77. Zhao G, Rodriguez BL. Molecular targeting of liposomal nanoparticles to tumor microenvironment. Int. J. Nanomed. 8, 61–71 (2013).
    • 78. Nguyen K T. Targeted nanoparticles for cancer therapy: promises and challenges. J. Nanomedic. Nanotechnol. 2(5), 103e (2011).
    • 79. Coates A, Abraham S, Kaye SB. On the receiving end – patient perception of the side-effects of cancer chemotherapy. Eur. J. Cancer. Clin. Oncol. (192), 203–208 (1983).
    • 80. Tannock IF, Lee CM, Tunggal JK, Cowan DS, Egorin MJ. Limited penetration of anticancer drugs through tumor tissue: a potential cause of resistance of solid tumors to chemotherapy. Clin. Cancer Res. 8(3), 878–884 (2002).
    • 81. Mousa SA, Bharali DJ. Nanotechnology-based detection and targeted therapy in cancer: nano-bio paradigms and applications. Cancers 3(3), 2888–2903 (2011).
    • 82. Krishna R, Mayer LD. Multidrug resistance (MDR) in cancer mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur. J. Pharm. Sci. 11(4), 265–283 (2000).
    • 83. Links M, Brown R. Clinical relevance of the molecular mechanisms of resistance to anti-cancer drugs. Expert Rev. Mol. Med. 1999, 1–21 (1999).
    • 84. Gottesman MM, Hrycyna CA, Schoenlein PV, Germann UA, Pastan I. Genetic analysis of the multidrug transporter. Annu. Rev. Genet. 29, 607–649 (1995).
    • 85. Harshita Barkat MA, Das SS, Pottoo FH, Beg S, Rahman Z. Lipid-based nanosystem as intelligent carriers for versatile drug delivery applications. Curr. Pharm. Des. 26(11), 1167–1180 (2020). •• Provides updates on various advantages of nanotechnology-based approaches.
    • 86. Shi J, Kanto PW, Wooster R, Farokhzad OC. Cancer nanomedicine: progress, challenges and opportunities. Nat. Rev. Cancer. 17(1), 20–37 (2016). • Overview of different approaches for overcoming the limitations associated with conventional chemotherapy.
    • 87. Patri AK, Kukowska-Latallo JF, Baker JR Jr. Targeted drug delivery with dendrimers: comparison of the release kinetics of covalently conjugated drug and non-covalent drug inclusion complex. Adv. Drug Deliver. Rev. 57(15), 2203–2214 (2005).
    • 88. Das SS, Hussain A, Verma PRP et al. Recent advances in liposomal drug delivery system of Quercetin for cancer targeting: a mechanistic approach. Curr. Drug Deliv. (17(10), 845–860 (2020).
    • 89. Soma CE, Dubernet C, Bentolila D, Benita S, Couvreur P. Reversion of multidrug resistance by co-encapsulation of doxorubicin and cyclosporin A in polyalkylcyanoacrylate nanoparticles. Biomaterials 21(1), 1–7 (2000).
    • 90. Amin ML. P-glycoprotein inhibition for optimal drug delivery. Drug Target Insights 7, 27–34 (2013).
    • 91. Matsuo H, Wakasugi M, Takanaga H et al. Possibility of the reversal of multidrug resistance and the avoidance of side effects by liposomes modified with MRK-16, a monoclonal antibody to P-glycoprotein. J. Control. Release 77(1–2), 77–86 (2001).
    • 92. Danson S, Ferry D, Alakhov V et al. Phase I dose escalation and pharmacokinetic study of pluronic polymer-bound doxorubicin (SP1049C) in patients with advanced cancer. Br. J. Cancer 90(11), 2085–2091 (2004).
    • 93. Batrakova EV, Dorodnych TY, Klinskii EY et al. Anthracycline antibiotics non-covalently incorporated into the block copolymer micelles: in vivo evaluation of anti-cancer activity. Br. J. Cancer 74(10), 1545–1552 (1996).
    • 94. Goren D, Horowitz AT, Tzemach D, Tarshish M, Zalipsky S, Gabizon A. Nuclear delivery of doxorubicin via folate-targeted liposomes with bypass of multidrug-resistance efflux pump. Clin. Cancer Res. 6(5), 1949–1957 (2000).
    • 95. Barkat A, Beg S, Panda SK, Alharbi KS, Rahman M, Ahmed FJ. Functionalized mesoporous silica nanoparticles in anticancer therapeutics. Semin. Cancer Biol. S1044-579X(19), 30104–X (2019).
    • 96. Yanes RE, Tamanoi F. Development of mesoporous silica nanomaterials as a vehicle for anticancer drug delivery. Ther. Deliv. 3, 389–404 (2012).
    • 97. Das SS, Bharadwaj P, Bilal M et al. Stimuli-responsive polymeric nanocarriers for drug delivery, imaging, and theragnosis. Polymers (Basel) 12, E1397 (2020).
    • 98. Hergt R, Andrä W. Magnetism in medicine. J. Appl. Phys. 404, 550–570 (2007).
    • 99. Conde J, Doria G, Baptista P. Noble metal nanoparticles applications in cancer. J. Drug Deliv. 2012, 751075 (2012).
    • 100. Kong FY, Zhang JW, Li RF, Wang ZX, Wang WJ, Wang W. Unique roles of gold nanoparticles in drug delivery, targeting and imaging applications. Molecules 22, 1445 (2017).
    • 101. Clark AJ, Davis ME. Increased brain uptake of targeted nanoparticles by adding an acid-cleavable linkage between transferrin and the nanoparticle core. Proc. Natl Acad. Sci. USA 112, 12486–12491 (2015).
    • 102. Qian W, Murakami M, Ichikawa Y, Che Y. Highly efficient and controllable PEGylation of gold nanoparticles prepared by femtosecond laser ablation in water. J. Phys. Chem. C 115, 23293–23298 (2011).
    • 103. El-Sayed IH, Huang X, El-Sayed MA. Surface plasmon resonance scattering and absorption of anti-EGFR antibody conjugated gold nanoparticles in cancer diagnostics: applications in oral cancer. Nano Lett. 5, 829–834 (2005).
    • 104. Wahajuddin Arora S. Superparamagnetic iron oxide nanoparticles: magnetic nanoplatforms as drug carriers. Int. J. Nanomed. 7, 3445–3471 (2012).
    • 105. Patra S, Roy E, Karfa P, Kumar S, Madhuri R, Sharma PK. Dual-responsive polymer coated superparamagnetic nanoparticle for targeted drug delivery and hyperthermia treatment. ACS Appl. Mater. Interfaces 7, 9235–9246 (2015).
    • 106. Eatemadi A, Daraee H, Karimkhanloo H, Kouhi M, Zarghami N. Carbon nanotubes: properties, synthesis, purification, and medical applications. Nanoscale Res. Lett. 9, 393 (2014).
    • 107. Matea C, Mocan T, Tabaran F, Pop T, Mosteanu O, Puia C. Quantum dots in imaging, drug delivery and sensor applications. Int. J. Nanomed. 12, 5421–5431 (2017).
    • 108. von Roemeling C, Jiang W, Chan CK, Weissman IL, Kim BYS. Breaking down the barriers to precision cancer nanomedicine. Trends Biotechnol. 35(2), 159–171 (2017).
    • 109. Garcia KP, Zarschler K, Barbaro L et al. Zwitterionic-coated ‘stealth’ nanoparticles for biomedical applications: recent advances in countering biomolecular corona formation and uptake by the mononuclear phagocyte system. Small 10(13), 2516–2529 (2014).
    • 110. Harshita Barkat, MA Beg S, Pottoo FH, Ahmad FJ. Nanopaclitaxel therapy: an evidence based review on the battle for next-generation formulation challenges. Nanomedicine 14(10), 1323–1341 (2019).
    • 111. Tran S, De Giovanni PJ, Piel B, Rai P. Cancer nanomedicine: a review of recent success in drug delivery. Clin. Transl. Med. 6(1), 1–22 (2017).
    • 112. Rodriguez PL, Harada T, Christian DA, Pantano DA, Tsai RK, Discher DE. Minimal ‘self” peptides that inhibit phagocytic clearance and enhance delivery of nanoparticles. Science 339(6122), 971–975 (2013).
    • 113. Nie S. Understanding and overcoming major barriers in cancer nanomedicine. Nanomedicine (London) 5, 523–528 (2010).
    • 114. Duan X, Li Y. Physicochemical characteristics of nanoparticles affect circulation, biodistribution, cellular internalization, and trafficking. Small 9(9–10), 1521–1532 (2013).
    • 115. Toy R, Hayden E, Shoup C, Baskaran H, Karathanasis E. The effects of particle size, density and shape on margination of nanoparticles in microcirculation. Nanotechnology 22(11), 115101 (2011).
    • 116. Hussain A, Singh S, Das SS, Anjireddy K, Karpagam S, Shakeel F. Nanomedicines as drug delivery carriers of anti-tubercular drugs: from pathogenesis to infection control. Curr. Drug Deliv. 16(5), 400–429 (2019).
    • 117. Li SD, Huang L. Nanoparticles evading the reticuloendothelial system: role of the supported bilayer. Biochim. Et Biophys. Acta 1788(10), 2259–2266 (2009).
    • 118. Choi HS, Liu W, Misra P et al. Renal clearance of quantum dots. Nat. Biotechnol. 25(10), 1165–1170 (2007).
    • 119. Longmire M, Choyke PL, Kobayashi H. Clearance properties of nanosized particles and molecules as imaging agents: considerations and caveats. Nanomedicine (London) 3(5), 703–717 (2008).
    • 120. Liu J, Yu M, Zhou C, Zheng J. Renal clearable inorganic nanoparticles: a new frontier of bionanotechnology. Mater. Today 16(12), 477–486 (2013).
    • 121. Hashizume H, Baluk P, Morikawa S et al. Openings between defective endothelial cells explain tumor vessel leakiness. Am. J. Pathol. 156(4), 1363–1380 (2000).
    • 122. Yuan H, Takeuchi E, Salant DJ. Podocyte slit-diaphragm protein nephrin is linked to the actin cytoskeleton. Am. J. Physiol. Renal. Physiol. 282(4), 585–591 (2002).
    • 123. Ruggiero A, Villa CH, Bander E et al. Paradoxical glomerular filtration of carbon nanotubes. Proc. Natl Acad. Sci. USA 107(27), 12369 (2010).
    • 124. Stylianopoulos T, Wong C, Bawendi MG, Jain RK, Fukumura D. Multistage nanoparticles for improved delivery into tumor tissue. Methods Enzymol. 508, 109–130 (2012).
    • 125. Pardridge WM. The blood–brain barrier: bottleneck in brain drug development. NeuroRx. 2(1), 3–14 (2005).
    • 126. Kreuter J. Mechanism of polymeric nanoparticle-based drug transport across the blood–brain barrier (BBB). J. Microencapsul. 30(1), 49–54 (2013).
    • 127. Michaelis K, Hoffmann M, Dreis S et al. Covalent linkage of apolipoprotein e to albumin nanoparticles strongly enhances drug transport into the brain. J. Pharmacol. Exp. Ther. 17(3), 1246–1253 (2006).
    • 128. Ulbrich K, Hekmatara T, Herbert E, Kreuter J. Transferrin- and transferrin-receptor-antibody-modified nanoparticles enable drug delivery across the blood–brain barrier (BBB). Eur. J. Pharm. Biopharm. 71(2), 251–256 (2009).
    • 129. Hu K, Li J, Shen Y et al. Lactoferrin-conjugated PEG–PLA nanoparticles with improved brain delivery: in vitro and in vivo evaluations. J. Control Release 134(1), 55–61 (2009).
    • 130. Kim HR, Gil S, Andrieux K et al. Low-density lipoprotein receptor-mediated endocytosis of PEGylated nanoparticles in rat brain endothelial cells. Cell. Mol. Life Sci. 64(3), 356–364 (2007).
    • 131. Lockman PR, Koziara JM, Mumper RJ, Allen DD. Nanoparticle surface charges alter blood–brain barrier integrity and permeability. J. Drug Target. 12(9–10), 635–641 (2004).
    • 132. Sharma HS, Sharma A. Neurotoxicity of engineered nanoparticles from metals. CNS Neurol. Disord. Drug Targets 11(1), 65–80 (2012).
    • 133. Xue Y, Wu J, Sun J. Four types of inorganic nanoparticles stimulate the inflammatory reaction in brain microglia and damage neurons in vitro. Toxicol. Lett. 214(2), 91–98 (2012).
    • 134. Cho CF. The blood–brain barrier: brain cancer therapy hits a wall. Oncol. Times 40, 1–6 (2018).
    • 135. Teleanu DM, Negut I, Grumezescu V, Grumezescu AM, Teleanu RI. Nanomaterials for drug delivery to the central nervous system. Nanomaterials 9(3), 2–18 (2019).
    • 136. Shilo M, Sharon A, Baranes K, Motiei M, Lellouche JP, Popovtzer R. The effect of nanoparticle size on the probability to cross the blood–brain barrier: an in vitro endothelial cell model. J. Nanobiotechnol. 13(19), 2–7 (2015).
    • 137. Blanco E, Shen H, Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat. Biotechnol. 33(9), 941–951 (2015).
    • 138. Chauhan VP, Stylianopoulos T, Martin JD et al. Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner. Nat. Nanotechnol. 7(6), 383–388 (2012).
    • 139. Matsumoto Y, Nichols JW, Toh K et al. Vascular bursts enhance permeability of tumour blood vessels and improve nanoparticle delivery. Nat Nanotechnol. 11(6), 533–538 (2016).
    • 140. Ko YJ, Kim WJ, Kim K, Kwon IC. Advances in the strategies for designing receptor-targeted molecular imaging probes for cancer research. J. Control. Release 305, 1–17 (2019).
    • 141. Rosenblum D, Joshi N, Tao W, Karp JM, Peer D. Progress and challenges towards targeted delivery of cancer therapeutics. Nat. Commun. 9, 1410 (2018).
    • 142. Sriraman SK, Aryasomayajula B, Torchilin VP. Barriers to drug delivery in solid tumors. Tissue Barriers 2, e29528 (2014).
    • 143. Zhang YR, Lin R, Li HJ, He WL, Du JZ, Wang J. Strategies to improve tumor penetration of nanomedicines through nanoparticle design. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 11(1), e1519 (2019).
    • 144. Harshita Barkat, Rizwanullah MA M et al. Paclitaxel-loaded nanolipidic carriers with improved oral bioavailability and anticancer activity against human liver carcinoma. AAPS PharmSciTech. 20(2), 87 (2019).
    • 145. Rathore B, Sunwoo K, Jangili P et al. Nanomaterial designing strategies related to cell lysosome and their biomedical applications: a review. Biomaterials 211, 25–47 (2019).
    • 146. Fortuni B, Inose T, Ricci M et al. Polymeric engineering of nanoparticles for highly efficient multifunctional drug delivery systems. Sci. Rep. 9(1), 2666 (2019). • Provides an overview on nanoparticles (NPs)-associated proton sponge effect and lysosomal/endosomal escape.
    • 147. Qiu L, Zhu M, Gong K et al. pH-triggered degradable polymeric micelles for targeted anti-tumor drug delivery. Mater. Sci. Eng. C Mater. Biol. Appl. 78, 912–922 (2017).
    • 148. Smita SA, Selby LI, Johnston A, Such GK. The endosomal escape of nanoparticles: towards more efficient cellular delivery. Bioconjugate Chem. 30(2), 263–272 (2019).
    • 149. Barar J, Omidi Y. Dysregulated pH in tumor microenvironment checkmates cancer therapy. BioImpacts 3, 149–162 (2013).
    • 150. Akinc A, Thomas M, Klibanov AM, Langer R. Exploring polyethylenimine-mediated DNA transfection and the proton sponge hypothesis. J. Gene Med. 7, 657–663 (2005).
    • 151. Benjaminsen RV, Mattebjerg MA, Henriksen JR, Moghimi SM, Andresen TL. The possible ‘proton sponge’ effect of polyethylenimine (PEI) does not include change in lysosomal pH. Mol. Ther. 21, 149–157 (2013).
    • 152. Godbey WT, Barry MA, Saggau P, Wu KK, Mikos AG. Poly(ethylenimine)-mediated transfection: a new paradigm for gene delivery. J. Biomed. Mater. Res. 51, 321–328 (2000).
    • 153. Saadat M, Zahednezhad F, Zakeri-Milani P, Heidari HR, Shahbazi-Mojarrad J, Valizadeh H. Drug targeting strategies based on charge dependent uptake of nanoparticles into cancer cells. J. Pharm. Pharm. Sci. 22, 191–220 (2019).