Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5919_Библиотеки_им_академика_М_И_Перельмана.pdf
Drug Delivery in Rare Diseases: Orphan Drugs and Therapies 429
the intermediate branches to ensure high purity and yield
[
111, 115]. Choose a multifunctional core molecule, such as ethy-
lenediamine, and couple the intermediate branches to the core
molecule [
100, 104]. Dissolve the core molecule and intermediate
branches in a suitable solvent, such as methanol or DMSO, and stir
the reaction mixture at controlled temperatures, usually between
25 and 50 °C, for a specific period, generally 24–48 hours
116,
[
118]. Purify the resulting dendrimer using advanced techni-
ques such as HPLC or SEC to remove unreacted reagents and
by-products [114, 117].
8 Challenges in Developing Orphan Drugs
The development of orphan drugs faces numerous challenges,
primarily due to the unique nature of rare diseases and the economic considerations involved (Table 5). One of the most significant challenges is the high cost of research and development.
Developing a new drug is an expensive and lengthy process, often
exceeding a decade and costing hundreds of millions of dollars
121]. For orphan drugs, the limited patient population means
[
that the potential market is much smaller, making it difficult for
pharmaceutical companies to recoup their investments [122].
Table 5
Challenges in developing orphan drugs
Challenge Description
Small patient population Limits clinical trial size, efficacy evaluation, and recruitment
High development costs R&D expenses may not be recouped with a small patient pool
Difficulty in diagnosis Delays identification of patients and hinders trial enrolment
Regulatory uncertainty Evolving regulations and unclear pathways for orphan drug approval
Lack of expertise Limited research on rare diseases and a shortage of specialists
Manufacturing challenges Difficulties in producing drugs for small patient populations
Reimbursement issues Securing insurance coverage for high-cost orphan drugs
Intellectual property
challenges
Ethical concer
Placebo selection Difficulty finding appropriate placebos for rare disease trials
Natural history variability Understanding the disease course in a limited patient pool
Biomarker d
ns
evelopment
Balancing innovation incentives with patient access
Protecting vulnerable
Identifying
response
reliable measures for disease progression and treatment
populations during clinical trials
430 Anil Kumar et al.
Clinical trials for orphan drugs present specific difficulties.
Recruiting enough participants for statistically significant results is
challenging due to the small number of patients affected by any
given rare disease [
123]. Patients are often geographically dis-
persed, increasing the complexity and cost of conducting multicenter trials [
124]. Regulatory requirements, while providing essential
safety and efficacy standards, can also add layers of complexity and
cost to the drug development process [125]. The heterogeneity of
rare diseases further complicates orphan drug development. Many
rare diseases are genetically diverse, meaning that treatments effective for some patients may not work for others with different
genetic mutations [
126]. This variability necessitates personalized
approaches and can require the development of multiple drugs or
targeted therapies for a single disease, further increasing development costs and times [
1].
Financial incentives provided by governments, such as tax credits, grant funding, and market exclusivity, are crucial to encouraging the development of orphan drugs [
127]. However, these
incentives may not fully offset the financial risks and high costs
involved, particularly for smaller biotechnology firms with limited
resources [
128]. Furthermore, the high price of orphan drugs,
necessary to ensure return on investment, often leads to issues
with reimbursement and access, as healthcare systems may struggle
to afford these expensive treatments [
129].
Another challenge is the need for greater understanding and
awareness of rare diseases among healthcare providers and the
general public. Many rare diseases are underdiagnosed or misdiagnosed, delaying appropriate treatment and complicating the
recruitment of patients for clinical trials [
130]. Increased education
and awareness are essential to improve diagnosis rates and patient
outcomes, but achieving this requires substantial investment in
outreach and education efforts [
131].
Despite these challenges, ongoing advancements in medical
research and technology offer hope for the future of orphan drug
development. Innovations in genomics and personalized medicine,
along with improved regulatory pathways, may help overcome
some of the existing barriers [
132]. Collaborative efforts among
governments, industry, academia, and patient advocacy groups are
also cr ucial to address the multifaceted challenges and to ensure the
continued development and availability of orphan drugs for
patients in need [
133].
References
1. Institute of Medicine (2010) Rare diseases
and orphan products: accelerating research
and development. National Academies Press
2. European Medicines
cines: overview [Internet]. Amsterdam:
European Medicines Agency; [2024 Oct 26].
Agency
. Orphan medi-
3. Richter T, Nestler-Parr S, Babela R et al
(2015) Rare disease terminology and
definitions—a systematic global review:
report of the ISPOR Rare Disease Special
Interest Group. Value Health 18(6):906–914
Drug Delivery in Rare Diseases: Orphan Drugs and Therapies 431
4.
Nguengang Wakap S, Lambert DM, Olry A
et al (2020) Estimating cumulative point
prevalence of rare diseases: analysis of the
Orphanet database. Eur J Hum Genet 28:
165–173
5. World Health Organization. Rare diseases
[Inter
net]. Geneva: World Health Organiza-
tion; [2024 Oct 26].
6. EvaluatePharma. Orphan Drug
Report 2018
7. Attwood MM, Rask-Andersen M, Schio¨th
Orphan drugs and their impact on phar-
HB.
maceutical development. Trends in pharmacological sciences. 2018 Jun 1;39(6):525-35.
8. Germain DP (2010) Fabry disease. Orphanet
Rare Dis 5:30
J
9. Desnick RJ, Ioannou Y, Eng CM (2003)
y disease: α-galactosidase A
Fabr
deficiency. In: The Metabolic and Molecular
Bases of Inherited Disease
10. Eng CM, Guffon N, Wilcox WR, Germain
DP
, Lee P, Waldek S, Caplan L, Linthorst
GE, Desnick RJ. Safety and efficacy of recombinant human α-galactosidase A replacement
therapy in Fabry’s disease. New England Journal of Medicine. 2001 Jul 5;345(1):9-16.
11. Rare Disease UK. Rare reality: an insight into
patient and family experience of rare dis-
the
eases. London: Rare Disease UK; 2016.
12. Tambuyzer E, Vandendriessche B, Austin CP
et
al (2020) Therapies for rare diseases: a
patient-centric approach. Nat Rev Drug Discov 19(2):93–111
13. Haffner ME, Torrent-Farnell J, Maher PD
(2002)
Does orphan drug legislation really
answer the needs of patients? Lancet
360(9341):260–262
14. Simoens S. Pricing and reimbursement of
orphan
drugs: the need for more transparency. Orphanet journal of rare diseases. 2011
Dec;6:1-8.
15. Nathwani AC, Tuddenham EGD, Rangarajan
et al (2014) Adenovirus-associated virus
S
vector-mediated gene transfer in hemophilia
B. N Engl J Med 371(21):1994–2004
16. Mendell JR, Al-Zaidy S, Shell R et al (2017)
Single-dose
gene-replacement therapy for spinal muscular atrophy. N Engl J Med 377(18):
1713–1722
17. Lambert JM, Morris CQ (2017) Antibodydr
ug conjugates (ADCs) for personalized
treatment of solid tumors. Drugs 77(6):
753–765
18. Beck A, Goetsch L, Dumontet C et al (2017)
Strategies
and challenges for the next generation of antibody-drug conjugates. Nat Rev
Drug Discov 16(5):315–337
19. Peters C, Brown S. Antibody–drug conjugates
as novel anti-cancer chemotherapeutics.
Bioscience reports. 2015 Jul 14;35(4):
e00225.
20. Farokhzad OC, Langer R. Impact of nanotechnology
on drug delivery. ACS nano.
2009 Jan 27;3(1):16-20.
21. Sercombe L, Veerati T, Moheimani F, Wu SY,
AK, Hua S. Advances and challenges of
Sood
liposome assisted drug delivery. Frontiers in
pharmacology. 2015 Dec 1;6:286.
22. Barenholz Y (2012) Doxil
®
—the first
FDA-approved nano-drug: lessons learned. J
Control Release 160(2):117–134
23. Allen TM, Cullis PR. Liposomal drug delivery
systems:
from concept to clinical applications.
Advanced drug delivery reviews. 2013 Jan
1;65(1):36-48.
24. Mahapatro A, Singh DK. Biodegradable
nanopar
ticles are excellent vehicle for site
directed in-vivo delivery of drugs and vaccines. J Nanobiotechnol. 2011 Dec;9:1-1.
25. Majid H, Verma N, Bhandari S, Gupta S,
Nidhi.
A Systematic Review on Safety and
Efficacy of Migalastat for the treatment of
Fabry’s Disease. Expert Opinion on Pharmacotherapy. 2024 Apr 12;25(6):769-82.
26. Salvalaio M, Rigon L, Belletti D, D’Avanzo F,
Pederzoli
F, Ruozi B, Marin O, Vandelli MA,
Forni F, Scarpa M, Tomanin R. Targeted
polymeric nanoparticles for brain delivery of
high molecular weight molecules in lysosomal
storage disorders. PloS one. 2016 11(5):
e0156452.
27. Sawamoto K, A´lvarez
JV, Herren˜o AM,
Otero-Espinar FJ, Couce ML, Alme´cigaDı´az CJ, Tomatsu S. Bone-specific drug delivery for osteoporosis and rare skeletal disorders. Current osteoporosis reports. 2020 18:
515-25.
28. To´th
GD, Kopla´nyi G, Kene´z B, BaloghWeiser D. Nanoformulation of therapeutic
enzymes: A short review. Periodica Polytechnica Chemical Engineering. 2023 Sep 25;67
(4):624-35.
29. Franiak-Pietryga I, Ziemba B, Messmer B,
Skowronska-Krawczyk
D. Dendrimers as
drug nanocarriers: the future of gene therapy
and targeted therapies in cancer. Dendrimers
Fundam. Appl. 2018 Apr 25;25(7).
30. Tripathy S, Das MK. Dendrimers and their
applications
as novel drug delivery carriers.
Journal of Applied Pharmaceutical Science.
2013 Sep 30;3(9):142-9.
31. Pan P,
Yue Q, Li J, Gao M, Yang X, Ren Y,
Cheng X, Cui P, Deng Y. Smart cargo delivery
432 Anil Kumar et al.
system based on mesoporous nanoparticles
for bone disease diagnosis and treatment.
Advanced Science. 2021 Jun;8(12):2004586.
32. Pinna A, Baghbaderani MT, Herna
Naruphontjirakul P, Li S, McFarlane T,
Hachim D, Stevens MM, Porter AE, Jones
JR. Nanoceria provides antioxidant and osteogenic properties to mesoporous silica nanoparticles for osteoporosis treatment. Acta
biomaterilia. 2021
33. Saraiva C, Praca C, Ferreira R et al (2016)
Nanoparticle-mediated brain drug delivery:
overcoming blood-brain barrier challenges.
Front Neurosci 10:234
34. Wohlfart S, Gelperina S, Kreuter J. Transport
of drugs across the blood–brain barrier by
nanoparticles. Journal of controlled release.
2012 Jul 20;161(2):264-73.
35. Kong L, Qiu J, Sun W, Yang J, Shen M,
Wang L, Shi X. Multifunctional
PEI-entrapped gold nanoparticles enable efficient delivery of therapeutic siRNA into glioblastoma cells. Biomaterials science. 2017;5
(2):258-66.
36. Grafals-Ruiz N, Rios-Vicil CI, LozadaDelgado EL, Quin˜ones-Dı´az BI, NoriegaRivera RA, Martı´nez-Zayas G, SantanaRivera Y, Santiago-Sa
Vivas-Mejı
somes improve RNAi delivery for glioblastoma. International journal of nanomedicine.
2020 Apr 23:2809-28.
37. Dong Y, Siegwart DJ, Anderson DG (2019)
Strategies, design, and chemistry in siRNA
delivery systems. Adv Drug Deliv Rev 144:
133–147
38. Bangham AD (1965) Lipid bilayers and biomembranes. Annu Rev Biochem 34:753–776
39. New RRC (1990) Liposomes: a practical
approach. Oxford University Press
40. Lasic DD (1993) Liposomes: from physics to
applications. Elsevier
41. Allen TM, Cullis PR (2013) Liposomal drug
delivery systems: from concept to clinical
applications. Adv Drug Deliv Rev 65(1):
36–48
42. Torchilin VP (2005) Liposomes as pharmaceutical carriers. Nat Rev Drug Discov 4:
145–160
43. Miceli MH, Chandrasekar P. Safety and efficacy of liposomal amphotericin B for the
empirical therapy of invasive fungal infections
in immunocompromised patients. Infection
and Drug Resistance. 2012 Jan 11:9-16.
44. Vyas SP, Sihorkar V. Endogenous carriers and
ligands in non-immunogenic site-specific
´
a PE. Brain targeted gold lipo-
1;122:365-76.
´
nchez GS, Valiyeva F,
´
ndez VV,
drug delivery. Advanced drug delivery
reviews. 2000;43(2-3):101-64.
45. Gregoriadis G (2006) Liposome technology:
liposome preparation and related techniques.
CRC Press
46. Tseu GY, Kamaruzaman KA. A review of different types of liposomes and their advancements as a form of gene therapy treatment for
breast cancer. Molecules. 2023 Feb 3;28(3):
1498.
47. Kirpotin D, Drummond DC, Shao Y et al
(1997) Targeting liposomes to tumor tissues.
Cancer Res 57:1469–1475
48. Slingerland M, Guchelaar HJ, Gelderblom
H. Liposomal drug formulations in cancer
therapy: 15 years along the road. Drug discovery today. 2012 Feb 1;17(3-4):160-6.
49. Huwyler J, Wu D, Pardridge WM (1996)
Brain drug delivery by surfactant-coated liposomes. Proc Natl Acad Sci 93(24):
14164–14169
50. Zalipsky S, Mullah N, Harding JA et al (1995)
Polyethylene glycol grafting to liposomes
using reactive succinimide esters. FEBS Lett
353(1):71–74
51. Hermanson GT (2013) Bioconjugate techniques. Academic Press
52. Veronese FM, Pasut G (2005) PEGylation,
successful approach to drug delivery. Drug
Discov Today 10(21):1451–1458
53. Li Z, Shen L, Ma A, Talkington A, Li Z,
Nyborg AC, Bowers MS, LaMoreaux B,
Livingston EW, Frank JE, Yuan
H. Pegloticase co-administered with high
MW polyethylene glycol effectively reduces
PEG-immunogenicity and restores prolonged
circulation in mouse. Acta biomaterialia. 2023
Oct 15;170:250-9.
54. Konkle BA, Stasyshyn O, Chowdary P, Bevan
DH, Mant T, Shima M, Engl W, Dyck-Jones J,
Fuerlinger M, Patrone L, Ewenstein
B. Pegylated, full-length, recombinant factor
VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood, The
Journal of the American Society of Hematology. 2015 Aug 27;126(9):1078-85.
55. Gabizon A, Shmeeda H, Barenholz Y (2003)
Pharmacokinetics of pegylated liposomal
doxorubicin. Clin Pharmacokinet 42(5):
419–436
56. Northfelt DW, Dezube BJ, Thommes JA et al
(1998) Pegylated liposomal doxorubicin vs
conventional doxorubicin in Kaposi’s sarcoma. J Clin Oncol 16(7):2445–2451
57. Silverman LB, Cooper TM, Fisher BT et al
(2013) Marqibo (vincristine sulfate liposome
Drug Delivery in Rare Diseases: Orphan Drugs and Therapies 433
injection) for relapsed or refractory acute lymphoblastic leukemia. Expert Opin Orphan
Drugs 1(6):469–479
58. Mantripragada SB, Howell SB. Sustainedrelease drug delivery with DepoFoam. In: Teicher BA, editor. Drug Delivery Systems in
Cancer Therapy. Totowa, NJ: Humana Press;
2004. p. 247-62.
59. Makadia
glycolic acid (PLGA) as biodegradable controlled drug delivery carrier. Polymers 3(3):
1377–1397
60. Jain RA (2000) The manufacturing techniques of various drug-loaded biodegradable
poly(lactide-co-glycolide) (PLGA) devices.
Biomaterials 21(23):2475–2490
61. Gentile P, Chiono V, Carmagnola I, Hatton
PV. An overview of poly (lactic-co-glycolic)
acid (PLGA)-based biomaterials for bone tissue engineering. International journal of
molecular sciences. 2014 Feb 28;15(3):
3640-59.
62. Bilati U, Alle´mann E, Doelker E (2005)
Nanoprecipitation versus emulsification
methods for the encapsulation of proteins
into biodegradable nanoparticles and the
release characteristics. J Control Release 104:
169–188
63. Panyam J, Labhasetwar V (2003) Biodegradable nanoparticles for drug and gene delivery
to cells and tissue. Adv Drug Deliv Rev 55(3):
329–347
64. Danhier F, Ansorena E, Silva JM et al (2012)
PLGA-based nanoparticles: an overview of
biomedical applications. J Control Release
161(2):505–522
65. Woodruff MA, Hutmacher DW (2010) The
return of a forgotten polymer: polycaprolactone in the 21st century. Prog Polym Sci
35(10):1217–1256
66. Fessi H, Puisieux F, Devissaguet JP et al
(1989) Nanocapsule formation by interfacial
polymer deposition following solvent displacement. Int J Pharm 55(1):R1–R4
67. Quintanar-Guerrero D, Fessi H, Alle
et al (1998) Influence of stabilizing agents
and preparative variables on the formation of
poly(DL-lactic acid) nanoparticles by an
emulsification-diffusion technique. Int J
Pharm 143(1):133–141
68. Gref R, Minamitake Y, Peracchia MT,
Trubetskoy V, Torchilin V, Langer R (1994)
Biodegradable long-circulating polymeric
nanospheres. Science 263(5153):1600–1603
69. Cheng J, Teply BA, Sherifi I, Sung J,
Luther G, Gu FX, Levy-Nissenbaum E,
HK, Siegel SJ (2011) Poly lactic-co-
´
mann E
Radovic-Moreno AF, Langer R, Farokhzad
OC (2007) Formulation of functionalized
PLGA-PEG nanoparticles for in vivo targeted
drug delivery. Biomaterials 28(5):869–876
70. Kumari
SC. Biodegradable polymeric nanoparticles
based drug delivery systems. Colloids and
surfaces B: Biointerfaces.
1-8.
71. Soppimath KS, Aminabhavi TM, Kulkarni
AR, Rudzinski WE (2001) Biodegradable
polymeric nanoparticles as drug delivery
devices. J Control Release 70(1–2):1–20
72. Rinaudo M (2006) Chitin and chitosan: properties and applications. Prog Polym Sci 31(7):
603–632
73. Younes I, Rinaudo M (2015) Chitin and chitosan preparation from marine sources. Structure, properties, and applications. Mar Drugs
13(3):1133–1174
74. Dash M, Chiellini F, Ottenbrite RM, Chiellini
E (2011) Chitosan: a versatile platform for the
delivery of therapeutics. Prog Polym Sci
36(8):981–1014
75. Kumar MNVR (2000) A review of chitin and
chitosan applications. React Funct Polym
46(1):1–27
76. Berger J, Reist M, Mayer JM, Felt O, Peppas
NA, Gurny R (2004) Structure and interactions in covalently and ionically crosslinked
chitosan hydrogels for biomedical applications. Eur J Pharm Biopharm 57(1):19–34
77. Croisier F, Je´roˆme C (2013) Chitosan-based
biomaterials for tissue engineering. Eur
Polym J 49(4):780–792
78. Agnihotri SA, Mallikarjuna NN, Aminabhavi
TM (2004) Recent advances on chitosanbased micro- and nanoparticles in drug delivery. J Control Release 100(1):5–28
79. Karayianni M, Sentoukas T, Skandalis A,
Pippa N, Pispas S. Chitosan-based nanoparticles for nucleic acid delivery: technological
aspects, applications, and future perspectives.
Pharmaceutics. 2023 Jun 29;15(7):1849.
80. Mao HQ, Roy K, Troung-Le VL, Janes KA,
Lin KY, Wang Y, August JT, Leong KW
(2001) Chitosan-DNA nanoparticles as gene
carriers: synthesis, characterization, and transfection efficiency. J Control Release 70(3):
399–421
81. Huang M,
and cytotoxicity of chitosan molecules and
nanoparticles: effects of molecular weight
and degree of deacetylation. Pharm Res
21(2):344–353
A, Y
Khor E, Lim LY (2004) Uptake
adav SK, Yadav
2010 Jan
1;75(1):
434 Anil Kumar et al.
82.
Park JH, Saravanakumar G, Kim K, Kwon IC
(2010)
drugs using chitosan and its derivatives. Adv
Drug Deliv Rev 62(1):28–41
83. Grenha A, Seijo B, Remun˜a´n-Lo´pez
Microencapsulated chitosan nanoparticles for
lung protein delivery. Eur J Pharm Sci
25(4–5):427–437
84. Hu Y, Jiang X, Ding Y,
Zhang J (2002) Preparation and characterization of poly (ε-caprolactone)-poly(ethylene
glycol)-poly(ε-caprolactone) (PCL-PEGPCL) nanoparticles. J Control Release 89(3):
149–159
85. Calvo P, Remun˜an-Lo´pez
Alonso MJ. Chitosan and chitosan/ethylene
oxide-propylene oxide block copolymer
nanoparticles as novel carriers for proteins
and vaccines. Pharmaceutical research. 1997
Oct;14:1431-6.
86. Fan W, Yan W, Xu Z, Ni H. Formation mechanism
chitosan nanoparticles by ionic gelation technique. Colloids and surfaces B: Biointerfaces.
2012 Feb 1;90:21-7.
87. Mikusˇova´ V
based nanoparticles for drug delivery. International journal of molecular sciences. 2021
Sep 6;22(17):9652.
88. Mao HQ, Roy K, Troung-Le VL, Janes KA,
Lin
(2011) Chitosan-DNA nanoparticles as gene
carriers: synthesis, characterization, and transfection efficiency. J Control Release 70(3):
399–421
89. Gokce Y, Cengiz B, Yildiz N, Calimli A, Aktas
Z.
suspension: Influence on particle size. Colloids and Surfaces A: Physicochemical and
Engineering Aspects. 2014 Nov 20;462:
75-81.
90. Agarwal M, Agarwal MK, Shrivastav N,
Pandey
osan nanoparticles and their in-vitro characterization. International Journal of LifeSciences Scientific Research. 2018 Mar;4(2):
1713-20.
91. Tehrani SF, Bharadwaj P, Chain JL, Roullin
VG.
particles: How to improve their clinical translation?. Journal of Controlled Release. 2023
Aug 1;360:591-612.
92. Loh JW, Schneider J, Carter M, Saunders M,
Lim
potential for large-scale manufacture of chitosan nanoparticles. Journal of pharmaceutical
sciences. 2010 Oct 1;99(10):4326-36.
Targeted delivery of low molecular
C (2005)
Zhang L, Yang C,
C, Vila-Jato JL,
of monodisperse, low molecular weight
, Mikusˇ P. Advances in chitosan-
KY, Wang Y, August JT, Leong KW
Ultrasonication of chitosan nanoparticle
S, Das R, Gaur P. Preparation of chit-
Purification processes of polymeric nano-
LY. Spinning disc processing technology:
93. Agnihotri SA, Mallikarjuna NN, Aminabhavi
TM
(2014) Recent advances on chitosanbased micro- and nanoparticles in drug delivery. J Control Release 100(1):5–28
94. Tomalia DA, Naylor AM, Goddard WA
95. Newkome GR, Yao Z, Baker GR, Gupta VK
96. Frechet JMJ, Tomalia DA (2001) Dendrimers
97. Gillies ER, Frechet JMJ (2005) Dendrimers
98. Lee CC, MacKay JA, Frechet JMJ, Szoka FC
99. Svenson S, Tomalia DA (2005) Dendrimers in
100. Patri AK, Majoros IJ, Baker JR (2005) Den-
101. Stiriba SE, Frey H, Haag R (2002) Dendritic
102. Kojima C, Kono K, Maruyama K, Takagishi T
103. Kojima C, Kono K, Maruyama K, Takagishi T
104. Mintzer MA, Grinstaff MW (2011) Biomedi-
105. Lundin KE, Gissberg O, Smith CIE (2010)
106. Geary RS, Norris D, Yu R, Bennett CF
107. Lu QL, Yokota T, Takeda S, Garcia L,
Starburst dendrimers: molecular-level
(1990)
control of size, shape, surface chemistry,
topology, and flexibility from atoms to macroscopic matter. Angew Chem Int Ed Engl
29(2):138–175
(1991)
Micelles. Part 1. Cascade molecules: a
new approach to micelles. J Org Chem
50(11):2003–2004
other dendritic polymers. Wiley
and
and
dendritic polymers in drug delivery. Drug
Discov Today 10(1):35–43
(2005)
applications. Nat Biotechnol 23(12):
1517–1526
biomedical
field. Adv Drug Deliv Rev 57(15):2106–
dritic
drug delivery. Curr Opin Chem Biol 6(4):
466–471
polymers
potential to clinical use in diagnostics and
therapy. Angew Chem Int Ed 41(8):
1329–1334
(2000)
mers having poly(ethylene glycol) grafts and
their ability to encapsulate anticancer drugs.
Bioconjug Chem 11(6):910–915
(2000)
mine dendrimers for targeted drug delivery.
Bioconjug Chem 11(6):910–915
cal
Chem Soc Rev 40(1):173–190
Oligonucleotide
present. Hum Gene Ther 21(9):1077–1088
(2015)
and cell uptake of antisense oligonucleotides.
Adv Drug Deliv Rev 87:46–51
Muntoni F, Partridge TA (2011) Functional
Designing dendrimers for biological
applications-reflections on the
2129
polymer macromolecular carriers for
in biomedical applications: from
Synthesis of polyamidoamine dendri-
Folic acid-conjugated polyamidoa-
applications of dendrimers: a tutorial.
therapies: the past and the
Pharmacokinetics, biodistribution,
Drug Delivery in Rare Diseases: Orphan Drugs and Therapies 435
amounts of dystrophin produced by skipping
the mutated exon in the mdx dystrophic
mouse. Nat Med 9(8):1009–1014
108. Andreana I, Repellin M, Carton F, Kryza D,
Brianc¸on S, Chazaud B, Mounier R,
Arpicco S, Malatesta M, Stella B, Lollo
G. Nanomedicine for gene delivery and drug
repurposing in the treatment of muscular dystrophies. Pharmaceutics. 2021 Feb 19;13(2):
278.
109. Tambe V, Thakkar S, Raval N, Sharma D,
Kalia K, Tekade RK. Surface engineered dendrimers in siRNA delivery and gene silencing.
Current pharmaceutical design. 2017 Jun
1;23(20):2952-75.
110. Medina SH, El-Sayed ME. Dendrimers as
carriers for delivery of chemotherapeutic
agents. Chemical reviews. 2009;109(7):
3141-57.
111. Hsu JF, Chu SM, Liao CC, Wang CJ, Wang
YS, Lai MY, Wang HC, Huang HR, Tsai
MH. Nanotechnology and nanocarrier-based
drug delivery as the potential therapeutic
strategy for glioblastoma multiforme: An
update. Cancers. 2021 Jan 7;13(2):195.
112. Kojima C, Kono K, Maruyama K, Takagishi T
(2000) Synthesis of polyamidoamine dendrimers having poly(ethylene glycol) grafts and
their ability to encapsulate anticancer drugs.
Bioconjug Chem 11(6):910–917
113. Kannan RM, Nance E, Kannan S, Tomalia DA
(2014) Emerging concepts in dendrimerbased nanomedicine: from design principles
to clinical applications. J Intern Med 276(6):
579–617
114. Patri AK, Kukowska-Latallo JF, Baker JR
(2005) Targeted drug delivery with dendrimers: comparison of the release kinetics of
covalently conjugated drug and
non-covalent drug inclusion complex. Adv
Drug Deliv Rev 57(15):2203–2214
115. Sarkar A, Kaganove SN, Dvornic PR, Satoh
PS. Colorimetric biosensors based on polydiacetylene (PDA) and polyamidoamine
(PAMAM) dendrimers. Polymer News.
2005;30(12):370-7.
116. Frechet JMJ, Tomalia DA (2001) Dendrimers
and other dendritic polymers. John Wiley
& Sons
117. Tomalia DA (2005) Birth of a new macromolecular architecture: dendrimers as quantized
building blocks for nanoscale synthetic
organic chemistry. Prog Polym Sci 30(3–4):
294–324
118. Ashford MB, England RM, Akhtar
N. Highway to success—developing advanced
polymer therapeutics. Advanced Therapeutics. 2021 May;4(5):2000285.
119. Newkome GR, Moorefield CN, Vo¨gtle F,
¨
Vo
gtle F, Vo¨gtle F, Chemist G. Dendrimers
and dendrons: concepts, syntheses, applications. Weinheim: Wiley-vch; 2001.
120. Tomalia DA, Frechet JMJ (2001) Dendrimers
and other dendritic polymers. John Wiley
& Sons
121. DiMasi JA, Grabowski HG, Hansen RW
(2016) Innovation in the pharmaceutical
industry: New estimates of R&D costs. J
Health Econ 47:20–33
122. Friedmann C, Levy P, Hensel P, Hiligsmann
M. Using multi-criteria decision analysis to
appraise orphan drugs: a systematic review.
Expert Review of Pharmacoeconomics &
Outcomes Research. 2018 Mar 4;18(2):
135-46.
123. Griggs RC, Batshaw M, Dunkle M (2009)
Clinical research for rare disease: opportunities, challenges, and solutions. Mol Genet
Metab 96(1):20–26
124. Orphanet (2021) Orphanet: the portal for
rare diseases and orphan drugs
125. Haffner ME, Torrent-Farnell J, Maher PD
(2002) Does orphan drug legislation really
answer the needs of patients? Lancet
360(9331):1823–1825
126. Boycott KM, Vanstone MR, Bulman DE,
MacKenzie AE (2013) Rare-disease genetics
in the era of next-generation sequencing: discovery to translation. Nat Rev Genet 14(10):
681–691
127. U.S. Food and Drug Administration (2020)
Orphan drug designations and approvals
128. Morel T, Cano SJ (2017) Measuring what
matters to rare disease patients: reflections
on the work by the IRDiRC Taskforce on
patient-centered outcome measures. Orphanet J Rare Dis 12(1):171
129. Simoens S (2011) Pricing and reimbursement
of orphan drugs: the need for more transparency. Orphanet J Rare Dis 6:42
130. Zurynski Y, Frith K, Leonard H, Elliott E
(2017) Rare childhood diseases: how should
we respond? Arch Dis Child 102(10):
984–990
131. Ibrahim N. Navigating the Complexity of
Rare Diseases: Challenges, Innovations, and
Future Directions. Global Journal of Medical
Therapeutics. 2023;5(4).
132. Wong CH, Siah KW, Lo AW (2019) Estimation of clinical trial success rates and related
parameters. Biostatistics 20(2):273–286
133. Chirmule
Choudhury MC. Orphan drug development:
Challenges, regulation, and success stories.
Journal of biosciences. 2024 Feb 19;49(1):
30.
N, Feng H, Cyril E, Ghalsasi VV,
Chapter 19
Drug Delivery to the Immune System: Immunotherapies
and Vaccines
Santanu Pal, Dumala Naveen, Bavadharani Mani, and Reddi Lokeswari
Abstract
Traditional drug delivery methods (tablets, capsules, syrups, ointments, etc.) are not able to produce
sustained release and have low bioavailability along with changes in plasma drug level. The entire therapy
process may be pointless in the absence of an effective delivery of the system. The drug must also be
delivered at a precise target spot at a predetermined controlled pattern to achieve optimal efficacy and safety.
Many aspects of therapeutic efficacy, like pharmacokinetics, distribution, absorption into cells and metabolism, excretion and clearance, and toxicity, are impacted by the route of delivery. Both innovative delivery
systems and a greater understanding of the basic principles underlying how drug distribution influences
safety and efficacy are required as the biotechnology sector develops novel kinds of biopharmaceuticals.
Drug resistance is still an ongoing issue though, mostly owing to our incomplete knowledge of the
biological barriers that prevent many drugs from reaching their intended targets. Despite the significant
advantages of immunotherapy, off-target effects continue to cause serious adverse immune reactions.
Recently, the research and development of drug delivery systems (DDS) have gained increased attention.
Over decades of innovation, DDS has proven effective in delivering drugs with precision, thereby reducing
side effects. They also offer benefits such as flexible control over drug release, improved pharmacokinetics,
and enhanced drug distribution. Therefore, in this book chapter, a detailed overview of combining the
approach of immunotherapies and vaccines with drug delivery systems is discussed to improve the therapeutic effect.
Key words Drug delivery systems (DDS), Bioavailability, Controlled release, Pharmacokinetics,
Immunotherapy
1 Introduction
For more than 60 years, engineers, chemists, physicists, biologists,
and physicians have worked together to develop biomaterials for
use in innovative drug delivery systems. The delivery and effectiveness of many drugs, such as antibodies, peptides, vaccines, medications, and enzymes, have been enhanced by biomaterials. Drugs
can be released from biomaterials for extended periods and at
specified sites. Silicone rubber was the first biomaterial for
437
438 Santanu Pal et al.
Fig. 1 A simplified diagram showing the interconnections between the immunological responses by drug
delivery systems along with the dashed arrows indicating potential, unconfirmed routes for platelet activation.
(Created by using BIORENDER)
controlled drug release to be documented. It is used to deliver a
variety of medications, such as steroids, atropine, histamine, anesthetics, antimalarials, and anti-schistosomal medicines [
11].
Systems for targeted delivery of drugs show promise in delivering active ingredients to specific tissues or cell populations. As a
result, drug concentrations that are elevated locally can be achieved,
leading to increased efficacy. Because innocent bystander cells are
less impacted, the negative consequences should be reduced. Targeting certain cell subsets or tissues has the potential to significantly
improve treatments. Targeting APCs is particularly interesting for
APCs are
therapeutically modulating immune responses (Fig.
1).
made up of tissue-resident macrophage subsets, circulating monocytes, and recirculating and tissue-resident dendritic cell subsets.
The most straightforward method of targeting a particular APC
subgroup would be to coat nanocarriers with antibodies that bind
cell type-specific surface receptors. Heat-shock proteins are the
basis of another APC-targeting strategy [
33]. This method results
in antigen-specific T-cell priming and peptide presentation that is
major histocompatibility complex (MHC)-restricted. Further, antiTLR antibody-decorated nanocarriers are capable of selectively
targeting individual APC subsets. In this manner, it has been
demonstrated that TLR-directed targeting can transport antigenic