1521-0103/388/1/54-66$35.00 dr doi.org/10.11245pet. 123.

001690
THE JoURNAL. OF PHARMACOLOGY AND EXPERMENTAL. THERAPEUTICS J Pharmacol Exp Ther 388:54-66, January 2024
Copyright© 2023 by The American Society for Pharmacalogy and Experimental Therapeutics

Therapeutics
Special Section on Nanotechnology-based Delivery Strategies
for Protein and Peptide Therapeutics-Minireview

Experimental
Recent Advances in Delivery of Peptide and Protein
Therapeutics to the Brain

Sanchit Arora,? Tania Bajaj,"2 Jayant Kumar, Manoj Goyal, Arti Singh, and Charan Singh
And Maa Saraswati College of Phamacy, Abohar-Sito Road, VPO Kala Tibba, Punjab, India (S.A); Department of Pharmaceutics, ISF
College of Pharmacy, Punjab, India Affiliated to I.K. Gujral Punjab Technical University, fommerly Punjab Technical University,
Punjab, India (T.B., C.S,); Department of Pharmaceutical Sciences, School of Sciences, Hermvati Nandan Bahuguna Garhwal
University (A Central University), Uttarakhand, India (J.K., M.G., C.S.); and Departrment of Pharmacology, ISF College of
PHARMACOLOGY
Phamacy, Punjab, India (A.S.)
Received January 10, 2023; accepted October 25, 2023

ABSTRACT
The classes of neurophamaceuticals known as proteins and pepti and their cariers to deliver therapeutic doses of medication into
des serve as diagnostic tools and are involved in specific communi- the brain for the treatment of various neurologic illnesses has also
cation in the peripheral and cetral nervous systems. However, due beene
to tight junctionsresemblingg epithelial cells found in the blood-brain errotectiveTherapeutic
impact in theuseabsence
of proteinsalland
of. thecepeptides has
methods.
barier (BBB) in vivo, they are typically excluded from transport from Each tactic, however, has unique drawbacks and considerations.
the blood to the brain. The drugs having molecular weight of less In this review, we discuss dfferent drug delivery methods for ther
than 400 Dalton are able to cross the BB8 via lipid-mediated free apeutic distribution of pharmaceuticals, primarily neuroproteins
diffusion. However, large molecule therapeutics are devoid of these and neuropeptides, through endothelial capillaries via blood-brain
characteristics. As an attermative, these substances may be camied barier. Finally, we have also discussed the challenges and future
via chimeric peptide drug delivery systems, and assist in transcyto- perspective of protein and peptide therapeutics delivery to the
sis through BBB with the aid of linker strategies. With their recet brain.
developments, several forms of nanoparticles, including poly (ethyl
ene glycol-polyl:-caprolactone) copohymers, nanogels, liposomes, SIGNIFICANCE STATEMENT
nanostructured lipid cariers, poly (D, L-lactide-co-gycolide) nano Very few reports on the delivery of therapeutic protein and pep
particles, chitosan, and solid lipid nanoparticles, have also been tide nanoformulations are available in the literature. Herein, we
considered for their therapeutic applications. Moreover, the neces- attempted to discuSS these nanoformulations of protein and
sity for physiologic optimization of cument drug delivery methods peptide therapeutics used to treat brain diseases.

Introduction has limited their clinical applicability (Wang et al, 2022). Due
to the lower penetration of the blood-brain barrier (BBB) by
Although the sector of peptide and protein therapeutics has lange molecule drugs such as peptide and protein
grown significantly in recent decades, their delivery to the brain
drugs in the
of brain, the discovery of innovative drugs to treat neurologic dis
orders has been slow (Pardridge, 2020). Currently, the physical
JournalThis work received no external funding. methods are used to transport the heavy molecules to bypass
k yral unjab Technical University, formerly various cell-based challenges such as the blood-brain barrier,
Pu drug transport pumps and tight endothelial junctions. However,
25.A. and T.B. contributed egually to this work.
The authors declare no conflict of interest. direct injection can overcome these challenges to deliver the
dx.doi.org/10.1124jpet.123.001690. drug to the central nervous system (CNS) (Upadhyay, 2014).
The
ABBREVIATIONS: AB, amyloid-B; AD, Alzheimer's disease; ALS, amyotrophic lateral scerosis; AMT, adsorptive-mediated transcytosis; BBB,
blood-brain barier, BSA, bovine serum albumin; CNS, central nervous system; DAL, dalargin; DGL-PLGA-angiopep/hGDNF, dendrigraft poly-L
ysine cojugated PLGA angiopep loaded human glial celline-derived neurotrophic factor, IDUA, z--iduronidase; IGF, insulin-like growth factor; IR,
insulin receptor; Lf@PEG-PCL, lactoferin loaded poly (ethylene glycol)-poly(e-caprolactone) copolymer; mAb, monoclonal antibody; MS, multi
ple sclerosis; NGF, nerve growth factor, NP, nanoparticle; PD, Parkinson's disease; PEG-PCL, poly (ethylene glycol)-poly(e-caprolactone) co
olvmer:
pol PLGA. Doly (D, L-lactide-co-glycolide) nanoparticles; HMI, :RVG29/TPP-MA-SLNS-GS, loaded
receptoredlatTo
with macrophage membrane-coated SLN and modified with the mitochondria-targeting d biee sinis alveoprmtein: SLN.
solid lipid nanoparticle; TfR, transferrin receptor; Vit D-BP-PLGA NPs, vitamin D-binding protein loaded PLGA nanoparticles.

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