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PEGylation
The main pharmacokinetic outcomes of PEGylation include: changes occurring in overall circulation life-
[61]
span, tissue distribution pattern, and elimination pathway of the parent drug/particle . PEG mainly
protects these particles from being phagocytosed by natural particle eliminating mechanisms, mainly organs
[62]
of the RES .

Pegylated nanoparticles are characterized by hydrophilic surfaces that circumvent opsonization and decrease
[51]
their clearance by macrophage, which results in prolonged circulation . PEGylation has been shown to
[63]
alter the pharmacokinetics of doxorubicin considerably; the total clearance was significantly reduced . In
[64]
the early 1990’s, PEGylated polymeric vesicles were introduced by Yokoyama et al. , which represented an
important milestone in the synthesis of long-circulating liposomal formulations (STEALTH® liposomes).
Liposomal formulations are the first novel controllable carrier systems to be sold in the market for cancer
©
(Doxil , PEGylated liposomal formulation encapsulating doxorubicin(PLD) [65-67] . PLD showed reduced
cardiotoxicity and prolonged activity.

[68]
Anders et al. encapsulated doxorubicin in pegylated liposomes (PLD) that achieved 20 folds higher
concentration of doxorubicin within intracranial tumors compared to non-liposomal doxorubicin, whose
distribution was compromised by BBTB. Moreover, co-administration of PLD and BBB permeable ABT-
888, an inhibitor of a poly (ADP-ribose) polymerase, showed better survival as compared to non-liposomal
doxorubicin and ABT-888.

TM
Nektar Therapeutics has several patents on PEGylation bioconjugation aiming to modify the
[76]
pharmacokinetic profile [69-75] . Adkins et al. formulated NKTR-102, an Irinotecan-PEG conjugate linked
with a hydrolysable ester bond, whose polymer moiety resulted in prolonged circulation and subsequently
increased tumor localization. The innovative nature of this PEGylated system is the adoption of the three-
dimensional (3D) branching technology in the PEGylation to provide superior pharmacokinetics and
pharmacokinetic parameters. The 3D propriety Nektar PEG technology offers weeks of half-lives compared
[76]
to days in conventional PEG . The preferential accumulation of NKTR-102 within brain metastases via
EPR, its reduced clearance and ability to escape P-glycoprotein mediated efflux resulted in continuous
release of the active metabolite SN38 and better therapeutic efficacy.

TM
Nektar Therapeutics is not the only pharmaceutical company relying on innovative PEGylation
technologies for passively targeting brain metastases of breast cancer. Other companies, such as 2-BBB,
is investing heavily on the use of PEGylation bioconjugated with liposomal vesicular carrier systems to
[77]
passively target brain metastases of breast cancer . BBB adopts a propriety G-Technology® for targeting
the brain. 2-BBB’s G-Technology® empowers sustained delivery of systemically administered therapeutics to
the brain with high safety and efficacy profiles. The G-Technology® uses PEG and glutathione bioconjugated
to active pharmaceutical ingredients loaded liposomal vesicular structures. Polyethylene glycol (PEG) is
attached to the liposomes to provide a prolonged circulation time in the blood stream with sustained half-
life pharmacokinetic profile. Glutathione is bioconjugated to the PEG molecules to offer targeted safe and
[78]
effective delivery of the therapeutics across the BBB .

2-BBB has adopted its G-Technology® in developing two lead clinical programs targeting multiple indications
of brain cancers and neuroinflammatory diseases. 2-BBB’s lead product 2B3-101 (glutathione PEGylated
liposomal doxorubicin) combines the G-Technology® with the existing chemotherapeutic agent doxorubicin
for the possible treatment of brain metastases and glioma. It has completed a Phase I/IIa trial treating
patients with various forms of brain cancer. 2-BBB’s second promising lead product is 2B3-102. 2B3-102 is
a glutathione PEGylated liposomal methylprednisolone. It applies the anti-inflammatory glucocorticoid
methylprednisolone to combat acute and chronic neuro-inflammation associated with several CNS