To overcome the limitation
of conventional nanodrugs in tumor targeting
efficiency, coupling targeting ligands to polymeric nanoparticles
can enhance the specific binding of nanodrugs to tumors. Cyclo(Arg-Gly-Asp-
d
-Phe-Lys) (abbreviated as c(RGDfK)) peptide has been widely
adopted due to its high affinity to the tumor marker α
v
β
3
integrin receptor. In this study, we develop
a cRGD peptide-conjugated camptothecin (CPT) prodrug, which enables
self-assembly of nanoparticles for precise targeting and enrichment
in tumor tissue. We first synthesized a camptothecin derivative (CPT-
ss
-N
3
) with a reduction-sensitive bond and simultaneously
modified PEG to obtain cRGD-PEG-N
3
. After ring-opening
polymerization of the 2-(but-3-yn-1-yolxy)-2-oxo-1,3,2-dioxaphospholane
(BYP), an amphiphilic polymeric prodrug, referred to as cRGD-PEG-
g
-(PBYP-
ss
-CPT), was obtained via copper-catalyzed
azide–alkyne cycloaddition (CuAAC) reaction. The self-assembly
in buffer solution of the cRGD-functional prodrug was studied through
DLS and TEM. The
in vitro
drug release behavior of
cRGD-PEG-
g
-(PBYP-
ss
-CPT) nanoparticles
was investigated. The results show that the nanoparticles are reduction-responsive
and the bonded CPT can be released. Endocytosis and MTT assays demonstrate
that the cRGD-conjugated prodrug has better affinity for tumor cells,
accumulates more intracellularly, and is therefore, more effective.
The
in vivo
drug metabolism studies show that nanoparticles
greatly prolong the retention time in circulation. By monitoring drug
distribution in tumor and in various tissues, we find that free CPT
can be rapidly metabolized, resulting in low accumulation in all tissues.
However, cRGD-PEG-
g
-(PBYP-
ss
-CPT)
nanoparticles accumulate in tumor tissues in higher amounts than PEG-
g
-(PBYP-
ss
-CPT) nanoparticles, except for
the inevitable capture by the liver. This indicates that the nanomedicine
with cRGD has a certain targeting property, which can improve drug
delivery efficiency.