Stimuli-responsive nanoparticles with multiple therapeutic/diagnostic functions are highly desirable for effective tumor treatment. Herein novel caspase-3 responsive functionalized upconversion nanoparticles (CFUNs) were fabricated with three-in-one functional integration: near-infrared (NIR) triggered photodynamic damage along with caspase-3 activation, subsequent caspase-3 responsive drug release, and cascade chemotherapeutic activation. CFUNs were formulated from the self-assembly of caspase-3 responsive doxorubicin (DOX) prodrug tethered with DEVD peptide (DEVD-DOX), upconversion nanoparticles (UCNP), a photosensitizer (pyropheophorbide-a methyl ester, MPPa), and tumor-targeting cRGD-PEG-DSPE to afford multifunctional CFUNs, MPPa/UCNP-DEVD-DOX/cRGD. Upon cellular uptake and NIR irradiation, the visible light emission of UCNP could excite MPPa to produce reactive oxygen species for photodynamic therapy (PDT) along with the activation of caspase-3, which further cleaved DEVD peptide to release DOX within tumor cells, thus accomplishing NIR-triggered PDT and cascade chemotherapy. CFUNs presented silent therapeutic potency and negligible cytotoxicity in the dark, whereas in vitro and in vivo experiments demonstrated the NIR-triggered cascade therapeutic activation and tumor inhibition due to consecutive PDT and chemotherapy. Current NIR-activated cascade tumor therapy with two distinct mechanisms is significantly favorable to overcome multidrug resistance and tumor heterogeneity for persistent tumor treatment.
Sikai Deng,Weiwei Li,Qiyu Chen,Jianqun Shao,Junbo Zhang,Yuji Wang,Yinghuan Li
The mucus layer and intestine epithelium pose challenges to the bioavailability of orally administered paclitaxel (PTX). A novel P-glycoprotein inhibitor, (S)-2-decanoylamino-3-(1-naphthyl)propionyl-leucyl-valine (PgpI), was synthesized in this study. Its structure was characterized using 1 H NMR, 13 C NMR, ESI-MS and IR spectroscopies. The efficacy and in vivo toxicity of PgpI were comprehensively evaluated by R8-PEG@PLs&PgpI, i.e. , the oral combination of PgpI and octaarginine R8-PEG-DSPE modified PTX liposomes (R8-PEG@PLs), for lung cancer treatment. The joint forms between PgpI and R8-PEG@PLs were investigated and the affinity of PgpI for intestinal P-glycoprotein remained unaffected when combined externally with R8-PEG@PLs (R8-PEG@PLs&PgpI), compared to the diminished affinity for internal combination. The primary endocytic pathway for R8-PEG@PLs&PgpI in Caco-2 cells was the lipid raft, with increased percentage of macropinocytosis compared to unmodified PTX liposomes (PLs). The established physiology-based cellular kinetic models revealed that the net internalization rate of PTX was 2.3 times higher in R8-PEG@PLs&PgpI than in PLs, correlating with in vivo 2.2 times of antitumor rate. R8-PEG@PLs&PgpI may address the deficits of PLs in human lung A549 tumor-bearing mice due to the lower drug concentration than in normal mice. The external combination of R8-PEG@PLs&PgpI, offering maximal efficacy and security of PgpI, is promising for oral PTX delivery.
Glioblastoma (GBM) is the most lethal primary intracranial tumor because of its high invasiveness and recurrence. Therefore, nanocarriers with blood–brain barrier (BBB) penetration and transcranial-controlled drug release and activation are rather attractive options for glioblastoma treatment. Herein, we designed a multifunctional nanocarrier (T-TKNPVP) that combined targeted X-ray-induced photodynamic therapy (X-PDT) and cascaded reactive oxygen species (ROS)-boosted chemotherapy. The T-TKNPVP loaded with verteporfin (VP) and paclitaxel (PTX) was self-assembled from an angiopep-2 (Ang) peptide, functionalized Ang-PEG-DSPE and ROS-sensitive PEG-TK-PTX conjugate. After systemic injection, the T-TKNPVP efficiently crossed the BBB and targeted the GBM cells via receptor-mediated transcytosis. Upon X-ray irradiation, they can generate a certain amount of ROS, which not only induces X-PDT but also locoregionally activates PTX release and action by cleaving the TK bridged bonds. As evidenced by 9.4 T MRI and other experiments, such nanocarriers offer significant growth inhibition of GBM in situ and prolong the survival times of U87-MG tumor-bearing mice. Taken together, the designed T-TKNPVP provided an alternative avenue for realizing transcranial X-PDT and X-ray-activated chemotherapy for targeted and locoregional GBM treatment in vivo.
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