Photo-mediated Polyphosphoester-based Nanoscale Delivery Systems For Cancer Therapy

It was proved that responsive drug delivery systems based on endogenous or external stimulus conditions were able to regulate the properties of drug carriers in vivo,overcome multiple delivery obstacles,improve the bioavailability and antitumor effect of drugs.Specifically,near-infrared light?NIR?has an effective penetration depth and less light scattering in biological tissues,and can be spatially and temporally controlled;thus,NIR-sensitive nanomaterials are of particular interest in the delivery active substances.In this article,we developed two NIR-regulated polymer nanocarriers for enhancing antitumor effect by regulating the target groups and scales,respectively.?1?Nanocarriers modified with cell penetrating?e.g.TAT?peptides possess the ability to quickly translocate into almost any live cells.However,nonspecific binding of peptide to nontumor cells is one of the biggest challenges,which causes nonspecifc uptake of nanocarriers by nontumor cells.Therefore,we designed a polymeric mixed micelles ^STAT-NP_IR&DOX with photoswitchable ultrafast TAT targeting effect.The hydrophilic shell of ^STAT-NP_IR&DOX consists of a TAT-functionalized short-chain poly?ethylene glycol??TAT-PEG?and a thermoresponsive long-chain polyphosphoester?PPE?.In the process of blood circulation,TAT peptide of ^STAT-NP_IR&DOX is masked by the long-chain PPE to avoid the interaction of TAT with proteins and normal cells.Upon near-infrared?NIR?photoactivation,the TAT peptide is ultrafastly reexposed?within 60 s?via the collapse of thermoresponsive PPE,resulting in signifcantly enhanced cellular uptake of nanocarrier by tumor cells and superior anticancer efficacy.?2?Tumor-related macrophages?TAMs?are a promising therapeutic target for tumor immunotherapy,and chemoimmunotherapy is considered to be one ideal tumor therapy model.However,nanocarriers are unable to achieve specific drug delivery due to the different spatial distribution of tumor cells and TAMs.Thus,we explored a light-triggered shrinkable nanoparticles ^SNP/Pt with deep tumor penetration capability for simultaneously depleting TAMs and tumor cells.The nanoparticles possessed a hydrophobic platinum?Pt?prodrug conjugated polyphosphoester?PPE/Pt?inner core co-encapsulated chlorin e6?Ce6,photosensitizer agent?,BLZ-945?a small molecule inhibitor of CSF-1R signal pathway of TAMs?and TK-PPE?a reactive oxygen species?ROS?-sensitive polymer?,while its hydrophilic outer shell consists of poly?ethylene glycol??PEG?.Upon 660 nm laser irradiation,ROS producted by Ce6 promoted the TK linker breaking,induced the BLZ-945 release for TAMs depletion;meanwhile,nanoparticle size shrinkage from?70 nm to?20 nm and platinum?Pt?prodrug was delivered to the deep tumor by the small-sized particles with the ability of deep penetration to enhance the chemotherapy.The strategy for spatiotemporal targeting of TAMs and tumor cells showed enhanced cancer chemoimmunotherapy,achieved superior anti-tumor effect and tumor metastasis inhibition effect.The survival period of tumor bearing mice were also significantly prolonged.