In recent years, much progress has been motivated in stimuli-responsive nanocarriers, which could response to the intrinsic physicochemical and pathological factors in diseased regions to increase the specificity of drug delivery. Currently, numerous nanocarriers have been engineered with physicochemical changes in responding to external stimuli, such as ultrasound, thermal, light and magnetic field, as well as internal stimuli, including pH, redox potential, hypoxia and enzyme, etc. Nanocarriers could respond to stimuli in tumor microenvironments or inside cancer cells for on-demanded drug delivery and accumulation, controlled drug release, activation of bioactive compounds, probes and targeting ligands, as well as size, charge and conformation conversion, etc., leading to sensing and signaling, overcoming multidrug resistance, accurate diagnosis and precision therapy. This review has summarized the general strategies of developing stimuli-responsive nanocarriers and recent advances, presented their applications in drug delivery, tumor imaging, therapy and theranostics, illustrated the progress of clinical translation and made prospects.

Stimuli-responsive nanocarriers for drug delivery, tumor imaging, therapy and theranostics.

Glutathione responsive polymers and their application in drug delivery systems

Activation of photosensitizers (PSs) in targeted lesion and minimization of reactive oxygen species (ROS) depletion by endogenous antioxidants constitute promising approaches to perform highly effective image-guided photodynamic therapy (PDT) with minimal non-specific phototoxicity. Traditional strategies to fabricate controllable PS platforms rely on molecular design, which requires specific modification of each PS before PDT. Therefore, construction of a general tumor-responsive PDT platform with minimum ROS loss from endogenous antioxidant, typically glutathione (GSH), is highly desirable. Herein, MOF-199, a Cu(II) carboxylate-based metal-organic framework (MOF), is selected to serve as an inert carrier to load PSs with prohibited photosensitization during delivery. After cellular uptake, Cu (II) in the MOFs effectively scavenges endogenous GSH, concomitantly induces decomposition of MOF-199 to release the encapsulated PSs, and recovers their ROS generation. In vitro and in vivo experiments demonstrate highly effective cancer cell ablation and anticancer PDT with diminished normal cell phototoxicity. This strategy is generally applicable to PSs with both aggregation-induced emission and aggregation-caused quenching to implement activatable and enhanced image-guided PDT.

Cancer-Cell-Activated Photodynamic Therapy Assisted by Cu(II)-Based Metal-Organic Framework.

Therapeutic systems with site-specific pharmaceutical activation hold great promise to enhance therapeutic efficacy while reducing systemic toxicity in cancer therapy. With operational flexibility, noninvasiveness, and high spatiotemporal resolution, photoactivatable nanomedicines have drawn growing attention. Distinct from traditional controlled release systems relying on the difference of biomarker concentrations between disease and healthy tissues, photoactivatable nanomedicines capitalize on the interaction between nanotransducers and light to either trigger photochemical reactions or generate reactive oxygen species (ROS) or heat effect to remotely induce pharmaceutical actions in living subjects. Herein, the recent advances in the development of photoactivatable protherapeutic nanoagents for oncology are summarized. The design strategies and therapeutic applications of these nanoagents are described. Representative examples of each type are discussed in terms of structure, photoactivation mechanism, and preclinical models. Last, potential challenges and perspectives to further develop photoactivatable protherapeutic nanoagents in cancer nanomedicine are discussed.

Photoactivatable Protherapeutic Nanomedicine for Cancer

Recent advances of two-dimensional materials in smart drug delivery nano-systems.

Nanocarrier-mediated photodynamic therapy (PDT), which involves the systemic delivery of photosensitizers (PSs) into tumor tissue and tumor cells, has emerged as an attractive treatment for cancer. However, insufficient PS release limits intracellular cytotoxic reactive oxygen species (ROS) generation, which has become a major obstacle to improving the PDT therapeutic efficacy. Herein, a novel hyperbranched polyphosphoester (hbPPE) containing numerous acetal bonds (S-hbPPE/Ce6) was explored as a chlorin e6 (Ce6) nanocarrier for PDT. S-hbPPE/Ce6 with a branched topological structure efficiently encapsulated Ce6 and then significantly enhanced its internalization by tumor cells. Subsequently, the endo-/lysosomal acid microenvironment rapidly cleaved the acetal linkage of S-hbPPE and destroyed the nanostructure of S-hbPPE/Ce6, resulting in increased Ce6 release and obviously elevated the intracellular ROS generation under illumination. Therefore, treatment with S-hbPPE/Ce6 noticeably enhanced the PDT therape...

Acetal-Linked Hyperbranched Polyphosphoester Nanocarriers Loaded with Chlorin e6 for pH-Activatable Photodynamic Therapy.

Rationale: PEGylation of nanocarriers could extend blood circulation time and enhance tumor accumulation via the enhanced permeability and retention (EPR) effect. Unfortunately, the PEG moiety suppresses tumor cell internalization of nanocarriers, resulting in limited therapeutic efficiency (known as the PEG dilemma). Designing stimuli-responsive shell-detachable nanocarriers, which could detach the PEG corona from the nanocarriers in desired tumor tissues in response to the local environment, is an appealing approach to overcome the PEG dilemma, but nanocarrier applications are also limited by a lack of universal stimuli for PEG detachment. Methods: In this study, we synthesized red light-responsive, amphiphilic mPEG bridged to the photosensitizer Ce6 via a thioketal (TK) bond (mPEG-TK-Ce6), which was then used to achieve the PEGylation of polylactide (PLA)-based nanoparticles encapsulating the Pt(IV) prodrug. The therapeutic efficacy of the prepared nanoparticles was evaluated in vitro and in vivo. Results: We demonstrated that the amphiphilic mPEG-TK-Ce6 can realize the PEGylation of Pt(IV) prodrug-loaded PLA nanoparticles and consequently enhanced nanoparticle accumulation in tumor tissues. When the tumor tissues were subjected to 660 nm irradiation, reactive oxygen species (ROS) generated by Ce6 induced the rapid degradation of the adjacent TK bond, resulting in PEG detachment and enhanced tumor cell internalization. Therefore, mPEG-TK-Ce6 facilely achieved PEGylation and light-responsive dePEGylation of the nanocarrier for enhanced antitumor efficacy in nanomedicine. Conclusion: Such red light-responsive amphiphilic mPEG-TK-Ce6 facilely achieved PEGylation and dePEGylation of the nanocarrier, providing a facile strategy to overcome PEG dilemma.

On-demand PEGylation and dePEGylation of PLA-based nanocarriers via amphiphilic mPEG-TK-Ce6 for nanoenabled cancer chemotherapy.

Redox-responsive polymers exhibit great potential as drug delivery systems. Herein, a redox-responsive PEGylated hyperbranched polyphosphoester (PPE) was synthesized through (A2 + B3) type polycondensation. The obtained hyperbranched PPE can self-assemble into nanoparticles in water. The biocompatibility of the nanoparticles was evaluated. The hydrophobic chemotherapy drug doxorubicin (DOX) can be efficiently encapsulated into the obtained nanoparticles. Such DOX-loaded nanoparticles exhibited excellent stability due to the PEGylation, and showed redox-responsive drug release behavior. In addition, flow cytometric analyses demonstrated that the redox-responsive nanoparticles could be efficiently internalized into the human breast cancer cell line MDA-MB-231, and intracellular glutathione enhanced the intracellular drug release from the redox-responsive hyperbranched PPE based nanoparticles. Therefore, such nanoparticles resulted in the enhanced inhibition of tumor cell growth, suggesting the potential of redox-responsive PEGylated hyperbranched PPE in anticancer drug delivery.

Chao Chen

Papers

Acetal-Linked Hyperbranched Polyphosphoester Nanocarriers Loaded with Chlorin e6 for pH-Activatable Photodynamic Therapy.

On-demand PEGylation and dePEGylation of PLA-based nanocarriers via amphiphilic mPEG-TK-Ce6 for nanoenabled cancer chemotherapy.

PEGylated hyperbranched polyphosphoester based nanocarriers for redox-responsive delivery of doxorubicin