5-Aminolevulinic acid (ALA), the precursor of photosensitizer protoporphyrin IX (PpIX), is a U.S. FDA-approved photodynamic therapeutic agent. However, realizing efficient delivery of ALA is still a big challenge as it is hydrophilic and cannot be recognized and selectively accumulated in tumor cells. In this study, matrix metalloproteinase-2 (MMP-2) and pH dual-sensitive ALA prodrug nanocarriers were constructed as a programmed delivery strategy for the targeted delivery of ALA. The nanocarriers were prepared by the co-modification of gold nanoparticles (AuNPs) with hydrazone-linked ALA and MMP-2-activatable cell-penetrating peptides (CPPs). Cationic CPP RRRRRRRR (R8) was shielded by zwitterionic stealth peptide EKEKEKEKEKEKEKEKEKEK (EK10) via MMP-2 substrate peptide PLGLAG. The zwitterionic stealth peptide EK10 is designed to endow ALA prodrug nanocarriers with strong antifouling ability and prolonged circulation time. Upon arriving at the tumor tissue, the shielded cationic CPP R8 can be activated by tumor-microenvironment-overexpressed MMP-2, which enabled enhanced cellular uptake of ALA. The results of drug loading and release, cellular uptake, PpIX generation and accumulation, photodynamic cytotoxicity, and photodynamic tumor inhibition demonstrated that such tumor-microenvironment-sensitive ALA prodrug nanocarriers could be considered as potential candidates for targeted photodynamic cancer therapy.Keywords: 5-aminolevulinic acid; enzyme; photodynamic cancer therapy; prodrug nanocarriers; programmed targeting;

5-Aminolevulinic acid (ALA) is a FDA-approved photodynamic therapy (PDT) precursor of protoporphyrin IX (PpIX) used for treating various cancers. However, the internalization of ALA is a big challenge due to its hydrophilic nature and low specificity to cancer cells. In this work, ALA conjugated prodrug nanoparticles were prepared by conjugation of thiolated stealth peptide sequence CPPPPEKEKEKEKEKEDGR and hydrazone-containing ALA to gold nanoparticles (AuNPs). Remarkable anti-fouling ability of ALA prodrug nanoparticles in complex environment was achieved owing to the zwitterionic stealth peptide sequence EKEKEKEKEK. The release of ALA could be greatly accelerated upon incubation of ALA prodrug nanoparticles in lysosomal/endosomal pH (pH 5.5). Meanwhile, the cellular internalization could be greatly enhanced by RGD moieties. MTT results demonstrated that ALA prodrug nanoparticles exhibited better photodynamic cytotoxicity than free ALA after light irradiation, suggesting enhanced photodynamic therapeutic efficacy.

Dual enzymatic reactions were introduced to fabricate programmed gemcitabine (GEM) nanovectors for targeted pancreatic cancer therapy. Dual-enzyme-sensitive GEM nanovectors were prepared by conjugation of matrix metalloproteinase-9 (MMP-9) detachable poly(ethylene glycol) (PEG), cathepsin B-cleavable GEM, and targeting ligand CycloRGD to CdSe/ZnS quantum dots (QDs). The GEM nanovectors decorated with a PEG corona could avoid nonspecific interactions and exhibit prolonged blood circulation time. After GEM nanovectors were accumulated in tumor tissue by the enhanced permeability and retention (EPR) effect, the PEG corona can be removed by overexpressed MMP-9 in tumor tissue and RGD would be exposed, which was capable of facilitating cellular internalization. Once internalized into pancreatic cancer cells, the elevated lysosomal cathepsin B could further promote the release of GEM. By employing dual enzymatic reactions, the GEM nanovectors could achieve prolonged circulation time while maintaining enhanced cellular internalization and effective drug release. The proposed mechanism of the dual enzymatic reaction-assisted GEM delivery system was fully investigated both in vitro and in vivo. Meanwhile, compared to free GEM, the deamination of GEM nanovectors into inactive 2′,2′-difluorodeoxyuridine (dFdU) could be greatly suppressed, while the concentration of the activated form of GEM (gemcitabine triphosphate, dFdCTP) was significantly increased in tumor tissue, thus exhibiting superior tumor inhibition activity with minimal side effects.Keywords: enzyme sensitive; gemcitabine; pancreatic cancer therapy; programmed targeting; tumor microenvironment;

A targeted cathepsin B-activatable gemcitabine prodrug with caspase-3 specific light-up tetraphenylene (TPE) as an apoptotic probe based on aggregation-induced emission (AIE) properties was designed for in situ self-therapeutic monitoring of pancreatic cancer cells.

Development of gemcitabine (GEM) nanocarriers as theranostic agents for pancreatic cancer chemotherapy has received extensive attention in recent years. A novel enzyme-sensitive albumin-based GEM delivery nanoplatform was developed in this research by simple conjugation of GEM to human serum albumin (HSA) via cathepsin B cleavable peptide GFLG and then complexing with near-infrared (NIR) dye IR780, forming a HSA-GEM/IR780 complex. The successful preparation of HSA-GEM/IR780 complex was confirmed by Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS), UV–vis–NIR absorption spectra and fluorescent emission spectra. The in vivo performance of HSA-GEM/IR780 complex was carried out on BxPC-3 pancreatic tumor xenografted mice. As revealed by in vivo NIR imaging, HSA-GEM/IR780 exhibited enhanced accumulation and long-term retention in tumor tissues compared to free IR780. Meanwhile, compared to free GEM, the deamination of GEM nanovectors into inactive 2′,2′-difluorodeoxyuridine (dFdU) can be greatly suppressed, while the concentration of the activated form of GEM (gemcitabine triphosphate, dFdCTP) was significantly increased in tumor tissue, thus exhibiting superior tumor inhibition activity with minimal side effects.Download high-res image (196KB)Download full-size image

In the present study, we have successfully fabricated a biocompatible polyamino acid-based nanocarrier with reduction-sensitivity and targeting ability for gemcitabine (GEM) delivery. GEM-conjugated polyamino acid biotin-poly(ethylene glycol)-block-poly[(L-lysine-co-L-leucine)-graft-(GEM-co-rhodamine B)] (Biotin-PEG-b-P[(Lys-co-Leu)-graft-(GEM-co-Rho B)]) was synthesized by ring-opening copolymerization of L-lysine-N-carboxyanhydride (Lys-NCA) and L-leucine-N-carboxyanhydride (Leu-NCA) using biotin-poly(ethylene glycol)-amine (Biotin-PEG-NH2) as an initiator, and then disulfide linked GEM derivatives (HSEA-GEM) and Rhodamine B isothiocyanate (Rho B) were grafted onto polyamino acids. The obtained GEM-conjugated polyamino acids could self-assemble into nano-sized micelles in aqueous solution with a uniform spherical shape. The GEM nanocarriers showed reduction-sensitive drug release. Cell culture demonstrated that the polyamino acid itself showed excellent biocompatibility but high cytotoxicity when conjugated with GEM. What's more, the biotin-conjugated polyamino acid-based micelles could induce a remarkably higher internalization via receptor mediated endocytosis than non-biotin micelles. Hence, such biocompatible GEM-conjugated polyamino acids might provide a potential strategy for cancer therapy.

A biodegradable and reduction-cleavable gemcitabine (GEM) polymeric prodrug with in vivo near-infrared (NIR) imaging ability was reported. This theranostic GEM prodrug PEG-b-[PLA-co-PMAC-graft-(IR820-co-GEM)] was synthesized by ring-opening polymerization and “click” reaction. The as-prepared reduction-sensitive prodrug could self-assemble into prodrug micelles in aqueous solution confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). In vitro drug release studies showed that these prodrug micelles were able to release GEM in an intracellular-mimicking reductive environment. These prodrug micelles could be effectively internalized by BxPC-3 pancreatic cancer cells, which were observed by confocal laser scanning microscopy (CLSM). Meanwhile, a methyl thiazolyl tetrazolium (MTT) assay demonstrated that this prodrug exhibited high cytotoxicity against BxPC-3 cells. The in vivo whole-animal near-infrared (NIR) imaging results showed that these prodrug micelles could be effectively accumulated in tumor tissue and had a longer blood circulation time than IR820-COOH. The endogenous reduction-sensitive gemcitabine prodrug micelles with the in vivo NIR imaging ability might have great potential in image-guided pancreatic cancer therapy.

Polymeric micelles have emerged as a promising nanoplatform for cancer theranostics. Herein, we developed doxorubicin (DOX) encapsulated pH-responsive polymeric micelles for combined aggregation induced emission (AIE) imaging and chemotherapy. The novel zwitterionic copolymer poly(2-methacryloyloxyethylphosphorylcholine-co-2-(4-formylphenoxy)ethyl methacrylate) (poly(MPC-co-FPEMA)) was synthesized via RAFT polymerization and further converted to PMPC-hyd-TPE after conjugation of tetraphenylethene (TPE, a typical AIE chromophore) via acid-cleavable hydrazone bonds. The AIE activatable copolymer PMPC-hyd-TPE could self-assemble into spherical PC-hyd-TPE micelles, and DOX could be loaded through hydrophobic interactions. The zwitterionic micelles exhibited excellent physiological stability and low protein adsorption due to the stealthy phosphorylcholine (PC) shell. In addition, the cleavage of hydrophobic TPE molecules under acidic conditions could induce swelling of micelles, which was verified by size changes with time at pH 5.0. The in vitro DOX release profile also exhibited accelerated release rate with pH value decreasing from 7.4 to 5.0. Fluorescent microscopy and flow cytometry studies further demonstrated fast internalization and accumulation of drug loaded PC-hyd-TPE-DOX micelles in HepG2 cells, resulting in considerable time/dose-dependent cytotoxicity. Meanwhile, high-quality AIE imaging of PC-hyd-TPE micelles was confirmed in HepG2 cells. Notably, ex vivo imaging study exhibited efficient accumulation and drug release of PC-hyd-TPE-DOX micelles in the tumor tissue. Consequently, the multifunctional micelles with combined nonfouling surface, AIE active imaging, and pH-responsive drug delivery showed great potential as novel nanoplatforms for a new generation of cancer theranostics.Keywords: aggregation induced emission; bioimaging; drug delivery; pH-responsive; theranostics; zwitterionic polymers

Novel 5-aminolevulinic acid (ALA) pseudopolyrotaxane prodrug micelles with dual pH-responsive properties were prepared by the host–guest interaction of α-cyclodextrin (α-CD) and poly(ethylene glycol) (PEG). The micelles exhibited pH dependent cellular uptake and pH-sensitive ALA release, enabling enhanced photodynamic therapy.

A simple method to achieve host–guest assembly of gold nanoparticles triggered by intracellular glutathione was demonstrated. The increased size of nanoparticles not only enhanced their retention time within cancer cells, but also induced apoptosis. This strategy may open an avenue for the development of smart nanocarriers for intracellular diagnosis and therapy.

IR-780 iodide, a near-infrared (near-IR) fluorescent dye, can be utilized as an effective theranostic agent for both imaging and photothermal therapy. However, its lipophilicity limits its further biomedical applications. Herein, we synthesized a phospholipid mimicking amphiphilic homopolymer poly(12-(methacryloyloxy)dodecyl phosphorylcholine) (PMDPC) via reversible addition–fragmentation chain transfer (RAFT) polymerization. The amphiphilic homopolymer PMDPC can be self-assembled into micelles and used for the encapsulation of IR-780. The IR-780 loaded micelles (PMDPC-IR-780) exhibited low cytotoxicity in the dark, whereas remarkable photothermal cytotoxicity to pancreatic cancer cells (BxPC-3) was observed upon near-IR laser irradiation. We further investigated in vivo biodistribution of PMDPC-IR-780 micelles. Higher accumulation of PMDPC-IR-780 than that of free IR-780 in tumor tissue was verified, which might be ascribed to the enhanced permeability and retention (EPR) effect and long circulation time benefiting from the zwitterionic phosphorylcholine surface. Therefore, the IR-780 loaded phospholipid mimicking homopolymeric micelles could have great potential for cancer theranostics.Keywords: homopolymeric micelle; IR-780 dye; near-infrared (near-IR) imaging; pancreatic cancer; photothermal therapy; zwitterion

•Theranostic nanoparticles were easily obtained by miniemulsion polymerization.•The as-prepared nanoparticles showed good monodispersity and significant stability.•The nanoparticles possessed better photothermal cytotoxicity than free IR-820.•The nanoparticles showed better diagnosis effects than free IR-780.Miniemulsion reversible addition-fragmentation chain transfer (RAFT) polymerization was used to synthesize biomimetic poly (2-methacryloyloxyethyl phosphorylcholine)-b-Poly (n-butyl methacrylate) (PMPC-b-PBMA) nanoparticles which were used as nanocarriers to encapsulate theranostic IR-780 molecules. IR-780 endowed the PMPC-b-PBMA nanoparticles with dual functions including tumor near-infrared (NIR) imaging and photothermal therapy (PTT). The IR-780 encapsulated PMPC-b-PBMA (PMPC-b-PBMA/IR-780) nanoparticles showed good monodispersity and significant stability. The photothermal effects and photothermal cytotoxicity of the PMPC-b-PBMA/IR-780 nanoparticles were studied in vitro. High accumulation of the PMPC-b-PBMA/IR-780 nanoparticles in tumor tissue was verified by whole-animal NIR imaging. The resulted IR-780 encapsulated biomimetic nanoparticles can be an alternative safe theranostic agent for imaging-guided cancer treatment.

•The prodrug nanoparticles are formed based on host-guest interactions.•The prodrug nanoparticles possess zwitterionic phosphorylcholine surface.•The prodrug nanoparticles exhibit pH-responsive drug release profile.•The prodrug nanoparticles can efficiently delivery DOX into cancer cells.A novel zwitterionic pendant copolymer poly(2-(methacryloyloxy)ethyl phosphorylcholine)-co-poly(2-(methacryloyloxy)ethyl adamantane-1-carboxylate) (poly(MPC-co-Ada)) is synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. The pendant adamantane guest molecules and doxorubicin (DOX) decorated β-cyclodextrins (DOX-hyd-CD) can form inclusion complexation through host-guest interactions. The resultant supramolecular polymers can self-assemble into polymeric prodrug nanoparticles in the size range of 25–60 nm, with the zwitterionic phosphorylcholine grafts acting as hydrophilic shell. In vitro drug release results indicates that the release of DOX at pH 5.0 is faster than that at pH 7.4, since DOX is conjugated to β-CD with pH-responsive hydrazone bond. Efficient cellular internalization is observed by flow cytometry and fluorescence microscopy, resulting in the inhibitation of cancer cell proliferation. Importantly, taking advantage of the host-guest interaction, such kind of zwitterionic pendant polymer can be further developed as promising platforms for multifunctional cancer theranostics.

Ideal drug delivery systems should have prolonged circulation in blood, high accumulation in tumors with fast cellular uptake and burst drug release in cancer cells. Herein, a pH-sensitive small-molecule phospholipid prodrug based on phosphorylcholine (PC) was designed to overcome these challenges. The prodrug was synthesized by conjugating doxorubicin (DOX) to 11-mercaptoundecyl phosphorylcholine via an acid-labile hydrazone linker (UnPC-hyd-DOX). This phospholipid prodrug can self-assemble into core–shell micelles with exact and very high drug loading content (56.2%). Interestingly, the PC prodrug micelles can strongly minimize nonspecific phagocytosis by macrophages. They exhibited better ability to be internalized by cancer cells than that of the PEG prodrug micelles, which indicated that the PC shell facilitated cancer cell internalization. Moreover, in vitro results further demonstrated that DOX of phospholipid prodrug micelles can effectively escape from endo/lysosomes to the cytosol and enter the nucleus. An in vivo study demonstrated that these PC prodrug micelles exhibited much lower cardiotoxicity than free DOX. Importantly, PC prodrug micelles showed significantly slower blood clearance than PEG prodrug micelles and free DOX.

A novel type of dual pH-responsive supramolecular prodrug micelles based on host–guest interactions of water-soluble pillar[5]arene (WP5) and methyl viologen functioned doxorubicin (MV-DOX) was prepared. It was found that the prodrug micelles could be aggregated upon acidic condition, which led to enhanced accumulation and better therapy effect.

An enzyme and reduction-activatable gemcitabine prodrug (TPE-GEM-RGD) with aggregation-induced emission (AIE) properties was designed for targeted and image-guided cancer therapy. TPE-GEM-RGD was successfully used for intracellular light-up imaging and glutathione (GSH)-responsive release of gemcitabine to suppress pancreatic cancer cells.

Ideal drug delivery systems are required to be stable in circulation, while instable at targeted sites to induce rapid drug release. To address this dilemma, novel light cross-linkable and pH de-cross-linkable micelles were developed as drug nanocarriers. Poly(ethylene glycol)-poly-(hydrazone umbelliferone)-aspartamide (mPEG-OMC) with light responsive coumarin moieties and pH responsive hydrazone groups in the side chains was synthesized. The polymers can self-assemble into micelles, which can be conveniently stabilized via UV-light induced cross-linking based on the dimerization of coumarin moieties. While under slight acidic conditions, the cross-linked micelles can also be de-cross-linked by the cleavage of hydrozone bonds in the cross-linking segments, accelerating the release of encapsulated drugs. Thus the benefits of pH and light stimuli-responsiveness can be combined and their disadvantages are avoided. The doxorubicin-loaded micelles showed high mortality towards HepG2 cells. We have demonstrated the UV light cross-linkable micelles with pH-triggered de-cross-linking properties as a new approach for designing smart drug delivery systems.

•Hyaluronic acid prodrugs with pH and reduction responsiveness were prepared.•The prodrug can form remarkable micelles with a narrow size distribution.•The micelles could accumulate at the tumor site actively.•The prodrug system can inhibit the proliferation of the cancer cells effectively.Biomimic hyaluronic acid (HA) prodrug micelles with pH and reduction responsiveness were prepared by chemical graft of phosphorylcholine and doxorubicin (DOX) to the backbone of HA. DOX was conjugated to HA by pH-sensitive hydrazone bonds which could be hydrolyzed under acidic conditions and thus resulted in controlled release of DOX. Besides, the HA prodrug micelles were cross-linked via reduction-responsive disulfide bonds to improve the stability of the micelles. The HA prodrug can form remarkable core–shell micelles with a quite narrow size distribution which was confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The in vitro drug release studies showed that there was a dramatic release under endosome pH (pH = 5.0) and reductive environment (10 mM of dithiothreitol) than that at normal physiological environment (pH = 7.4). Greater uptake of DOX from HA prodrug micelles was observed in the CD44 receptor highly expressed MDA-MB-231 cell line, compared to the results from the CD44-negative cell line, NIH3T3, which was demonstrated by the flow cytometry and fluorescence microscopy. The glutathione (GSH)-responsive behaviors were studied as well. The micelles showed higher cellular proliferation inhibition against glutathione monoester (GSH-OEt) pretreated MDA-MB-231 cells than that of the non-pretreated and buthionine sulfoximine (BSO) pretreated ones. These results suggested that such pH/reduction dual-responsive prodrug micelles may enhance the selective inhibition to cancer cells which exhibit higher levels of GSH concentration and provide favorable platforms for cancer therapy.

The first attempt of constructing pH responsive supramolecular prodrug micelles based on cucurbit[8]uril is reported. The obtained prodrug micelles are found to be able to inhibit proliferation of cancer cells. It is anticipated that this facile strategy may open a novel avenue for the development of multifunctional drug delivery systems.

A biodegradable and endosomal pH-sensitive polymeric prodrug poly(5-methyl-5-allyloxycarbonyl-1,3-dioxan-2-one)-graft-12-acryloyloxy dodecyl phosphorylcholine-co-6-maleimidocaproyl-doxorubicin (PMAC-graft-(ADPC-co-Mal-DOX) was synthesized by ring-opening polymerization (ROP) and “click” reaction. DOX was conjugated to the polymer by hydrazone bonds which would result in a pH-sensitive controlled release of drug. The polymeric prodrug can form a self-assembled micellar structure which was confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Flow cytometry and fluorescence microscopy results demonstrated that prodrug micelles could be internalized by cancer cells remarkably. In vitro drug release studies showed that the release of DOX was faster at endosomal pH (pH = 5.0) than at normal physiological environment (pH = 7.4). Moreover, this prodrug exhibited high cytotoxicity against HepG2 cells and HeLa cells, indicating its great potential for cancer therapy.

A truly novel strategy for fabricating reducible supramolecular assemblies based on the host–guest interaction between cucurbit[8]uril (CB[8]) and methyl viologen (MV) is reported. The anticancer drug doxorubicin is loaded into the assemblies and a reducing agent Na2S2O4 can be used to successfully trigger release of drugs because of the redox chemistry of MV.

Functional 2-methylene-1,3-dioxepane (MDO) terpolymers were explored here as a versatile platform to construct biodegradable pH sensitive polymeric prodrugs for intracellular drug delivery. A series of MDO-based biodegradable functional polyester P(MDO-co-PEGMA-co-PDSMA) with different compositions were synthesized by terpolymerization of MDO, poly(ethylene glycol) methyl ether methacrylate (PEGMA) and pyridyldisulfide ethylmethacrylate (PDSMA) via a simple one-pot radical ring-opening copolymerization. Mal-DOX, which contains a pH-sensitive hydrazone bond between doxorubicin (DOX) and the maleimide group, was covalently conjugated in one pot to free thiol groups of PDSMA units via thiol–ene click chemistry in the presence of tri(2-carboxyethyl)phosphine (TCEP). The DOX-conjugated P(MDO-co-PEGMA-co-PDSMA) can self-assemble into prodrug micelles. The diameter and morphology of the polymeric prodrug micelles were measured by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Because of the existence of the pH-sensitive hydrazone bonds, in vitro drug release results showed that the release of DOX was much faster at pH 5.5 than that at pH 7.4. Flow cytometry and fluorescence microscopy demonstrated that the prodrug micelles could be efficiently internalized by cancer cells. In vitro cytotoxicity showed that the DOX-conjugated prodrug micelles can strongly inhibit the proliferation of cancer cells remarkably. Importantly, this work provides a versatile strategy for the fabrication of biodegradable polymeric prodrug nanocarriers.

•A new β-CD based prodrug molecule was synthesized.•A facile way to address dual stimuli in cancer cells (endosomal pH and over produced H2O2) was proposed and realized by orthogonal assembly of β-CD-hydrazone-DOX and PEG-Fc.•The supramolecular prodrug micelles developed could be potentially used as nanocarriers for drug delivery.Nowadays, cancer is one of the most fatal threatens to human health. By utilizing the differences of cell environment between cancer cells and their normal counterparts as assembly-disassembly triggers, various smart drug nanocarriers have been designed to fight the cancer. Nevertheless, most of them are still not robust enough. One important reason is that they merely focus on a single stimulus. Thus, in order to achieve a better therapeutic effect, constructing multi responsive polymers is of great significance. However, most of multi responsive polymers used, up until now, are mainly based on block polymers synthesized via traditional polymerization methods, which are relatively time-consuming and laborious. Here in this article, a facile strategy preparing smart polymers with dual responsiveness (endosomal pH and over produced H2O2) was proposed and realized by orthogonal assembly of β-CD-hydrazone-DOX and PEG-Fc. The obtained polymers were found to be able to spontaneously assemble into micelles in water, indicating their potential applications as drug nanocarriers. In vitro study revealed that the release of the encapsulated DOX was significantly enhanced by both H2O2 and low pH at 5.0. Furthermore, fluorescence microscopy and flow cytometry analysis showed that the assembled supramolecular prodrug micelles could be internalized into cancer cells. These properties suggested their promising application in cancer therapy.

A novel amphiphilic photo-degradable hyperbranched polymer was reported at the first time. The hyperbranched o-nitrobenzyl containing poly(amino ester)s (HPAE) were prepared by one-pot Michael addition polymerization. The photo-induced degradation of hyperbranched poly(amino ester)s was confirmed by gel permeation chromatography (GPC) and UV-vis spectra. Bioinspired phosphorylcholine grafted HPAE (HPAE-PC) was synthesized via thiol-ene click chemistry. HPAE-PC can self-assemble to micelles and the micelles could be disassembled under UV irradiation because of the photo-degradation of HPAE. HPAE-PC micelles were used to load anticancer drug Doxorubicin (DOX). In vitro drug release studies showed that the release of DOX was much faster in the presence of UV irradiation than that without UV irradiation. The fluorescence microscope results indicated that DOX-loaded micelles exhibited faster drug release in A549 cells after UV irradiation. Moreover, the DOX-loaded HPAE-PC micelles under UV irradiation exhibited better anticancer activity against A549 cells than that of the nonirradiated ones. The novel amphiphilic photo-degradable hyperbranched polymers can be used to construct spatiotemporal on-demand drug delivery system for cancer therapy.

The pH-triggered biodegradable micelles based on poly(β-amino ester)-graft-12-acryloyloxy dodecyl phosphorylcholine (PAE-graft-ADPC) were explored as an efficient acid-triggered anticancer drug delivery system. A pH-responsive biodegradable polymer was synthesized by using hydrophilic 12-acryloyloxy dodecyl phosphorylcholine (ADPC) and poly(β-amino ester) (PAE) via Michael addition reaction. Micelles with phosphorylcholine shells were prepared in aqueous solution and doxorubicin (DOX) was loaded into the core of the micelles with high efficiency (73%). Dynamic light scattering (DLS) and transmission electron microscopy (TEM) demonstrated that the size of the drug-loaded micelles was about 230 nm. DOX-loaded micelles were stable in the physiological environment, whereas they disassembled at pH 6.5 which is similar to the extracellular pH of most tumors. In vitro drug release showed that DOX release from micelles was faster at pH 6.5 than at 7.4. Intracellular uptake demonstrated that DOX was delivered into the cells effectively after the cells were incubated with DOX-loaded micelles at pH 6.5. Moreover, an in vitro cytotoxicity study indicated that the growth of HepG2 cells was inhibited remarkably when the cells were preincubated with DOX-loaded micelles at pH 6.5. The results indicated that the pH-triggered biodegradable micelles could serve as promising drug carriers for cancer therapy.

A simple method to achieve host–guest assembly of gold nanoparticles triggered by intracellular glutathione was demonstrated. The increased size of nanoparticles not only enhanced their retention time within cancer cells, but also induced apoptosis. This strategy may open an avenue for the development of smart nanocarriers for intracellular diagnosis and therapy.

A novel type of dual pH-responsive supramolecular prodrug micelles based on host–guest interactions of water-soluble pillar[5]arene (WP5) and methyl viologen functioned doxorubicin (MV-DOX) was prepared. It was found that the prodrug micelles could be aggregated upon acidic condition, which led to enhanced accumulation and better therapy effect.

The first attempt of constructing pH responsive supramolecular prodrug micelles based on cucurbit[8]uril is reported. The obtained prodrug micelles are found to be able to inhibit proliferation of cancer cells. It is anticipated that this facile strategy may open a novel avenue for the development of multifunctional drug delivery systems.

Ideal drug delivery systems should have prolonged circulation in blood, high accumulation in tumors with fast cellular uptake and burst drug release in cancer cells. Herein, a pH-sensitive small-molecule phospholipid prodrug based on phosphorylcholine (PC) was designed to overcome these challenges. The prodrug was synthesized by conjugating doxorubicin (DOX) to 11-mercaptoundecyl phosphorylcholine via an acid-labile hydrazone linker (UnPC-hyd-DOX). This phospholipid prodrug can self-assemble into core–shell micelles with exact and very high drug loading content (56.2%). Interestingly, the PC prodrug micelles can strongly minimize nonspecific phagocytosis by macrophages. They exhibited better ability to be internalized by cancer cells than that of the PEG prodrug micelles, which indicated that the PC shell facilitated cancer cell internalization. Moreover, in vitro results further demonstrated that DOX of phospholipid prodrug micelles can effectively escape from endo/lysosomes to the cytosol and enter the nucleus. An in vivo study demonstrated that these PC prodrug micelles exhibited much lower cardiotoxicity than free DOX. Importantly, PC prodrug micelles showed significantly slower blood clearance than PEG prodrug micelles and free DOX.

Novel 5-aminolevulinic acid (ALA) pseudopolyrotaxane prodrug micelles with dual pH-responsive properties were prepared by the host–guest interaction of α-cyclodextrin (α-CD) and poly(ethylene glycol) (PEG). The micelles exhibited pH dependent cellular uptake and pH-sensitive ALA release, enabling enhanced photodynamic therapy.