Azide-Locked Prodrug Co-Assembly into Nanoparticles with Indocyanine Green for Chemophotothermal Therapy.

Fabrication of self-delivery drug systems can surmount low drug bioavailability and achieve a precise therapeutic process. In this study, a hydrogen sulfide-responsive (H2S) small molecule prodrug was synthesized by linking two chemotherapy drugs, camptothecin (CPT) and gemcitabine (GT), using a reductive disulfide bond simultaneously with a lock GT strategy using a H2S-responsive azide group (denoted as N3-GT-CPT). The ingenious design endows the easy coprecipitation peculiarity of the prodrug with clinical indocyanine green (ICG) via a combined interaction force of hydrophobic, π-π stacking, and electrostatic interactions of anions and cations, thus producing a more stable and multifunctional therapeutic nanosystem. Considering the great photothermal and imaging ability of ICG, the obtained nanosystem showed an excellent therapeutic ability against colon tumors in vitro and in vivo with selective response to intercellular H2S, thus offering a good combination-based multiple therapy for treatment of tumors.

A Reduction-responsive Amphiphilic Methotrexate-Podophyllotoxin Conjugate for Targeted Chemotherapy.

Owing to the naturally high toxicity, poor water solubility, and other side effects of podophyllotoxin (PPT), its applications are limited. To address these issues, we developed a new PPT delivery system, in which the hydrophilic drug methotrexate (MTX) and the hydrophobic drug PPT were linked by a reduction-responsive disulfide bond to form an amphiphilic drug-drug conjugate prodrug (MTX-SS-PPT). The conjugate could self-assemble into spherical nanoaggregates in aqueous solution and self-deliver to tumor tissues. In addition, MTX could target to folate-receptor-positive cells. Over-expression of glutathione in tumor cells broke the disulfide bonds and released the free drug. In vitro and in vivo experiments indicated that the nanodrug could effectively improve the biocompatibility and reduce the toxicity of PPT.

Codelivery of doxorubicin and camptothecin by dual-responsive unimolecular micelle-based ß-cyclodextrin for enhanced chemotherapy.

Tumor microenvironment (TME)-induced drug delivery technology is a promising strategy for improving low drug accumulation efficiency, short blood circulation and weak therapeutic effect. In this work, a dual-responsive (reduction- and pH-responsive) polyprodrug nanoreactor based on ß-cyclodextrin (ß-CD) was constructed for combinational chemotherapy. Specifically, the dual-responsive star polymeric prodrug was synthesized by atom transfer radical polymerization (ATRP) based on a starburst initiator of ß-CD-Br. The obtained polyprodrug contained a hydrophilic chain of poly-(ethylene glycol) methyl ether methacrylate (POEGMA) and a hydrophobic part of camptothecin (CPT) prodrug and poly[2-(diisopropylamino)ethyl methacrylate] (PDPA), denoted as ß-CD-PDPA-POEGMA-PCPT (CCDO for short). The obtained CCDO could form stable unimolecular micelles, which could be efficiently internalized by cancer cells. To enhance the curative effect, the anticancer agent doxorubicin (DOX) could be encapsulated into the hydrophobic cavity of the CCDO by hydrophobic-hydrophobic interaction. In vitro drug release studies showed that the obtained CCDO/DOX micelles controlled the release of active CPT and DOX occurring in a reductive environment and at low pH. In vitro cytotoxicity results suggested that the anticancer efficacy of dual-responsive CCDO/DOX micelles was superior to that of CCDO micelles. In addition, in vivo results verified good blood compatibility of the unimolecular micelles. This integrated dual-responsive drug delivery system may solve the low drug loading and poor controlled release problems found in traditional polymer-based drug carriers, providing an innovative and promising route for cancer therapy.

Starburst Diblock Polyprodrugs: Reduction-Responsive Unimolecular Micelles with High Drug Loading and Robust Micellar Stability for Programmed Delivery of Anticancer Drugs.

Polymeric prodrug based on therapeutic nanomedicine has demonstrated great promise for effective tumor growth inhibition, however, the drawbacks of low drug-loading and weak micellar stability limit its application for clinical cancer therapy. Herein, a reduction-responsive starburst block copolymer prodrug CCP [ß-cyclodextrin (ß-CD)-PCPTXX-POEGMA, XX: SS or CC] has been developed for cancer therapy. And CCP is composed of ß-CD-Br core with multiple reactive sites, as well as a diblock copolymer containing hydrophobic polymerized camptothecin (PCPT) prodrug chain and hydrophilic poly[(ethylene glycol) methyl ether methacrylate] (OEGMA) chain. A family of CCP polymeric prodrugs with different drug loading contents (up to 25%) and various sizes of unimolecular micelles (UMs) (around 30 nm) were obtained by adjusting the block ratio of PCPTXX and POEGMA. On account of the amphiphilic structure feature, CPP could take shape water-soluble UMs in aqueous medium with excellent micellar stability. Under imitatively reductive tumor microenvironment, anticancer drug CPT could rapidly escape from CCP UMs in terms of disulfide bond breakage. However, this behavior is strongly refrained in the physiological environment. In vitro and in vivo outcome confirmed that CCP UMs showed excellent performance of sufficient tumor accumulation, high-efficiency tumor growth inhibition and low-toxicity for healthy tissues. Based on these gratifying therapeutic efficacy, it is believed that as-present starburst prodrug strategy can offer a brand-new insight for high-efficiency therapeutic nanoplatforms for chemotherapy application.

Oral Drug Delivery Systems for Ulcerative Colitis Therapy: A Comparative Study with Microparticles and Nanoparticles.

BACKGROUND: Oral administrations of microparticles (MPs) and nanoparticles (NPs) have been widely employed as therapeutic approaches for the treatment of ulcerative colitis (UC). However, no previous study has comparatively investigated the therapeutic efficacies of MPs and NPs. METHODS: In this study, curcumin (CUR)-loaded MPs (CUR-MPs) and CUR-loaded NPs (CUR-NPs) were prepared using a single water-in-oil emulsion solvent evaporation technique. Their therapeutic outcomes against UC were further comparatively studied. RESULTS: The resultant spherical MPs and NPs exhibited slightly negative zeta-potential with average particle diameters of approximately 1.7 µm and 270 nm, respectively. It was found that NPs exhibited a much higher CUR release rate than MPs within the same period of investigation. In vivo experiments demonstrated that oral administration of CUR-MPs and CUR-NPs reduced the symptoms of inflammation in a UC mouse model induced by dextran sulfate sodium. Importantly, CUR-NPs showed much better therapeutic outcomes in alleviating UC compared with CUR-MPs. CONCLUSION: NPs can improve the anti-inflammatory activity of CUR by enhancing the drug release and cellular uptake efficiency, in comparison with MPs. Thus, they could be exploited as a promising oral drug delivery system for effective UC treatment.

Acid-active supramolecular anticancer nanoparticles based on cyclodextrin polyrotaxanes damaging both mitochondria and nuclei of tumor cells.

As a supramolecular macrocyclic polymer, cyclodextrin (CD) polyrotaxanes (PRs) have many advantages for developing nanomedicines, such as stable chemical composition, abundant functionalized hydroxyl groups, moving across biological barriers, adjustable nanoparticle size and good biocompatibility. Herein, we synthesized a class of acid-active therapeutic nanoparticles comprising a α-CD-based PR polymeric prodrug of PRs-poly(doxorubicin)-co-poly[(ethylene glycol) methyl ether methacrylate] (PR-PDOX-co-POEGMA, denoted as PRMO@DOX) to reduce drug leakage and selectively deliver drugs into tumor cells, aiming to achieve maximal treatment efficacy of supramolecular therapeutics. The obtained PRMO@DOX showed desirable features of high drug loading rates (>25 wt%), fast cellular uptake, acid-active controlled release, effective anti-tumor activity and low systemic toxicity. Benefiting from its unique amphiphilic nanostructure, PRMO@DOX can form water-soluble prodrug nanoparticles in aqueous media. The acid-active hydrazone bond in the prodrug can break and thus release drug molecules precisely and in a timely manner under an acidic tumor microenvironment, damaging the nuclei and mitochondria of tumor cells. Both in vitro and in vivo experiments clearly demonstrated a remarkable antitumor efficacy of this therapeutic platform, which provided a new strategy for the development of polyrotaxane-based nanomedicine for enhanced cancer therapy.

Irinotecan delivery by unimolecular micelles composed of reduction-responsive star-like polymeric prodrug with high drug loading for enhanced cancer therapy.

Nanomedicine based polymeric prodrug have showed high impact in the inhibition of tumor growth due to its high therapeutic efficiency and improved biocompatibility. Herein, we synthesized a novel star-like amphiphilic copolymer [ß-CD-P(Ir-co-OEGMA), denoted as CPIO] through atom transfer radical polymerization (ATRP) to deliver the hydrophilic anticancer drug irinotecan (Ir). The polymer could form monodisperse unimolecular micelles and had excellent stability in aqueous solution. Moreover, the reduction-responsive feature of the micelles facilitated controlled release of drug, thus achieving targeted therapy and reduced toxicity to healthy cells. The in vitro cytotoxicity assays indicated that CPIO had a notable anticancer effect against HeLa and MCF-7 tumor cells. The confocal laser scanning microscopy and flow cytometry experiments revealed that CPIO micelles could be internalized into tumor cells efficiently. Furthermore, the obtained prodrug micelles produced better efficacy compared to free Ir. Moreover, the CPIO micelles showed excellent biocompatibility in vivo after intravenous injection on a mouse model. This study demonstrated that CPIO carrier could provide a rational design of a stimuli-responsive polymeric prodrug for delivery of irinotecan.

Methotrexate-based amphiphilic prodrug nanoaggregates for co-administration of multiple therapeutics and synergistic cancer therapy.

The goal of nanomedicine is to seek strategies that are more efficient to address various limitations and challenges faced by conventional medicines, including lack of target specificity, poor bioavailability, premature degradability, and undesired side effects. Self-assembling drug amphiphiles represent a prospective nanomedicine for cancer therapy owing to their favorable route of administration and therapeutic efficiency compared with pristine drug counterparts. In this work, we report a class of self-deliverable prodrug amphiphiles consisting of the hydrophilic drug methotrexate (MTX) and the hydrophobic anticancer drugs camptothecin (CPT) and doxorubicin (DOX) for targeted and combinational chemotherapy. The disulfide bond and hydrazone bond, which are subject to stimuli-triggered bond cleavage, were introduced to link these therapeutic agents and form two prodrug amphiphiles, named as MTX-CPT and MTX-DOX, respectively, which could self-assemble into stable prodrug nanoaggregates (NAs) in aqueous media. MTX molecules in the prodrug NAs facilitated NA uptake into tumor cells with high expression of folic acid receptors (FRs). This systemic study provided clear evidence of the synergistic therapeutic effect by co-administrating dual prodrug NAs on various tumor cells in vitro and a xenograft tumor model in vivo. The obtained prodrug amphiphiles provide an efficient strategy for the design of multifunctional drug delivery systems and elaborate therapeutic nanoplatforms for cancer chemotherapy. STATEMENT OF SIGNIFICANCE: This work presents two kinds of prodrug amphiphiles that are carrier free and integrate targeted drug delivery, stimuli-triggered drug release, synergistic therapy, and theranostic function into a single system. Reduction/acid active prodrug amphiphiles can self-assemble into micellar nanoaggregates (NAs) at a very low critical aggregation concentration. These NAs exhibit superior stability in physiological environment and disassemble in the presence of tumor cells expressing folic acid receptors or the high glutathione or in low pH tumoral endosomal environment. The induced disassembly of prodrug NAs can "switch on" the inherent fluorescence of the internalized camptothecin or doxorubicin for the detection of tumor cells. Compared to a single type of prodrug NA, co-administration of dual prodrug combination can produce an evident synergistic therapeutic effect against various tumor cells in vitro and inhibit xenograft tumor growth in vivo. The methotrexate-based prodrug amphiphiles may provide a potential strategy for developing multifunctional nanoplatforms and delivery of multiple therapeutics in chemotherapy.

Reduction-active polymeric prodrug micelles based on α-cyclodextrin polyrotaxanes for triggered drug release and enhanced cancer therapy.

As one of the medical polymers approved by US Food and Drug Administration (FDA), poly(ethylene glycol) has low toxicity, high stability, good biocompatibility, unique physical and chemical properties. Cyclodextrin is an ideal candidate as a drug carrier due to its special structures and characteristics. These two materials were successfully assembled through chemosynthesis in combination with the hydrophilic poly(ethylene glycol) methyl ether methacrylate (OEGMA) chain and hydrophobic polymeric camptothecin (CPT) chain by atom transfer radical polymerization (ATRP). The introduction of disulfide bond of monomer was aimed to realize reduction agent-triggered release of active CPT. The obtained amphipathic prodrug [(Denoted as PC-PCPT-b-POEGMA (PCCO)] could form nano-sized polymeric micelles, which could release more than 85% of the loaded CPT via triggered cleavage of the disulfide linker. The cellular co-localization study revealed the potential pathway of drug internalization. Moreover, the PCCO micelles showed good biocompatibility in vivo after intravenous injection on a mouse model. This new CPT-loaded prodrug system could be prepared with low cost, and showed efficient and controlled drug release and favorable biocompatibility, demonstrating a promising potential as a stimuli-responsive polymeric prodrug for future clinical applications.

Water-soluble fluorescent unimolecular micelles: ultra-small size, tunable fluorescence emission from the visible to NIR region and enhanced biocompatibility for in vitro and in vivo bioimaging.

Fluorescent unimolecular micelles (FUMs) with multicolor emission acting as fluorescent nanoagents for optical fluorescence imaging have, for the first time, been reported. The FUMs show good water-solubility, ultra-small size, and enhanced biocompatibility, which endow the FUMs with versatile applications including organelle labeling, multicolor markers and high tumor accumulation, revealing that our design can serve as a rational strategy for the development of UM-based fluorescent nanoagents for bioprocess monitoring.

Improving the carrier stability and drug loading of unimolecular micelle-based nanotherapeutics for acid-activated drug delivery and enhanced antitumor therapy.

Nanomedicines based on unimolecular micelles (UMs) have shown unique advantages such as high micellar stability, programmed cargo delivery and enhanced therapeutic efficiency. Herein, we report an acid-activated amphiphilic prodrug based on a dextran (DEX) polymeric framework (DEX-PDOX-b-POEGMA, labelled DMO@DOX), which conjugates a diblock copolymer of a hydrophobic doxorubicin (DOX) prodrug block and a hydrophilic poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) block by atom transfer radical polymerization. The DMO@DOX prodrug can form nano-sized UMs in aqueous media attributed to its amphiphilic structure and achieve a very high drug loading rate of 80.4 wt%. In the presence of an acidic medium resembling a tumor microenvironment, the hydrazone bond embedded in the prodrug is broken, which releases the loaded drug of DOX. The DMO@DOX prodrug shows a notable and preferential inhibition effect on the growth of tumor cells in vitro compared to healthy cells, leading to advantageous biocompatibility and effective antitumor activity. For verification, the DMO@DOX prodrug was applied in the treatment of a mouse model bearing xenograft tumors and showed a remarkable therapeutic performance. This study demonstrates an effective design of UM-based nanoagents to improve the micellar stability of polymeric prodrug micelles with enhanced performance in cancer therapy.

Reduction stimuli-responsive unimolecular polymeric prodrug based on amphiphilic dextran-framework for antitumor drug delivery.

We report a new reduction-responsive amphiphilic polymeric prodrug based on a linear dextran (DEX) backbone, which was conjugated with an hydrophobic camptothecin (CPT) prodrug block and an hydrophilic poly[poly(ethylene glycol) methyl ether methacrylate] (POEGMA) block [DEX-PCPT-b-POEGMA (DCO)] by atom transfer radical polymerization (ATRP). This amphiphilic prodrug has a unique molecular structure with prominent features, including strong practicability for methacrylate prodrug monomer, high drug loading rate (up to 23wt%), adjustable proportion of hydrophobic and hydrophobic portions, superior stability in aqueous solution, and easy access to cells. Introduction of a disulfide bond linker between the drug and the carrier can realize the function of reduction-responsive controlled drug-release. The experimental study indicated that the prodrug exhibited notable antitumor activity against HeLa cells and MCF-7 cells in vitro. Compared to similar DCO prodrug based on double carbon bond, the disulfide bond-conjugated DCO prodrug induced higher level of tumor cell apoptosis. Considering the drug-loading efficiency, micellar stability, cost of preparation and controlled drug release, the presented prodrug is more advantageous than traditional unimolecular prodrug and represents a promising approach for design of stimuli-responsive polymeric prodrug for effective cancer therapeutics.

A new red fluorophore with aggregation enhanced emission by an unexpected "One-step" protocol.

In this work, a triphenylamine-benzothiadiazole-based new fluorophore is obtained from a facile "one-step" protocol. A possible reduction mechanism is proposed, and an amine containing α-H plays a key role in the reduction reaction. The resultant product A1H2 exhibits bright red emission in solid state, with an absolute quantum yield of 44.5%. Aggregation induced emission enhancement of A1H2 is also observed with the increased water fraction in THF-H2O mixture. The nanoparticles of A1H2 reveal good stability and biocompatibility, which are successfully applied in cellular cytoplasm imaging.

Oral delivery of curcumin via porous polymeric nanoparticles for effective ulcerative colitis therapy.

Oral drug delivery has been considered as a promising strategy for ulcerative colitis (UC) therapy. Here, an emulsion solvent evaporation technique was employed to prepare non-porous curcumin (CUR)-loaded polymeric nanoparticles (NPs) and porous CUR-loaded polymeric NPs in the absence or presence of ammonium bicarbonate. The resultant CUR-loaded NPs (non-porous NPs and porous NPs) had a desirable mean particle size of around 260 nm with a narrow size distribution, a uniform pore size distribution, slightly negative-charged surface, high encapsulation efficiency and controlled drug release capacity. In vitro experiments indicated that Raw 264.7 macrophages exhibited time-dependent accumulation profiles of NPs during the initial 2 h of co-incubation. Furthermore, we found that porous NPs inhibited the secretion of the main pro-inflammatory cytokines (TNF-α, IL-6 and IL-12) and the production of reactive oxygen species much more efficiently than non-porous NPs. Most importantly, in vivo studies demonstrated that oral administered porous NPs had a superior therapeutic efficiency in alleviating UC compared with non-porous NPs. The results collectively suggest that porous polymeric NPs can be exploited as efficient oral drug carriers for UC treatment.

Acid-Activatable Theranostic Unimolecular Micelles Composed of Amphiphilic Star-like Polymeric Prodrug with High Drug Loading for Enhanced Cancer Therapy.

Stimuli-responsive nanomedicine with theranostic functionalities with reduced side-effects has attracted growing attention, although there are some major obstacles to overcome before clinical applications. Herein, we present an acid-activatable theranostic unimolecular micelles based on amphiphilic star-like polymeric prodrug to systematically address typical existing issues. This smart polymeric prodrug has a preferable size of about 35 nm and strong micellar stability in aqueous solution, which is beneficial to long-term blood circulation and efficient extravasation from tumoral vessels. Remarkably, the polymeric prodrug has a high drug loading rate up to 53.1 wt%, which induces considerably higher cytotoxicity against tumor cells (HeLa cells and MCF-7 cells) than normal cells (HUVEC cells) suggesting a spontaneous tumor-specific targeting capability. Moreover, the polymeric prodrug can serve as a fluorescent nanoprobe activated by the acidic microenvironment in tumor cells, which can be used as a promising platform for tumor diagnosis. The superior antitumor effect in this in vitro study demonstrates the potential of this prodrug as a promising platform for drug delivery and cancer therapy.

Highly cell-penetrating and ultra-pH-responsive nanoplatform for controlled drug release and enhanced tumor therapy.

A stimuli-triggered drug release strategy could considerably reduce side effects while improving the bioavailability of chemotherapeutics. Here, we report that a series of ultra-pH-responsive copolymers are highly efficient drug delivery systems for near-infrared (NIR) imaging and controlled drug release. These polymers self-assemble into nano-sized micelles due to their amphipathic structure and deliver hydrophobic drugs (maximum drug loading rate ∼10wt%) into tumor cells via a controlled and pH-triggered modality. By altering the proportion of hydrophilic and hydrophobic chains, the drug loading rate and the in vitro drug release efficiency can be regulated. Moreover, the drug-loaded micelles with optimized compositions exhibited excellent antitumor efficacy in HeLa and MCF-7 cells, while the blank micelles had minimal cytotoxicity. Cellular uptake experiments further indicated that the ultra-pH-responsive micelles could be rapidly internalized in the tumor cells. This study demonstrated the strong potential of the ultra-pH-responsive platform as a universal carrier for the delivery of anticancer drugs to maximize their therapeutic effect.

Gemcitabine-camptothecin conjugates: a hybrid prodrug for controlled drug release and synergistic therapeutics.

Drug self-delivery systems represent an important approach to enhance the therapeutic efficacy for cancer therapy. We report the design, synthesis and characterization of a new amphiphilic small molecule prodrug based on two types of anticancer drugs, the hydrophilic gemcitabine and hydrophobic camptothecin, linked by a disulfide bond and abbreviated as GT-CPT. The obtained amphiphilic prodrug conjugates self-assembled into nanoparticles in water and showed strong micellar stability and excellent blood compatibility in vivo. The GT-CPT prodrug conjugates could realize precise drug loading as high as ∼75 wt% demonstrating a carrier-free model for efficient drug delivery. Furthermore, the reduction-responsive disulfide bond enabled controlled drug release in the presence of tumour-specific microenvironment. It was found that each of these hybrid drug components (CPT and GT) not only showed enhanced cytotoxicity individually but also exhibited a prominent synergistic effect on HeLa and MCF-7 cancer cells. This study demonstrated the promising potential of this stimuli-responsive hybrid prodrug conjugate for highly efficient co-delivery of multiple anticancer chemotherapeutics, which could inspire further applications using such hybrid prodrug conjugates for combination cancer chemotherapy.

Rapidly cell-penetrating and reductive milieu-responsive nanoaggregates assembled from an amphiphilic folate-camptothecin prodrug for enhanced drug delivery and controlled release.

Accurate diagnosis and treatment based on small molecular prodrugs can enhance drug efficiency and reduce side-effects during cancer therapy. Herein, we report the preparation of a type of glutathione (GSH)-responsive small prodrug delivery system based on targeting folic acid (FA) and conjugating with the hydrophobic antitumor drug camptothecin (CPT) via disulfide bonds. The obtained prodrug is capable of high and precise drug loading (36.8 wt%) and can self-assemble into nanoaggregates with an average size of 46.4 nm in an aqueous solution. The GSH-triggered release of CPT can reach a maximum of 82% under 10 mM GSH in 60 h, which is dramatically higher than 12% of CPT released in a physiological environment. More interestingly, the resulting prodrug can also work as a "switchable" fluorescence probe, which exhibits fluorescence changes in response to GSH stimulus or FA receptors on the membranes of tumor cells. Specifically, the fluorescence of the prodrug is quenched in the physiological environments, whereas strong fluorescence is activated in the tumoral microenvironment expressing high levels of GSH or when the FA terminal is conjugated with the receptors on the membranes of tumor cells. Furthermore, the FA-CPT prodrug shows a superior specificity and higher cytotoxicity for FA receptor-positive KB tumor cells as compared to those of FA receptor-negative A549 tumor cells. Therefore, we believe that this FA-CPT prodrug can be used for the recognition and diagnosis of tumor cells and it also provides a promising modality towards an effective cancer therapy.

pH-Responsive unimolecular micelles based on amphiphilic star-like copolymers with high drug loading for effective drug delivery and cellular imaging.

Herein, we report pH-responsive star-like polymers (denoted as CPO) with amphiphilic diblock copolymers poly(2-(diisopropylamino) ethylmethacrylate)-b-poly[(ethylene glycol) methyl ether methacrylate] (PDPA-b-POEGMA) grafted from ß-cyclodextrin (ß-CD) for efficient antitumor drug delivery. A series of amphiphilic CPO polymers were synthesized via two-step atom transfer radical polymerization (ATRP) utilizing ß-CD-21Br as an initiator. Transmission electron microscopy and dynamic light scattering results demonstrated that these amphiphilic star-like polymers formed unimolecular micelles (UMs) in aqueous media and showed favorable robust micellar stability. The PDPA blocks are hydrophobic at pH = 7.4, which enabled these UMs to carry hydrophobic drugs such as doxorubicin (DOX) in their inner layer with a high drug loading content. Under an acidic environment, the hydrophobility-hydrophilicity transition of PDPA blocks induced the rapid pH-triggered release of drugs for cancer therapy. To endow these UMs with diagnostic functions, near-infrared fluorescent dye cyanine 5 (Cy5) was incorporated by post-decoration on the amine-functionalized precursor where their inner layer was replaced with copolymerized blocks of P(DPA-co-AMA). The UMs of the obtained Cy5 containing polymers (denoted as CPO-Cy5) exhibited switchable fluorescence in response to different pH conditions, where the fluorescence intensity could be enhanced by 7-fold with the change of pH from 9 to 4. The cytotoxicity experiments demonstrated that the DOX-loaded CPO or CPO-Cy5 micelles presented high cytotoxicity against HeLa and MCF-7 cancer cells but low cytotoxicity against normal L929 cells, likely implying their potential tumor-specific targeting ability. The integration of NIR imaging and effective therapeutic functions made DOX-loaded CPO-Cy5 a promising nanomedicine, providing new insights into the design of theranostic nanoplatforms.

pH-responsive polymeric micelles based on poly(ethyleneglycol)-b-poly(2-(diisopropylamino) ethyl methacrylate) block copolymer for enhanced intracellular release of anticancer drugs.

We present a pH-responsive poly(ethyleneglycol)-b-poly(2-(diisopropylamino) ethyl methacrylate) block copolymer (MPEG-PPDA) that can self-assemble into micelles at very low critical micelle concentration. The formed micelles exhibit superior stability in physiological environment and pH-triggered transforming capability between self-assembly and disassembly. Moreover, the resulting micelles can load hydrophobic anticancer drug molecules such as doxorubicin in the core of micelles. The pH-triggered drug release kinetics matches the classical hydrazone bond model. The blank micelles demonstrate minimal cytotoxicity while the drug-loaded micelles exhibit significantly improved anticancer efficacy. These results indicate that this MPEG-PPDA block copolymer could be utilized as a universal pH-responsive delivery system for controlled release of hydrophobic anticancer drug in chemotherapy.