Prodrug Micelles Research Articles

TPGS2000-DOX Prodrug Micelles for Improving Breast Cancer Therapy

BackgroundDoxorubicin (DOX) is an anthracycline antibiotic that inhibits the growth of several solid and hematologic malignant tumors. Increasing the targeting ability of DOX and reducing the multi-drug resistance (MDR) of tumor cells to DOX are major aims for researchers.PurposeIn this study, to increase therapeutic efficiency, reduce the side effects and the MDR of tumor cells to DOX, D-alpha-tocopheryl polyethylene glycol 2000 succinate monoester (TPGS2000)-DOX prodrug micelles were developed by grafting DOX to TPGS2000 via an amide bond that release DOX in the slightly acidic conditions in tumor tissue.Materials and MethodsThe TPGS2000-DOX micelles were constructed using polyethylene glycol 12-hydroxy stearate (Solutol HS15) as the carrier. The in vitro drug release profile and dilution stability of the nanomicelles were determined. The in vitro cytotoxicity and distribution of the nanomicelles in the tumor cells were also investigated. Moreover, we explored the therapeutic outcomes using the MCF-7/ADR tumor-bearing murine model.ResultsThe average particle size was approximately 30 nm with a narrow distribution, which was conducive for solid tumor accumulation. The results of in vivo imaging and in vitro cellular uptake assays demonstrated that the TPGS2000-DOX micelles increased the tumor-targeting ability and cellular uptake of DOX. The anticancer potential of TPGS2000-DOX micelles was higher than that of DOX, as revealed by in vitro cytotoxic assays with MCF-7/ADR cells and in vivo antitumor assays with MCF-7 tumor-bearing nude mice.ConclusionTPGS2000-DOX prodrug micelles reverse the MDR of tumor cells, achieve passive targeting by forming nanomicelles, and subsequently enhance the efficacy and reduce the toxicity of DOX.

Intelligent self-assembly prodrug micelles loading doxorubicin in response to tumor microenvironment for targeted tumors therapy

Compared with physical drug-loaded nanocarriers, polymeric prodrug micelles have many advantages such as high drug loading and enhanced stability in blood, so they have great potential in cancer therapy. However, these micelles have a big disadvantage, which cannot achieve long-term circulation in vivo and high absorption of tumor cells simultaneously, resulting in low administration efficiency and poor therapeutic effect on cancer. To solve problems of traditional polymeric prodrug micelles, novel polymeric micelles with tumor microenvironment response were designed in this work. The prodrug formed by covalently linking D-α-tocopherol polyethylene glycol succinate (TPGS 3350 ), peptide (Pep), and doxorubicin (DOX) (TPGS 3350 -Pep-DOX) was self-assembled into micelles by encapsulating DOX physically. When the micelles entered the tumor tissue, the long-chain polyethylene glycol (PEG) was sensitively cut by the matrix metalloproteinase 2/9 (MMP2/9) enzyme, exposing the targeting molecule folate, then it entered the cell through the endocytic pathway mediated by the folate receptor. The drug loading content, encapsulation efficiency, critical micelle concentration, and invitro release of the micelles invented in this study were measured to characterize their properties. The particle size and zeta potential of micelles were characterized by dynamic light scattering. Images were scanned by transmission electron microscopes. In vitro cytotoxicity, cellular uptake, and in vivo antitumor effect evaluation experiments were measured to show that smart micelles have made much progress in material chemistry and drug delivery, making it possible to apply a stimulus–response carrier drug delivery system in clinical application.

A Co-delivery System Based on a Dimeric Prodrug and Star-Shaped Polymeric Prodrug Micelles for Drug Delivery.

Chemotherapy is one of the commonly used therapies for the treatment of malignant tumors. Insufficient drug-loading capacity is the major challenge for polymeric micelle–based drug delivery systems of chemotherapy. Here, the redox-responsive star-shaped polymeric prodrug (PSSP) and the dimeric prodrug of paclitaxel (PTX) were prepared. Then the dimeric prodrug of PTX (diPTX, diP) was loaded into the core of the star-shaped polymeric prodrug micelles of PSSP by hydrophobic interaction forming the redox-responsive prodrug micelles of diPTX@PSSP for intracellular drug release in tumor cells. The hydrodynamic diameter of diPTX@PSSP nanoparticles was 114.3 nm ± 2.1 (PDI = 0.219 ± 0.016), and the micelles had long-term colloidal stability and the drug-loading content (DLC) of diPTX and PTX is 16.7 and 46.9%, respectively. The prepared micelles could broke under the reductive microenvironment within tumor cells, as a result, the dimeric prodrug of diP and polymeric prodrug micelles of PSSP were rapidly disassembled, leading to the rapid release of intracellular drugs. In vitro release studies showed that under the condition of reduced glutathione (GSH) (10 mM), the release of PTX was significantly accelerated with approximately 86.6% released within 21 h, and the released PTX in cytoplasm could promote the disintegration of microtubules and induce cell apoptosis. These results indicated that the new type of this reduction-sensitive nanodrug delivery system based on dimeric prodrug@polymeric prodrug micelles would be a promising technology in chemotherapy.

Zwitterionic Block Copolymer Prodrug Micelles for pH Responsive Drug Delivery and Hypoxia-Specific Chemotherapy.

Tirapazamine (TPZ) and its derivatives (TPZD) have shown their great potential for efficiently killing hypoxic cancer cells. However, unsatisfactory clinical outcomes resulting from the low bioavailability of the low-molecular TPZ and TPZD limited their further applications. Precise delivery and release of these prodrugs via functional nanocarriers can significantly improve the therapeutic effects due to the targeted drug delivery and enhanced permeability and retention (EPR) effect. Herein, zwitterionic block copolymer (BCP) micelles with aldehyde functional groups are prepared from the self-assembly of poly(2-methacryloyloxyethyl phosphorylcholine-b-poly(di(ethylene glycol) methyl ether methacrylate-co-4-formylphenyl methacrylate) [PMPC-b-P(DEGMA-co-FPMA)]. TPZD is then grafted onto PMPC-b-P(DEGMA-co-FPMA) to obtain a polymer-drug conjugate, PMPC-b-P(DEGMA-co-FPMA-g-TPZD) (BCP-TPZ), through the formation of a pH-responsive imine bond, exhibiting a pH-dependent drug release profile owing to the cleavage of the imine bond under acidic conditions. Outstandingly, BCP-TPZ shows around 13.7-fold higher cytotoxicity to hypoxic cancer cells in comparison to normoxic cancer cells evaluated through an in vitro cytotoxicity assay. The pH-responsiveness and hypoxia-specific cytotoxicity confer BCP-TPZ micelles a great potential to achieve precise delivery of TPZD and thus enhance the therapeutic effect toward tumor-hypoxia.

A pH-Responsive Zwitterionic Polyurethane Prodrug as Drug Delivery System for Enhanced Cancer Therapy.

Numerous nanocarriers with excellent biocompatibilities have been used to improve cancer therapy. However, nonspecific protein adsorption of nanocarriers may block the modified nanoparticles in tumor cells, which would lead to inefficient cellular internalization. To address this issue, pH-responsive polyurethane prodrug micelles with a zwitterionic segment were designed and prepared. The micelle consisted of a zwitterionic segment as the hydrophilic shell and the drug Adriamycin (DOX) as the hydrophobic inner core. As a pH-responsive antitumor drug delivery system, the prodrug micelles showed high stability in a physiological environment and continuously released the drug under acidic conditions. In addition, the pure polyurethane carrier was demonstrated to be virtually non-cytotoxic by cytotoxicity studies, while the prodrug micelles were more efficient in killing tumor cells compared to PEG-PLGA@DOX. Furthermore, the DOX cellular uptake efficiency of prodrug micelles was proved to be obviously higher than the control group by both flow cytometry and fluorescence microscopy. This is mainly due to the modification of a zwitterionic segment with PU. The simple design of zwitterionic prodrug micelles provides a new strategy for designing novel antitumor drug delivery systems with enhanced cellular uptake rates.

Near-infrared light triggered activation of pro-drug combination cancer therapy and induction of immunogenic cell death

Disulfiram copper complex [Cu(DDC)2] nanoparticles have been explored as promising anticancer agents but with concerns of toxic side effects. To improve tumor specificity and enhance anticancer efficacy, we developed a novel [copper sulfide nanoparticle (CuS NP) + disulfiram prodrug (DQ) micelle + near-infrared (NIR) laser] (CDL) combination therapy. DQ, a reactive oxygen species (ROS)-responsive prodrug, can be selectively activated at the tumor site with elevated ROS to release DDC and form Cu(DDC)2in situ. The CuS NP + NIR laser treatment can effectively increase the intra-tumor ROS levels and efficiently activate the DQ prodrug. The CDL therapy kills cancer cells through multiple mechanisms, including ROS amplification cascade and Cu(DDC)2 chemotherapy. NIR light-triggered tumor-specific “nontoxic-to-toxic” transition can significantly improve the specificity of anticancer effects and reduce systemic toxicity. Also, CDL therapy can effectively induce immunogenic cell death (ICD) and has the potential of eliciting antitumor immunity.

TGF-β blockade-improved chemo-immunotherapy with pH/ROS cascade-responsive micelle via tumor microenvironment remodeling

Immunosuppressive tumor microenvironment and low delivery efficiency severely impede the tumor chemotherapy effect. To address this issue, we develop a pH/ROS cascade-responsive prodrug micelle to deliver siTGF-β with size-shrinkage and charge-reversal property, leading to synergistical tumor microenvironment remodeling. The nanosystem highly improved endocytosis efficiency and tumor penetration depth through charge reversal and size reduction upon exposure to weakly acidic tumor microenvironment. Moreover, the nanocarrier would rapidly escape from endo/lysosome, disassemble and release siTGF-β and hydroxycamptothecin in response to high intracellular ROS. Furthermore, the nanosystem significantly boosted antitumor immune response and reduced immune tolerance with remodeling tumor microenvironment, which significantly prolonged the survival time of tumor-bearing mice (75% survival rate upon 35 days). It is realized by the combined effects of chemotherapy-enhanced immunogenicity and recruitment of effector T cells, TGF-β-blockade immunotherapy-activated inhibition immunosuppressive tumor microenvironment and epithelial-to-mesenchymal transition (EMT), and regulation physical tumor microenvironment via reducing the dense tumor extracellular matrix and the high tumor interstitial pressure obstacles. To this end, the nanosystem not only overcame biobarriers and reinforced antitumor immune response, but also effectively inhibited tumor growth, metastasis and recurrence in vivo.

Degradable pH-responsive polymer prodrug micelles with aggregation-induced emission for cellular imaging and cancer therapy

Polymeric micelles with simultaneous bioimaging, drug delivery monitoring, and effective delivery of therapeutic agents to target sites have attracted increasing attention in cancer therapy. In this study, a new biodegradable, pH-responsive, aggregation-induced emission (AIE)-active polycarbonate brush-like polymer was developed by combining ring-opening polymerization with click reaction. The anticancer drug, doxorubicin (DOX), was covalently conjugated to the polymer backbone via acid-sensitive Schiff base linkage, resulting in the pH-sensitive controlled release of DOX. The prodrug polymer self-assembled into nanomicelles in an aqueous solution, as confirmed using dynamic light scattering and transmission electron microscopy. Fluorescence imaging results demonstrated that prodrug micelles could be traced owing to the AIE features of micelles. In vitro drug release studies showed that DOX release was faster in acidic conditions (pH 5.0), whereas only a minimal amount of DOX was released in a physiological environment (pH 7.4). In summary, these smart prodrug micelles could be promising candidates for simultaneous intracellular imaging and cancer therapy.

Simultaneous Determination of 1-Methyltryptophan and Indoleamine 2,3-Dioxygenase Biomakers of Tryptophan and Kynurenine in Mice Tumors by HPLC–MS/MS

Indoleamine 2,3-dioxygenase (IDO), an immune checkpoint protein, can cause the depletion of tryptophan (Trp) and accumulation of its metabolite of kynurenine (Kyn) in cancer cells, and generates the immunosuppressive microenvironment that supports tumor cell growth. A novel immunoregulatory prodrug micelle based on polyethylene glycol-derivatized an IDO-selective inhibitor of 1-methyltryptophan (1-MT), PEG-Fmoc-1-MT, was developed for inhibiting the IDO activity of the conversion of Trp to Kyn in tumor microenvironments. To investigate the 1-MT distribution and Trp/Kyn ratios in mice tumors with PEG-Fmoc-1-MT prodrug micelles treatment, a HPLC–MS/MS method for simultaneous determination of 1-MT and IDO biomakers of Trp and Kyn in mouse tumors was developed and validated. Triple-quadrupole mass spectrometry with positive electrospray ionization as source ionization in multiple reaction monitoring at m/z 219.0 → 160.1, 205.0 → 118.2, 209.0 → 146.1 and 249.3 → 148.3 was used for determination of 1-MT, Trp, Kyn and matrine (internal standard). The method demonstrated good linearity at the concentrations ranging from 10 to 10,000 ng/mL and lower limits of quantitation of 1 ng/mL for 1-MT, Trp and Kyn, respectively. The validated method was successfully applied to 1-MT tumor biodistribution and Trp/Kyn ratio studies in 4T1 tumor bearing mice i.v. with PEG-Fmoc-1-MT prodrug micelles. The mice tumors with PEG-Fmoc-1-MT prodrug micelles treatment exhibited higher 1-MT accumulation and lower Trp/Kyn ratio, in comparison with those of mice with 1-MT solution treatment. The developed PEG-Fmoc-1-MT prodrug micelles could be a promising IDO immunoregulatory prodrug micelles for cancer immunotherapy.

Fluorescent turn-on carbon dot-cored pseudo unimolecular prodrug micelles for tumor-specific dual-triggered drug delivery

Polymer prodrugs have attracted intense attention in tumor chemotherapy in the form of nanoparticles, nanogels or micelles. However, it is still a challenge to control their particle size and stability. Here, carbon dot-cored star-like copolymer hybrid prodrug (CD-PMHyDOX-ssPEG) has been designed for the tumor-specific fluorescent turn-on and pH/reduction dual-triggered drug delivery. The fluorescence of CDs was almost completely quenched after the surface modification and drug conjugation via both static and dynamic quenching effects. It could easily self-assemble into pseudo unimolecular prodrug micelles in aqueous system with CDs as fluorescent off-on core, acid-labile polymer prodrug block as shell and reduction-triggered detached PEG block as corona, possessing excellent tumor-specific pH and reduction dual-triggered drug release performance. Furthermore, the fluorescence of CDs could be partially recovered after the drug release because of the relief of the dynamic quenching during the drug release.

Polymeric Nanovectors Incorporated with Ganciclovir and HSV-tk Encoding Plasmid for Gene-Directed Enzyme Prodrug Therapy.

In the area of gene-directed enzyme prodrug therapy (GDEPT), using herpes simplex virus thymidine kinase (HSV-tk) paired with prodrug ganciclovir (GCV) for cancer treatment has been extensively studied. It is a process involved with two steps whereby the gene (HSV-tk) is first delivered to malignant cells. Afterward, non-toxic GCV is administered to that site and activated to cytotoxic ganciclovir triphosphate by HSV-tk enzyme expressed exogenously. In this study, we presented a one-step approach that both gene and prodrug were delivered at the same time by incorporating them with polymeric micellar nanovectors. GCV was employed as an initiator in the ring-opening polymerization of ε-caprolactone (ε-CL) to synthesize hydrophobic GCV-poly(caprolactone) (GCV–PCL), which was furthered grafted with hydrophilic chitosan to obtain amphiphilic polymer (GCV–PCL–chitosan) for the fabrication of self-assembled micellar nanoparticles. The synthesized amphiphilic polymer was characterized using Fourier transform infrared spectroscopy and proton nuclear magnetic resonance. Micellar prodrug nanoparticles were analyzed by dynamic light scattering, zeta potential, critical micelle concentration, and transmission electron microscopy. Polymeric prodrug micelles with optimal features incorporated with HSV-tk encoding plasmids were cultivated with HT29 colorectal cancer cells and anticancer effectiveness was determined. Our results showed that prodrug GCV and HSV-tk cDNA encoded plasmid incorporated in GCV–PCL–chitosan polymeric nanocarriers could be delivered in a one-step manner to HT-29 cells and triggered high cytotoxicity.

Smart Responsive Quercetin-Conjugated Glycol Chitosan Prodrug Micelles for Treatment of Inflammatory Bowel Diseases.

The incidence and progression of inflammatory bowel disease are closely related to oxidative stress caused by excessive production of reactive oxygen species (ROS). To develop an efficacious and safe nanotherapy against inflammatory bowel diseases (IBD), we designed a novel pH/ROS dual-responsive prodrug micelle GC-B-Que as an inflammatory-targeted drug, which was comprised by active quercetin (Que) covalently linked to biocompatible glycol chitosan (GC) by aryl boronic ester as a responsive linker. The optimized micelles exhibited well-controlled physiochemical properties and stability in a physiological environment. Time-dependent NMR spectra traced the changes in the polymer structure in the presence of H2O2, confirming the release of the drug. The in vitro drug release studies indicated a low release rate (<20 wt %) in physiological conditions, but nearly complete release (>95 wt % after 72 h incubation) in a pH 5.8 medium containing 10 μM H2O2, exhibiting a pH/ROS dual-responsive property and sustained release behavior. Importantly, the negligible drug release in a simulated gastric environment in 1 h allowed us to perform intragastric administration, which has potential to achieve the oral delivery by mature enteric-coating modification in future. Further in vivo activities and biodistribution experiments found that the GC-B-Que micelles tended to accumulate in intestinal inflammation sites and showed better therapeutic efficacy than the free drugs (quercetin and mesalazine) in a colitis mice model. Typical inflammatory cytokines including TNF-α, IL-6, and iNOS were significantly suppressed by GC-B-Que micelle treatment. Our work promoted inflammatory-targeted delivery and intestinal drug accumulation for active single drug quercetin and improved the therapeutic effect of IBD. The current study also provided an alternative strategy for designing a smart responsive nanocarrier for a catechol-based drug to better achieve the target drug delivery.

Self-Guiding Polymeric Prodrug Micelles with Two Aggregation-Induced Emission Photosensitizers for Enhanced Chemo-Photodynamic Therapy.

Nowadays, aggregation-induced emission luminogens (AIEgens) with reactive oxygen species (ROS) generating ability have been used as photosensitizers for imaging guided photodynamic therapy (PDT). To achieve enhanced antitumor outcomes, combining AIEgens-based PDT with chemotherapy is an efficient strategy. However, the therapeutic efficiency is hampered by the limited cellular uptake efficiency and the appropriate light irradiation occasion. In this paper, a self-guiding polymeric micelle (TB@PMPT) composed of two AIE photosensitizers and a reduction-sensitive paclitaxel prodrug (PTX-SS-N3) was established for enhanced chemo-photodynamic therapy by a dual-stage light irradiation strategy. When the micelles were accumulated in tumor tissues, the first light irradiation (L1, 6 min) was utilized to facilitate cellular uptake by "photochemical internalization" (PCI). Then, the intracellular glutathione (GSH) would induce the PTX release, micelles disassembly and the aggregation state change of AIEgens. The fluorescence signal change of two AIEgens-based ratiometric fluorescent probe could not only precisely guide the second light irradiation (L2, 18 min) for sufficient ROS production, but also monitor the nonfluorescent drug PTX release in turn. Both in vivo and in vitro studies demonstrated that the dual-stage light irradiation strategy employed for TB@PMPT micelles exhibited a superior therapeutic effect over only 24 min continuous light irradiation.

Bacterial infection microenvironment sensitive prodrug micelles with enhanced photodynamic activities for infection control

Because of the severe antibiotic resistance, photodynamic therapy is considered as a potent method for the treatment of bacterial infection with bare drug resistance. However, its therapeutic efficacy is not always satisfactory in practical treatment. In this study, pH-responsive prodrug micelles were prepared by conjugation of chlorin e6 to polyethylene glycol-b-poly(2-(hexamethyleneimino) ethyl methacrylate-co-aminoethyl methacrylate) for improving the antimicrobial activity of photodynamic therapy. The micelles were negatively charged in normal physiological environment, which was very important for long blood circulation. However, the micelles could turn to be positively charged in bacterial infection microenvironment and then adhere to negatively charged bacterial membranes, which could significantly improve their antibacterial activity against both methicillin-resistant Staphylococcus aureus and Escherichia coli after laser irradiation. The in vivo experiment showed excellent antibacterial effect of pH-sensitive micelles in a subcutaneous infection model. The micelles showed great potential in the photodynamic therapy of stubborn bacterial infections.

PH and ROS sequentially responsive podophyllotoxin prodrug micelles with surface charge-switchable and self-amplification drug release for combating multidrug resistance cancer

Multidrug resistance (MDR) is one of the main reasons for tumor chemotherapy failure. Podophyllotoxin (PPT) has been reported that can suppress MDR cancer cell growth; however, effective delivery of PPT to MDR cancer cells is challenged by cascaded bio-barriers. To effectively deliver PPT to MDR cancer cells, a PPT polymeric prodrug micelle (PCDMA) with the charge-conversion capability and self-acceleration drug release function are fabricated, which is composed of a pH and reactive oxygen species (ROS) sequentially responsive PPT-polymeric prodrug and an ROS generation agent, cucurbitacin B (CuB). After reach to tumor tissue, the surface charge of PCDMA could rapidly reverse to positive in the tumor extracellular environment to promote cellular uptake. Subsequently, the PCDMA could be degraded to release PPT and CuB in response to an intracellular high ROS condition. The released CuB is competent for generating ROS, which in turn accelerates the release of PPT and CuB. Eventually, the released PPT could kill MDR cancer cells. The in vitro and in vivo studies demonstrated that PCDMA was effectively internalized by cancer cells and produces massive ROS intracellular, rapid release drug, and effectively overcame MDR compared with the control cells, due to the tumor-specific weakly acidic and ROS-rich environment. Our results suggest that the pH/ROS dual-responsive PCDMA micelles with surface charge-reversal and self-amplifying ROS-response drug release provide an excellent platform for potential MDR cancer treatment.

The design and synthesis of redox-responsive oridonin polymeric prodrug micelle formulation for effective gastric cancer therapy.

Advanced gastric cancer (GC) is a significant threat to human health. Oridonin (ORI), isolated from the Chinese herb Rabdosia rubescens, has demonstrated great potential in GC therapy. However, the application of ORI in the clinic was greatly hindered by its poor solubility, low bioavailability, and rapid plasma clearance. Herein, a simple and novel redox-sensitive ORI polymeric prodrug formulation was synthesized by covalently attaching ORI to poly(ethylene glycol)-block-poly(l-lysine) via a disulfide linker, which can self-assemble into micelles (P-ss-ORI) in aqueous solutions and produce low critical micelle concentrations (about 10 mg L-1), characterized by small size (about 80 nm), negative surface charge (about -12 mV), and high drug loading efficiency (18.7%). The in vitro drug release study showed that P-ss-ORI can rapidly and completely release ORI in a glutathione (GSH)-rich environment and under low pH conditions. Moreover, in vitro and in vivo investigations confirmed that P-ss-ORI could remarkably extend the blood circulation time of ORI, enrich in tumor tissue, be effectively endocytosed by GC cancer cells, and quickly and completely release the drug under high intracellular GSH concentrations and low pH conditions, all these characteristics ultimately inhibit the growth of GC. This redox and pH dual-responsive P-ss-ORI formulation provides a useful strategy for GC treatment.

Crizotinib Prodrug Micelles Co-Delivered Doxorubicin Synergistic Immunogenic Cell Death Induction for Chemo-Immunotherapy on Breast Cancer

Crizotinib Prodrug Micelles Co-Delivered Doxorubicin Synergistic Immunogenic Cell Death Induction for Chemo-Immunotherapy on Breast Cancer

Increased the TMZ concentration in brain by poly(2-ethyl-2-oxazoline) conjugated temozolomide prodrug micelles for glioblastoma treatment

The current treatment of glioblastoma (GBM) remains challenging. Temozolomide (TMZ), a first-line chemotherapy drug used to treat glioblastoma, is rapidly cleared under normal physiological conditions and has poor stability, which severely limits its efficacy. In current work, poly(2-ethyl-2-oxazoline) (PEtOz) conjugated TMZ (PEtOz-TMZ) was synthesized and directly dissolved in PBS to form prodrug micelles. This PEtOz-TMZ conjugation did not affect the DNA alkylation of TMZ and enhanced the stability of TMZ, prolonged the circulation time in vivo and increased the TMZ accumulation in glioblastoma. In vivo, the PEtOz-TMZ micelle significantly enhanced the efficiency of TMZ to inhibit the growth of glioblastoma. These results indicate that binding to the polymer can effectively improve the efficacy and stability of TMZ, and is a promising route of administration of TMZ in clinic.

Redox/NIR dual-responsive PEG-betulinic acid/pluronic-cypate prodrug micelles for chemophotothermal therapy

Betulinic acid (BA) is a new class of anticancer drug, but its relatively short half-life and poor water solubility limit its therapeutic effect and clinical application. Herein, to tackle the dilemma, BA prodrugs were prepared by conjugating BA onto the polyethylene glycol (PEG) polymer via cleavable disulfide bonds. The prodrugs exhibited high water solubility (270-fold of free BA) and a relatively high drug-loading efficiency of 14.2 %. To further endow the BA prodrugs with a photothermal therapeutic effect, the near-infrared (NIR) agent Cypate was grafted on the Pluronic triblock copolymer. The different PEG polymers and different Pluronic polymers were chosen to obtain the optimal drug loading efficiency and the photothermal generation effect. The P-SS-BA/F68-Cy prodrug micelles integrate the redox-responsive BA prodrugs and the NIR-responsive amphiphilic triblock polymer into one single nanocomposite. The release of BA was less than 20 % in pH 7.4 PBS in the absence of glutathione (GSH), whereas the release of BA was obviously accelerated in pH 5.0 PBS with 10 mM GSH. In addition, the release of BA was further accelerated under the NIR irradiation. The P-SS-BA/F68-Cy micelles showed an excellent photothermal heating effect under NIR irradiation. The prepared P-SS-BA/F68-Cy micelles showed the synergistic thermochemotherapeutic effect on tumors both in vitro and in vivo. Therefore, the present study shows the great potential of dual-triggered drug delivery and thermochemotherapy for combination therapy.

Acetal-linked polymeric prodrug micelles based on aliphatic polycarbonates for paclitaxel delivery: preparation, characterization, in vitro release and anti-proliferation effects

Acidic tumor microenvironment has been extensively explored to design pH-responsive paclitaxel prodrug micelles for cancer therapy. The object of this study is to investigate the pH-responsive drug release behavior and the anti-proliferation capacity of acetal-linked paclitaxel polymeric prodrug micelles. The prodrug was synthesized and evaluated for paclitaxel content. The prodrug micelles were fabricated and characterized for morphology, size, in vitro pH-responsive paclitaxel release, cellular uptake, and anti-proliferation. Paclitaxel content was 33 wt%. The prodrug micelles exhibited spherical structure with the hydrodynamic diameter of 154 nm. Besides, the in vitro paclitaxel release behavior was verified to be pH-responsive, and 77%, 38%, and 17% of parent free paclitaxel was released from the nano-sized prodrug micelles in 13 h at pH 5.5, 6.5, and 7.4, respectively. The cellular uptake assessment demonstrated the time-dependent internalization of prodrug micelles. Meanwhile, CCK-8 analysis showed that prodrug micelles possessed the potent anti-proliferation effects. Prodrug micelles based on aliphatic polycarbonates present a promising platform for cancer chemotherapy due to the pH-responsive characteristics of acetal bond, potent anti-proliferation effects, and outstanding cytocompatibility of aliphatic polycarbonates.