Polyamino acid calcified nanohybrids induce immunogenic cell death for augmented chemotherapy and chemo-photodynamic synergistic therapy.
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ABSTRACT:
SUBMITTER: Qiu W
PROVIDER: S-EPMC8490510 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Melanin, as a natural product, has been used as an extraordinary ingredient for nanomedicine due to its great biocompatibility and light responsive property. In this study, polydopamine (PDA), an analog of melanin, was extracted from dopamine and encapsulated with doxorubicin (DOX). The as-prepared nanoparticles (NPs) with good stability, great biosafety and high near infrared (NIR) responsive property ameliorated the cell uptake of DOX in OS-RC-2/ADR cells, exhibited synergistic chemo/photothermal (PTT)/photodynamic (PDT) effects, induced the release of damage associated molecular patterns (DAMPs), and finally, led to immunogenic cell death (ICD). In general, it was suggested that PDA-DOX NPs with NIR irradiation could serve as a promising agent for tumor therapy.
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Project description:The simple integration of chemotherapeutic drugs and photosensitizers (PSs) into the same nanocarriers only achieves a combination of chemo-photodynamic therapy but may not confer synergistic effects. The boosted intracellular release of chemotherapeutic drugs during the photodynamic therapy (PDT) process is necessary to achieve a cascade of amplified synergistic therapeutic effects of chemo-photodynamic therapy. Methods: In this study, we explored an innovative hyperbranched polyphosphate (RHPPE) containing a singlet oxygen (SO)-labile crosslinker to boost drug release during the PDT process. The photosensitizer chlorin e6 (Ce6) and doxorubicin (DOX) were simultaneously loaded into RHPPE nanoparticles (denoted as SOHNPCe6/DOX). The therapeutic efficacy of SOHNPCe6/DOX against drug-resistant cancer was evaluated in vitro and in vivo. Results: Under 660-nm light irradiation, SOHNPCe6/DOX can produce SO, which not only induces PDT against cancer but also cleaves the thioketal linkers to destroy the nanoparticles. Subsequently, boosted DOX release can be achieved, activating a chemotherapy cascade to synergistically destroy the remaining tumor cells after the initial round of PDT. Furthermore, SOHNPCe6/DOX also efficiently detected the tumor area by photoacoustic/magnetic resonance bimodal imaging. Under the guidance of bimodal imaging, the laser beam was precisely focused on the tumor areas, and subsequently, SOHNPCe6/DOX realized a cascade of amplified synergistic chemo-photodynamic therapeutic effects. High antitumor efficacy was achieved even in a drug-resistant tumor model. Conclusion: The designed SOHNPCe6/DOX with great biocompatibility is promising for use as a co-delivery carrier for combined chemo-photodynamic therapy, providing an alternative avenue to achieve a cascade of amplified synergistic effects of chemo-photodynamic therapy for cancer treatment.
| S-EPMC5996363 | biostudies-literature
Project description:BackgroundsSurgical resection and adjunct chemotherapy or radio-therapy has been applied for the therapy of superficial malignant tumor in clinics. Whereas, there are still some problems limit its clinical use, such as severe pains and side effect. Thus, it is urgent need to develop effective, minimally invasive and low toxicity therapy stagey for superficial malignant tumor. Topical drug administration such as microneedle patches shows the advantages of reduced systemic toxicity and nimble application and, as a result, a great potential to treat superficial tumors.MethodsIn this study, microneedle (MN) patches were fabricated to deliver photosensitizer IR820 and chemotherapy agent cisplatin (CDDP) for synergistic chemo-photodynamic therapy against breast cancer.ResultsThe MN could be completely inserted into the skin and the compounds carrying tips could be embedded within the target issue for locoregional cancer treatment. The photodynamic therapeutic effects can be precisely controlled and switched on and off on demand simply by adjusting laser. The used base material vinylpyrrolidone-vinyl acetate copolymer (PVPVA) is soluble in both ethanol and water, facilitating the load of both water-soluble and water-insoluble drugs.ConclusionsThus, the developed MN patch offers an effective, user-friendly, controllable and low-toxicity option for patients requiring long-term and repeated cancer treatments.
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Project description:Carrier-free prodrug-nanoassemblies have emerged as promising nanomedicines. In particular, the self-assembled nanoparticles (NPs) composed of homodimeric prodrugs with ultrahigh drug loading have attracted broad attention. However, most homodimeric prodrugs show poor self-assembly ability due to their symmetric structures. Herein, we developed photosensitizer-driven nanoassemblies of homodimeric prodrug for self-enhancing activation and chemo-photodynamic synergistic therapy. Methods: In this work, a pyropheophorbide a (PPa)-driven nanoassemblies of an oxidation-responsive cabazitaxel homodimer (CTX-S-CTX) was fabricated (pCTX-S-CTX/PPa NPs). The assembly mechanisms, aggregation-caused quenching (ACQ) effect alleviation, singlet oxygen generation, self-enhancing prodrug activation, cellular uptake, intracellular reactive oxygen species (ROS) generation and synergistic cytotoxicity of pCTX-S-CTX/PPa NPs were investigated in vitro. Moreover, the pharmacokinetics, ex vivo biodistribution and in vivo therapeutic efficacy of pCTX-S-CTX/PPa NPs were studied in mice bearing 4T1 tumor. Results: Interestingly, PPa was found to drive the assembly of CTX-S-CTX, which cannot self-assemble into stable NPs alone. Multiple intermolecular forces were found to be involved in the assembly process. Notably, the nanostructure was destroyed in the presence of endogenous ROS, significantly relieving the ACQ effect of PPa. In turn, ROS generated by PPa under laser irradiation together with the endogenous ROS synergistically promoted prodrug activation. As expected, the nanoassemblies demonstrated potent antitumor activity in a 4T1 breast cancer BALB/c mice xenograft model. Conclusion: Our findings offer a simple strategy to facilitate the assembly of homodimeric prodrugs and provide an efficient nanoplatform for chemo-photodynamic therapy.
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Project description:The combination of chemotherapy and photodynamic therapy (PDT) based on nanoparticles (NPs) has been extensively developed to improve the therapeutic effect and decrease the systemic toxicity of current treatments. However, overexpressed glutathione (GSH) in tumor cells efficiently scavenges singlet oxygens (1O2) generated from photosensitizers and results in the unsatisfactory efficacy of PDT. To address this obstacle, here we design H2O2-responsive polymer prodrug NPs with GSH-scavenger (Ce6@P(EG-a-CPBE) NPs) for chemo-photodynamic synergistic cancer therapy. They are constructed by the co-self-assembly of photosensitizer chlorin e6 (Ce6) and amphiphilic polymer prodrug P(EG-a-CPBE), which is synthesized from a hydrophilic alternating copolymer P(EG-a-PD) by conjugating hydrophobic anticancer drug chlorambucil (CB) via an H2O2-cleavable linker 4-(hydroxymethyl)phenylboronic acid (PBA). Ce6@P(EG-a-CPBE) NPs can efficiently prevent premature drug leakage in blood circulation because of the high stability of the PBA linker under the physiological environment and facilitate the delivery of Ce6 and CB to the tumor site after intravenous injection. Upon internalization of Ce6@P(EG-a-CPBE) NPs by tumor cells, PBA is cleaved rapidly triggered by endogenous H2O2 to release CB and Ce6. Ce6 can effectively generate abundant 1O2 under 660 nm light irradiation to synergistically kill cancer cells with CB. Concurrently, PBA can be transformed into a GSH-scavenger (quinine methide, QM) under intracellular H2O2 and prevent the depletion of 1O2, which induces the cooperatively strong oxidative stress and enhanced cancer cell apoptosis. Collectively, such H2O2-responsive polymer prodrug NPs loaded with photosensitizer provide a feasible approach to enhance chemo-photodynamic synergistic cancer treatment. Graphical abstract Schematic diagram of the H2O2-responsive P(EG-a-CPBE) prodrug with GSH-scavenger to encapsulate Ce6 for enhanced chemo-photodynamic synergistic cancer therapy.Image 1 Highlights • Polymer prodrug P(EG-a-CPBE) was synthesized by conjugating the chemodrug CB to the hydrophilic alternating copolymer P(EG-a-PD) via a H2O2-cleavable linker 4-(hydroxymethyl)phenylboronic acid (PBA).• H2O2-responsive P(EG-a-CPBE) prodrug with GSH-scavenger was used to encapsulate photosensitizer Ce6 to form the Ce6@P(EG-a-CPBE) NPs for chemo-photodynamic synergistic cancer therapy.• Upon irradiation by 660 nm laser, the Ce6@P(EG-a-CPBE) NPs showed superior synergistic therapeutic effect and excellent biosafety.
| S-EPMC9932349 | biostudies-literature
Project description:Synergistic chemo-photodynamic therapy has garnered attention in the field of cancer treatment. Here, a pH cascade-responsive micellar nanoplatform with nucleus-targeted ability, for effective synergistic chemo-photodynamic cancer treatment, was fabricated. In this micellar nanoplatform, 5-(4-carboxyphenyl)-10,15,20-triphenylporphyrin (Por), a photodynamic therapy (PDT) agent was utilized for carrying the novel anticancer drug GNA002 to construct a hydrophobic core, and cyclic RGD peptide (cRGD)-modified polyethylene glycol (PEG) (cRGD-PEG) connected the cell-penetrating peptide hexaarginine (R6) through a pH-responsive hydrazone bond (cRGD-PEG-N = CH-R6) to serve as a hydrophilic shell for increasing blood circulation time. After passively accumulating in tumor sites, the self-assembled GNA002-loaded nanoparticles were actively internalized into cancer cells via the cRGD ligands. Once phagocytosed by lysosomes, the acidity-triggered detachment of the cRGD-PEG shell led to the formation of R6-coated secondary nanoparticles and subsequent R6-mediated nucleus-targeted drug delivery. Combined with GNA002-induced nucleus-specific chemotherapy, reactive oxygen species produced by Por under 532-nm laser irradiation achieved a potent synergistic chemo-photodynamic cancer treatment. Moreover, our in vitro and in vivo anticancer investigations revealed high cancer-suppression efficacy of this ideal multifunctional nanoplatform, indicating that it could be a promising candidate for synergistic anticancer therapy.
| S-EPMC8130269 | biostudies-literature
Project description:Rationale: The combination of photosensitizers, oxygen supply agents, and adjuvant therapy drugs in a single nano-drug delivery system for photodynamic therapy (PDT) has been showing great promises to overcome the inherent challenges of PDT for tumor treatment. However, the complicated preparation of integrating multiple components hampers their further developments. Here, we describe a self-assembly nanomicelle with rationally designed building blocks, which shows a high efficiency of synergistic chemo-photodynamic therapy in the animal modal. Methods: The nanomicelle was prepared by a coordination-driven self-assembly based on a rationally designed ferrocene cyclopalladated compound coupled with photosensitizers and hyaluronic acid (referred to as FCP-Tph/HA). The morphology, targeting drug delivery, pharmacokinetics, hemolysis, and multimodal synergistic therapy of FCP-Tph/HA were investigated. Results: The formation of nanomicelles presents a low hemolysis rate and a prolonged blood circulation time. FCP-Tph/HA possesses an enhanced antitumor effect in vitro through the specific binding of HA to CD44 and combining chemotherapy with oxygen self-supplying PDT. Simultaneously, the nanomicelle facilitates a significantly improved antitumor efficacy (>90% tumor regression) on a breast cancer model in vivo. Conclusion: Our results present a modular self-assembled nanomicellar platform with synergistic chemo-photodynamic therapy for challenging PDT-based tumor treatment.
| S-EPMC8899564 | biostudies-literature
Project description:Stimuli-responsive drug release and photodynamic therapy (PDT) have aroused extensive attention for their enormous potential in antitumor treatment. pH-responsive drug delivery systems (PFE-DOX-1 and PFE-DOX-2) based on water-soluble conjugated polymers were constructed in this work for high-performance synergistic chemo-/PDT therapy, in which the anticancer drug doxorubicin (DOX) is covalently attached to the side chains of the conjugated polymers via acid-labile imine and acylhydrazone bonds. Concurrently, the intense fluorescence of poly(fluorene-co-ethynylene) (PFE) is effectively quenched due to the energy/electron transfer (ET) between the PFE-conjugated backbone and DOX. Effective pH-responsive drug release from PFE-DOX-2 is achieved by the cleavage of acylhydrazone linkages in the acidic tumor intracellular microenvironment. Additionally, the drug release process can be monitored by the recovered fluorescence of conjugated polymers. Furthermore, the conjugated polymers can produce reactive oxygen species (ROS) under light irradiation after drug release in an acidic environment, which prevents possible phototoxicity to normal tissues. It is noted that PFE-DOX-2 demonstrates remarkable antitumor cell performance, which is attributed to its efficient cell uptake and powerful synergistic chemo-/PDT therapeutic effectiveness. This report thus provides a promising strategy for in vivo anticancer treatment with the construction of a stimuli-responsive multifunctional drug delivery system.
| S-EPMC9823741 | biostudies-literature
Project description:BackgroundThe integration of photodynamic therapy with a chemical drug-delivery system has displayed great potential in enhancing anticancer therapy. However, the solubility and non-specific biodistribution of both chemotherapeutic agents and photosensitizers continue to pose challenges that hinder their clinical applications.MethodA polypeptide-based nanoscale drug delivery system was fabricated to address the prementioned issues. An amphiphilic polymer was formed by conjugating the photosensitizer chlorin e6 (Ce6) onto a polypeptide poly-(L-lysine)-b-polyphenylalanine (PKF) for encapsulating the model drug dimeric camptothecin (DCPT), and the nanoparticles (PCD) with high drug loading efficiency were further modified with acid-sensitive polyethylene glycol (PEG) to yield the drug delivery sytem (PPCD).ResultsThe DCPT and Ce6 encapsulation efficiency were analyzed as 99% and 73.5%, respectively. In phosphate-buffered saline (PBS) solution at a pH of 7.4, the PEG shell improved the stability of micelles and shielded their positive charge while in the acidic tumor microenvironment, the pH-sensitive PEG layer was removed to expose the cationic nanoparticles, thus facilitating the cellular uptake of PPCD micelles. Benefiting from the enhanced cellular internalization, the amount of intracellular reactive oxygen species (ROS) treated with PCD and PPCD micelles were obviously increased. Furthermore, the enhanced anti-cancer efficacy prompted by PPCD micelles was validated through cellular and animal study.ConclusionThis study presents a promising method to promote the solubility and biodistribution of both chemotherapeutic agent and photosensitizer, thereby facilitating the further application of chemo-photodynamic cancer therapy.
| S-EPMC10576266 | biostudies-literature
Project description:The limited clinical efficacy of monotherapies in the clinic has urged the development of novel combination platforms. Taking advantage of light-triggered photodynamic treatment combined together with the controlled release of nanomedicine, it has been possible to treat cancer without eliciting any adverse effects. However, the challenges imposed by limited drug loading capacity and complex synthesis process of organic nanoparticles (NPs) have seriously impeded advances in chemo-photodynamic combination therapy. In this experiment, we utilize our previously synthesized porphyrin-grafted lipid (PGL) NPs to load highly effective chemotherapeutic drug, doxorubicin (DOX) for synergistic chemo-photodynamic therapy. Methods: A relatively simple and inexpensive rapid injection method was used to prepare porphyrin-grafted lipid (PGL) NPs. The self-assembled PGL NPs were used further to encapsulate DOX via a pH-gradient loading protocol. The self-assembled liposome-like PGL NPs having a hydrophilic core were optimized to load DOX at an encapsulation efficiency (EE) of ~99%. The resultant PGL-DOX NPs were intact, highly stable and importantly these NPs successfully escaped from the endo-lysosomal compartment after laser irradiation to release DOX in the cytosol. The therapeutic efficacy of the aforementioned formulation was validated both in vitro and in vivo. Results: PGL-DOX NPs demonstrated excellent cellular uptake, chemo-photodynamic response, and fluorescence imaging ability in different cell lines. Under laser irradiation, cells treated with a low molar concentration of PGL-DOX NPs reduced cell viability significantly. Moreover, in vivo experiments conducted in a xenograft mouse model further demonstrated the excellent tumor accumulation capability of PGL-DOX NPs driven by the enhanced permeability and retention (EPR) effect. Through fluorescence imaging, the biodistribution of PGL-DOX NPs in tumor and major organs was also easily monitored in real time in vivo. The inherent ability of porphyrin to generate ROS under laser irradiation combined with the cytotoxic effect of the anticancer drug DOX significantly suppressed tumor growth in vivo. Conclusion: In summary, the PGL-DOX NPs combined chemo-photodynamic nanoplatform may serve as a potential candidate for cancer theranostics.
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