Table 2.
Preclinical studies on organic nanoparticles for codelivery in PDT plus chemotherapy.
| PS | Chemo Drugs | Delivery System | Specific Function of Delivery System | Cancer Models | Therapeutic Outcomes of Combination | Ref |
|---|---|---|---|---|---|---|
| Polymeric Nanoparticles | ||||||
| Ce6 | DOX | RGD–PEG–DOX nanoparticles | pH-responsive; tumor targeting by RGD peptide | MDA-MB-231 cells, MCF-7 cells; MDA-MB-231 tumor-bearing mouse model | High cytotoxicity effect in vitro due to improved cellular uptake; significantly enhanced antitumor effect with lower cardiotoxicity of DOX, according to the pathological analysis | [98] |
| Ce6 | Curcumin | Crosslinked polyphosphazene nanoparticles (FHCPCe NPs) | PH/redox dual-stimuli-responsive; dual-modal imaging (fluorescent imaging (FL) and computed tomography (CT)) | HeLa xenograft cervical cancer mouse model | Synergistic antitumor activity both in vitro and in vivo | [105] |
| Ce6 | DOX | MnO2-loaded PCLA–PEG–PCLA NPs (CDM NPs) | Intratumoral self-sufficiency of O2; trimodal imaging (FL, PA, MRI) | MCF-7 xenograft human breast tumors | Enhanced tumor growth inhibition and the inhibition ratio (IR) calculated by tumor weight was 92.35%, with no appreciable impact on body weight or the major organs in mice | [106] |
| HPPH | Camptothecin (CPT) | Polymeric nanoparticles | ROS-responsive; dual-imaging (PA and FL) | Nude mice bearing CT26 colorectal cancer | Effectively inhibit tumor proliferation and growth in vitro and in vivo | [107] |
| TPPS2a | DOX | Copolymer nanoparticles | O2-evolving and ROS-activable; tumor targeting by F7 peptide | MCF-7/ADR tumor-bearing mice | Enhanced cell killing effects in vitro; prolonged survival time of combined therapy to 41 days, compared to NP-based PDT (32 days) and free DOX (25 days). | [108] |
| TPCS2a | DTX | Polymeric nanoparticles (HA@DTX/TPCS2a-NPs) | Tumor targeting ability | CD44high MDA-MB-231 and the CD44low MCF-7 cells; mammosphere | Enhanced killing CSCs effects in vitro by 2D and 3D assay | [100] |
| TPCS2a | CPT | Double-layered polymeric nanoparticles | Tumor targeting due to HA | DTX-sensitive (HeLa-P, MDA-MB-231) and DTX-resistant (HeLa-R) cancer cells | Synergistic antitumor activity in vitro and reduced DTX dose in NPs by ~2.6- and 10.7-fold in HeLa-P and MDA-MB-231, respectively; reduced DTX doses in NPs by more than 100 times in DTX-resistant HeLa-R cells | [109] |
| Polymer PFV materials | Prodrug BDOX | DSPE–PEG–iRGD–PFV–BDOX conjugated polymer NPs | Tumor targeting by iRGD peptide; ROS-responsive | PC-3 human prostate cancer cells | Enhanced cancer cell killing effects in vitro due to enhanced tumor cell targeting and uptake | [110] |
| ICG | Oxaliplatin (OXP) | PLGA–PFP–OXP–ICG NPs | Photoacoustic and ultrasonic imaging | ID8 ovarian tumor mouse model | Improved antitumor effects on cancer cell due to enhanced DAMPs expression | [111] |
| IR780 | DOX | Amphiphilic nanoparticles (F-IR780–PEG) | Intratumorally self-sufficiency of O2; NIR-responsive; high oxygen capacity | Nude mice bearing MCF-7 human breast cancer | Remarkable therapeutic efficacy in killing tumor cells and destroying solid tumor | [112] |
| Hematoporphyrin (HP) | DOX | PEG-modified hematoporphyrin (HPP)-based NPs (HPPD) | Enhanced drug release at pH 5.8, along with laser radiation | MCF-7 human breast cancer cells and MHCC-97H human hepatoma cancer cells; nude mice bearing ADR/MCF-7 human breast tumors | A 12-fold decreased IC50 value due to improved drug penetration, resulting in promoted apoptosis in vitro; compared to free Dox, which failed to constrain tumor growth, combined therapy had efficient drug-resistant tumor ablation to an undetectable level in 2 weeks without inducing myocardial injury | [113] |
| Protoporphyrin (Por) | Epirubicin (EPI) | EPI-loaded cRGD–PEG–PH–PCL–Por | pH sensitivity; tumor targeting due to cRGD | CT26 murine colorectal tumor mouse model | Higher anticancer effectiveness, both in vitro with an IC50 = 0.47 μg/mL and in vivo, than that of free EPI | [114] |
| 5,10,15,20-Tetraphenylchlorin (TPC) | PTX dimer (PTX2-TK) | RBC-membrane-coated (TPC–PTX2–TK–PEG) NPs | Prolonged blood circulation and improved tumor accumulation by coating RBC membrane | Nude mice bearing HeLa human cervical carcinoma | Enhances anticancer therapeutic activity; reduces systematic toxicity due to light-triggered drug release, as certificated by H&E staining and serum biochemical analysis of main organs | [115] |
| NPs | SN38 | Multifunctional SN38-conjugated polymeric nanosystem (FA-PDA@PZM/SN38@BSA-MnO2) | Intratumoral self-sufficiency of O2; MRI imaging | Eca-109-esophageal tumor-bearing mice | Superior antitumor efficacy in Eca-109 tumor-bearing mice with low gastrointestinal toxicity and myelosuppression | [116] |
| Pyrolipid | Pt | Polymer-based core–shell nanoparticles | Drug release in a triggered manner | Human head and neck cancer SQ20B xenograft murine model | Superior potency and efficacy in tumor regression (83% reduction in tumor volume) at low drug doses in a cisplatin-resistant cancer model | [117] |
| ZnPc | DTX | Biodegradable core–shell nanoassemblies | Biodegradability and biosafety | HeLa cells, nude mice bearing A375 human amelanotic melanoma | Improved tumor growth-inhibitory effects compared to single therapy | [118] |
| Lipid-based NPs | ||||||
| Photosan-2 | Cisplatin (CDDP) | Lipid platinum-chloride nanoparticles (LPC NPs) | - | Nude mice bearing SAS squamous cell carcinoma | Significantly enhanced the therapeutic outcome in tumor volume reduction, compared to single therapies (~110.8% tumor growth inhibition); reduced the tumor growth rate | [119] |
| porphyrin | PTX | Porphyrin–lipid nanoemulsions | Imaging ability | KB xenografts tumor-bearing nude mice | Fourfold reduced PTX (1.8 mg/kg) dose in combined therapy with a superior antitumor effect, compared to single PTX therapy (7.2 mg/kg), resulting in reduced side-effects associated with chemotherapy | [120] |
| VP | Nano-Pt | Nano-Pt/VP@MLipo | Intratumoral self-sufficiency of O2 | 4T1 breast tumor mouse model | Significantly inhibited tumor cell viability in vitro (2D and 3D model); enhanced tumor inhibition and extended mice survival time with no lung metastasis, compared to monotherapies | [101] |
| ICG | TPZ | Hybrid PLGA/lipid-PEG NPs | Tumor targeting by RGD peptide; improved penetration | 3D tumor spheroids and orthotopic 4T1 breast tumor model | Synergistic cell-killing effect in vitro and effective primary tumor growth and metastasis inhibition; enhanced necrosis (~95% necrotic area) compared to control group (~30%), by analysis of the H&E tumor sections | [102] |
| Hydrogel | ||||||
| ZnPc | DOX | Polymer hydrogel | Thermosensitive | Nude mice bearing 5637 human bladder tumors | Excellent cell-inhibitory effects in vitro, with cell viability of 18.5%, which is attributed to a high level of ROS generation (4.8-fold free ZnPC); slightly higher increased survival rate compared to chemo and PDT single groups | [103] |
| Micelles | ||||||
| Mitoxantrone (MX) | MX | PEGylated UCNP (UPG) micelles | Tumor targeting by grafting with an anti-EpCAM antibody; dual-modality MR/UCL imaging | BEL-7404 liver carcinoma mouse model | 94.4% cell death in vitro for combined therapy, compared to 67.6% for chemo only, which was attributed to the physicochemical property of micelles; remarkable antitumor effect with final tumor volume: 235.5 ± 87.4 mm3, with negligible side-effects, as demonstrated by the images of H&E-stained major organs slices | [121] |
| IR780 | DOX | Polydopamine nano clustered micelles (TPGS-IR780@PDA) | Enhanced intracellular accumulation by TPGS (a drug efflux inhibitor) | Nude mice bearing ADR/MCF-7 human breast tumors | Improved tumor-inhibitory efficiency, as evidenced by tumor sizes starting to reduce after 2 days of treatment (8 days for PDT group) | [122] |
| Ce6 | DOX | Polymer–UCNP hybrid micelles (PUHMs) | NIR-triggered | HeLa human cervical carcinoma cells | High cytotoxicity for cancer cells in vitro, due to upconverted emission energy triggering ROS generation and faster DOX release | [123] |
| Ce6 | DOX prodrug (PDOX) | Gd3+-loaded copolymeric micelles conjugated with PS | Acid-switchable multimodal imaging (FL, PA, MR) capability | Nude mice bearing ADR/MCF-7 human breast tumors | Notably inhibited the tumor growth and completely eradicated two of the tumors, compared to single therapy; obvious DNA damage and membrane lysis revealed by H&E staining and notable apoptosis of tumor cells revealed by TUNEL staining | [124] |
| Ce6 | DOX | Self-assembled polyethyleneimine–nitroimidazole (PEI–NI) micelles | Hypoxia trigger; PA imaging; tumor targeting by HA | LLC xenograft tumor-bearing mice | Significantly stronger anticancer efficacy than single therapy in vitro, evidenced by IC50 value of DOX (1.15 µg/mL) or Ce6 (0.16 µg/mL) in combined group lower than those of chemotherapy (>10 µg/mL) or PDT (0.75 µg/mL); compared therapy showed remarkably prolonged survival after 35 days observation. | [104] |
| 5-(4-Carboxyphenyl)-10,15,20-triphenylporphyrin (Por) | GNA002 | Micellar GNA002@cPRP | pH-sensitive; tumor targeting by cRGD; improved drug penetrability in vitro and prolonged tumor-retainability in vivo | HeLa, HN6, A375, MCF-7, and HN30 cancer cells and HeLa tumor-bearing mice | Decreased IC50 and increased cell apoptosis for combined group, compared to single therapy, due to increased ROS generation in vitro; tumor weight on day 14 was just 6.3% and 6.7% of that of the saline group of the HeLa and HN6 cancer-bearing mice, respectively, with negligible body weight loss; widespread cancer cell necrosis and apoptosis caused by combined therapy in H&E staining images; highest TUNEL expression and lowest cancer cell proliferation in the TUNEL-staining and Ki-67 staining images, respectively | [125] |
| Porphyrin | DOX | PEG–PGMA–PDPA Janus macromolecular brushes | Improved drug loading capability by π–π stacking; pH-responsive | 4T1 breast cancer mouse model | In vitro studies showed the lowest cell viability (IC50: 7.2 µg/mL TPP and 2.5 µg/mL DOX); in vivo studies confirmed that NP-based combination exhibited high phototoxicity and significant tumor inhibition efficacy | [126] |
| Other Organic Nanoparticles | ||||||
| Ce6 | DTX | Redox-responsive polymer HA–cys-DHA/Ce6 (CHD) | Redox-responsive; Tumor-targeting by HA | MCF-7 breast tumor mouse model | Synergistic antitumor activity in vitro, due to inhibition of microtubule depolymerization, blocking cell cycle, and generating ROS, leading to best antitumor response in vivo | [127] |
| Ce6 | Pt(IV) | Oxygen and Pt(II) self-generating conjugate | Intratumoral self-sufficiency of O2 | BALB/c mice bearing HeLa, HCT116, and MDA-MB-231 tumors | Enhanced anticancer efficacy both in vitro and in vivo; specifically, in vivo results showed that two of the five mice in combined treatment group were healed, and the tumor volumes of the other three mice decreased to very little | [128] |
| Ce6 | TPZ | Self-assembly PA/HA–Ce6@TPZ NPs | Tumor targeting by HA; dual hypoxia-responsive | Nude mice bearing 4T1 breast cancer | Synergistic anticancer treatment due to PDT-mediated hypoxia-induced cascade TPZ therapy | [129] |
| Ce6 | DOX | DOX-NPs/Ce6-microbubble complex | Local release due to the cavitation of NPs; enhanced extravasation and penetration due to energy of ultrasound | Nude mice bearing MIA-paca-2 human pancreatic carcinoma | Increased therapeutic effects in vitro by cell viability assay and in vivo by normalized tumor volume | [130130] |
| Ce6 | DOX | Hyperbranched polyphosphate SOHNPCe6/DOX | NIR-triggered | Nude mice bearing ADR/MCF-7 human breast tumors | Enhanced in vitro apoptosis inducing efficiency (56.82%) and lower cell viability at 72 h (80.46 ± 6.31%), compared to single-therapy group; high antitumor efficacy in drug-resistant breast cancer nude mouse model | [131] |
| Ce6 | DOX | Ce6/Dox@NPs–cRGD | Tumor targeting by cRDG | MCF-7 xenograft human breast tumors | Significantly shrank tumor volume and prolonged survival time, compared to single therapies, with negligible body weight changes and staining organ slices | [132] |
| Ce6 | DOX precursor (CAD) | Co-assembly LA–CAT–CAD@Ce6 NPs | Tumor targeting by lactobionic acid; pH-sensitive; intratumorally self-sufficiency of O2 | Nude mice bearing human MCF-7/ADR breast tumor cells | Enhanced cell killing and apoptosis efficiency in vitro and the most effective tumor inhibition and ablation ability | [133] |
| Ce6 | Docetaxel (DTX) | Keratin nanoparticle | Monophasic release | DTX-sensitive HeLa (HeLa-P) and DTX-resistant HeLa (HeLa-R) cells | In monolayers, combined therapy had comparable cytotoxicity to free drugs toward HeLa-P cells, but synergic interaction in HeLa-R cells; induced stronger cytotoxicity and volume reduction rate in spheroids | [134] |
| Ce6 | SN38 | Carrier-free nanoparticles (SN38/Ce6 NPs) | Carrier-free | 4T1 murine breast cancer cell lines | Significant increase in the inhibition rate by 85%, compared to single therapy, in vitro due to enhanced tumor accumulation and higher cellular internalization | [135] |
| PheoA | DOX | DOX–PheoA–alginate NPs) | NIR-triggered drug release | B16 tumor-bearing mice | Enhanced tumor growth inhibition by combined therapy with increased serum IFN levels | [136] |
| PheoA | DOX | Self-assembly PEG–thioketal–DOX NPs | ROS-responsive; phototriggered release | Nude mice bearing CT-26 colorectal cancer | Enhanced anticancer therapeutic effect in vitro by cell viability assay and in vivo by tumor volume change, due to spatiotemporally controlled cascade drug release | [137] |
| VP | TMZ | Pluronic P85/F127 copolymers | Tumor targeting by biotin | T98-G, U87-MG, and U343 glioblastoma cells | Enhanced antiproliferative effect in vitro via different cell-cycle arrest mechanisms of drug action, especially at low TMZ concentrations and higher light doses | [138] |
| Hypocrellin B (HB) | PTX | Hyaluronic acid–ceramide nanoparticle | Tumor targeting due to HA | Nude mice bearing A549 human lung adenocarcinoma | Enhanced phototoxicity in vitro and improved anticancer efficacy, by tumor volume change, compared to single PDT and NP-based PDT | [139] |
| Pyropheophorbide a (PPa) | PTX | Self-assembly heterotypic chemo-photodynamic dimer | ROS-responsive | KB xenograft tumor-bearing nude mice, 4T1 xenograft tumor-bearing BABL/c mice | Synergistic antitumor activity, both in vitro and in vivo | [140] |
| Carbon dots (CDs) | Metformin (Met) | Traceable DOX/Met/BSA–HA–CDs | Dual-drug system; fluorescence imaging; tumor targeting by HA | MCF-7/ADR human breast cancer cells; S180 murine sarcoma tumor mouse model | Synergistic treatment achieved considerably highest cytotoxicity in vitro and enhanced cancer therapeutic efficiency in vivo, which was attributed to MET reducing the tumor O2 consumption, resulting in increased the therapeutic efficiency of oxygen-consumed PDT | [141] |
| ?? | DOX | Regenerated silk fibroin-based PC–Mn@Dox-NPs | Multimodality factors responding, resulting in controlled release; intratumoral self-sufficiency of O2 | 4T1 breast cancer mouse model | Enhanced in vitro and in vivo anticancer efficacies, compared to all other combination approaches of PDT and DOX, due to multifactor triggered DOX release and oxygen-dependent PDT enhanced by self-sufficient O2 | [142] |
| ICG | Cisplatin (DDP) | Human serum albumin (HSA)–ICG–DDP NPs | NIR-triggered drug release | HSC human oral squamous cell cancer cells and NCM-460 colonic epithelial cells | Improved cytotoxicity for cancer cells in vitro due to higher ROS generation; significantly enhanced tumor growth inhibition compared to 632.06 ± 52.49 mm3 in the NP-PDT group and 482.25 ± 42.69 mm3 in the NP-chemotherapy group | [143] |
| ZnPC | DOX | Phthalocyanine-conjugated Glyco-NPs | pH-responsive; good colloidal stability; tumor targeting owing to GLUT5 | 3T3, MCF7, and MDA-MB-231 human breast cancer cells | High cytotoxicity effect in vitro, due to higher cellular internalization and induction of ROS generation | [144] |
| ICG | Bromoisophosphoramide mustard intermediate (IPM-Br) | Semiconducting polymer NPs | Light-responsive; intratumoral self-sufficiency of O2; NIR imaging | Nude mice bearing 4T1 breast cancer cells | Synergetic anticancer effects due to improved chemo prodrug efficiency (4.3-fold higher, compared with its prodrug-free counterpart) due to PDT-enhanced degree of hypoxia; increased photodynamic efficacy (18-fold higher than ICG) | [145] |
| Boron-dipyrromethene (BODIPY) | Lenvatinib (VEGFR inhibitor) | Self-assembling NPs (LBPNPs) | pH-sensitive | Human HCC cell lines Hep3B and Huh7 | Effectively inhibited tumor growth in vitro by promoting the cascade of caspase apoptotic protease | [146] |