The Application of Nanoparticles Targeting Cancer-Associated Fibroblasts

Figures & data

Figure 1 The origin of cancer associated fibroblast (CAFs): the main original cell of CAFs are tissue normal fibroblasts, stellate cells, mesenchymal stem cells, endothelial cells, epithelial cells, adipocytes cells and perivascular cells. These cells can transform into CAFs by Epithelial–mesenchymal transition (EMT) pathway and Endothelial-to-mesenchymal transition (EndMT) or be activated by cytokines including TGF-β, SDF-1, WNT-3, IGF-3, CCL2, CCL5 and CXCL2.

Figure 2 The heterogeneity of CAFs: the main subtypes of CAFs are defined by their features. In the classification of mCAFs, the overexpressed genes such as ACTA2, CD36 and PDPN are define as the subtype of mCAFs. And subtypes of the iCAFs with different functions are define by their secreted cytokines. The way of defining apCAFs are similar to myCAFs but the markers are usually human leukocyte antigens and cluster of differentiations (CD).

Figure 3 Crosstalk of CAFs and immune cells: CAFs can inhibit CD8⁺ T cells by inducing exclusion, dysfunction and exhaustion and they can also inhibit their proliferation while induce the proliferation of Tregs. CAFs can induce M2 polarization while M2 can also enhance the function of CAFs. This kind mutual support also can be found in the interaction of CAFs and MDSCs. CAFs also can disrupt the functions of DCs and NK cells while recruit mast cells.

Table 1 Drugs for Targeting CAFs in Preclinical and Clinical Trials

Therapy Types	Drugs	Effects	Cancer Models	Stage of Clinical Trials	Source
FAP-expressing cells depletion	PT630	FAP participates in matrix degradation but fails to inhibit tumors	BRCA	Preclinical	[136]
	PT100	FAP-specific monoclonal antibody and inhibitors	COAD	Phase II	[117,118]
	Sibrotuzumab	Kill FAP-CAFs	COAD	Phase II	[112]
	RO7122290	Costimulates T cells for improved tumor cell killing in FAP-expressing tumors.	Solid tumors	Phase I	[116]
	DC/CAF fusion cells-tumor vaccine	Stimulating T cells	HCC	Preclinical	[113]
	FAPα DNA vaccine	FAPα-specific cytotoxic T lymphocyte responses	BRCA	Preclinical	[114]
	FAP based CAR-T	Ablate FAP-expressing cells	Lung cancer	Preclinical	[119]
TGF-βInhibitor	Galunisertib	Inhibit CAFs activation	HCC	Phase II	[123]
Vitamin A analogs	ATRA	Dampening multiple signalling cascades	PDAC	Preclinical	[124]
Vitamin D analogs	Calcipotriol	Reduced markers of inflammation and fibrosis	PDAC	Phase II	[128]
CXCL12-CXCR4 inhibitor	AMD3100	T-cell accumulation and PD-L1 diminished	PDAC	Preclinical	[131]
JAK inhibitors	Ruxolitinib	Alleviate tumor inflammation	PDAC	Phase II	[132]
Hedgehog pathway	Sonidegib	Sensitizes tumors to docetaxel	BRCA	Phase I	[133]
	IPI-926	Depletes tumor-associated stromal tissue	PDAC	Preclinical	[134]
	GDC-0449	Conflicting effects	PDAC	Phase II	[135]

Table 2 Constructed NPs and Their Effects for Targeting CAFs

Materials Type	NPs and Nanomaterials	Targeting Sites	Loaded Drugs	Pharmacological Effects	Source
Liposomes and lipo-based	DSPE‐PEG2000	CFH/OM-L (Tenascin C)	Oxymatrine	Reversing EMT, inactivate CAFs, M1 polarization and NK activation	[143]
	DSPE‐PEG2000	FH (Tenascin C)	Navitoclax, doxorubicin	CAFs selective apoptosis; facilitating drugs penetration	[144,145]
	LNCs	–	Paclitaxel and acriflavine	Inhibit CAFs and whole tumor	[146]
	DSPE-PEG-2000, DSPE-PEG-NHS, DSPE-PEG-AEAA	–	Fraxinellone	CAFs depletion and remolding TME	[147]
	PEG-lip	–	Salvianolic acid B	Inhibiting CAFs activation, remolding TME	[148]
	LPD	–	sTRAIL	Inactivate CAFs, remolding TME and induce drugs infiltration	[149]
	IR780/DPPC		BMS	Reducing CAFs, inducing CTL activation and blocking PD-1/PD-L1	[150]
	DSPE-PEG2000	HA and GA	Aprepitant, berberine and curcumin	Inhibit CAFs activation	[151,152]
	Nanoliposome	–	Doxorubicin, resiquimod (R848) and losartan (LOS).	Reduces the activity of CAFs	[153]
Metallic	SPIONs	–	Sodium citrate	CAFs apoptosis	[154]
	Gold-core silver-shell	–	–	Attenuated CAFs functions	[155]
	Gold NPs		Docetaxel	CAFs as NPs reservoirs	[156]
	SPIONs		FGF2	Inactivate CAFs	[157]
	3nm GNPs	–	–	Attenuated CAFs functions	[158]
	GNPs	–	–	Transform to quiescence; disturb CAFs communication	[159,160]
	Gold shell, SPIOs, PLGA	Her2	Doxorubicin	Reduce CAFs and remodel TME	[161]
	6nm USPOINs	CCK2R	–	Magnetic damage	[162]
	SPOINs	–	Relaxin	Inactivate CAFs	[163]
	GIONF	–	–	CAFs depletion	[164]
Polymeric micelles	TPP, PLGAs	–	Resveratrol	CAFs depletion and inactivation	[165]
	ONP-302	–	–	CAFs dysfunction and apoptosis	[166,167]
	SN38		Triptolide-naphthalene sulfonamide	Reduce CAFs activity	[168]
	Self-assembled Chol-R9	FAP	siCXCL12	Inactivate CAFs	[20]
	Drug self-polymerized		Cyclopamine (CPA) and paclitaxel (PTX)	CAFs depletion and tumor inhibition	[169]
	ZGP-PEOz-PLA, FA-PEOz-PLA, PEOz - PLA	FAP	Doxorubicin	CAFs deletion	[170]
	MLNPs	–	Docetaxel	CAFs deletion	[171]
	Cellax-DTX polymer	–	Docetaxel	CAFs depletion	[172]
	SN38	–	GDC-0449	Reducing CAFs	[173]
	PAMAM	FAP	Doxorubicin	CAFs as NPs reservoirs	[174]
	Self-assembled CAP	FAP	Doxorubicin	CAFs depletion	[175]
	PLGA-PEG	–	Sunitinib	Remolding CAFs	[176]
	PEG-PBLG	–	Tranilast	Remolding CAFs	[177]
	PLGA	–	siRNA for hepatocyte growth factor	Inhibit hepatocyte growth factor secreted from CAFs and prevent CAFs activation	[178]
	mPEG-PLGA	–	Baicalein	Prevent CAFs activation	[179]
	Amphipathic hydroxyethyl starch-polycaprolactone	–	LY2157299 and photosensitizer indocyanine green	Enhance CAR-T therapy effects and inhibit CAFs activation	[180]
Protein	Apoferritin, ferritin nanocage	FAP	ZnF16Pc	CAFs depletion, increase CTLs infiltration	[181,182]
	H-ferritin	FAP	Navitoclax	Killing CAFs	[183]
	HSA, CAP-TSL	FAP	Paclitaxel	CAFs depletion and tumor inhibition	[184]
Cell membrane	Fibroblasts membrane	–	SPN	Killing CAFs	[185]
	Tumor cells and fibroblasts membrane	–	Paclitaxel, PFK15	Reprogram TME	[186]
	Tumor cells membrane and thermosensitive LNPs	–	BMS	Disrupt CAFs and ECM, inhibit PD-1/PD-L1	[186]
	Red blood cells membrane, PEG-PLGA	FnBPA5	Retinoic acid, Doxorubicin	CAFs depletion and tumor inhibition	[187]
	Tumor cells membrane	–	Indocyanine green and calcipotriol	Modulate phenotype of CAFs and enhance PPT effects	[129]

Figure 4 Design, characteristics and effects of IR780/DPPC/BMS. (A) Scheme of IR780/DPPC/BMS. (B) Synthetic route of IR780-PEG-ODC. (C) In vitro NIR-triggered drug release profiles. (D) Transmission electron microscope (TEM) images of IR780/DPPC/BMS at different temperatures. (E) Cellular uptake and responsive drug release in 4T1 tumor cells. (F) In vivo photothermal effect. (G) Tumor volumes of 4T1 tumor-xenografted mice in different treatment groups. (H) The quantitative analysis of pulmonary metastatic nodules in various treatment groups. (I) Detection of released cytokines in primary tumor after synergistic immuno-photothermal therapy. *:P<0.05; **:P<0.01; ***P<0.001. Reprinted from Cancer Letters, volume 522, Tan Y-N, Li Y-P, Huang J-D, et al. Thermal-sensitive lipid nanoparticles potentiate anti-PD therapy through enhancing drug penetration and T lymphocytes infiltration in metastatic tumor. 238–254, Copyright 20221, with permission from Elservier.¹⁵⁰

Figure 5 Docetaxel (DTX)-Mediated Uptake and Retention of Gold Nanoparticles (GNPs) in Tumor Cells and in CAFs. (A) Schematic diagram of functionalized GNP. (B) TEM of GNPs. (C) Zeta Potentials for pure GNPs. Scheme of transportation of GNPs in cells (D) and effects of DTX on cell division (E). Confocal microscopy images of GNPs transportation (F) and effects of DTX on cell division (G). (H) Effect of DTX on GNP. Retention of NPs in the presence of DTX in tumor cells (I) and CAFs (J). (L) Retention of GNPs in tumor cells and CAFs (K) post recovery. *:P<0.05. Reprinted from Alhussan A, Bromma K, Perez MM, et al. Docetaxel-mediated uptake and retention of gold nanoparticles in tumor cells and in cancer-associated fibroblasts. Cancers (Basel). 2021;13(13):3157. Creative Commons.¹⁹⁷

Figure 6 Fibroblast growth factor 2 (FGF2) engineered SPIONs attenuate tumor stroma and potentiate the effect of chemotherapy in pancreatic tumor. (A) Schematic representation of conjugation of FGF2 to SPION. (B) Binding of FGF2-SPION on non-activated human pancreatic stellate cells (hPSCs) and activated hPSCs. Western blots demonstrating the differentiation-related biomarkers (C) and representative immunofluorescence images showing the effect of FGF2 and FGF2-SPION on the protein expression of α-SMA and col-1 in TGF-β-activated hPSCs (D). Effect of FGF2-SPION on hPSCs migration (E) and contractility (F). (G) Effect of FGF2-SPIONs on the tumor stroma and gemcitabine efficacy in 3D heterospheroids. (H) Magnetic driven iron oxide accumulation. *P<0.05; **P<0.01. Reprinted from Mardhian DF, Vrynas A, Storm G, et al. FGF2 engineered SPIONs attenuate tumor stroma and potentiate the effect of chemotherapy in 3D heterospheroidal model of pancreatic tumor. Nanotheranostics. 2020;4(1):26–39. Creative Commons.¹⁵⁷

Figure 7 On-demand responsive nanoplatform mediated targeting of CAFs and down-regulating mtROS-PYK2 signaling for antitumor metastasis. (A) Disintegration of the on-demand successively responsive HPBC@TRP/NPs and its therapeutic mechanism. (B) TEM images of HPBC@TRP/NPs. (C) Zeta potential reversal characteristic. (D) Evaluation of the relative cell viability and mechanism of the apoptosis signal pathway. (E) CLSM images of α-SMA activated CAFs in 4T1/NIH3T3 cells treated with PFD and HPBC@TRP/NPs. Down-regulation of the mitochondrial oxidation system and cancer associated fibroblasts in vitro: Western blot protein expression levels of PYK2 (F), α-SMA (G), and TGF-β (G) in 4T1/NIH3T3 co-cultured cells. (H) Enhanced in vivo therapeutic effect. (I) Normalization of the tumor ECM to remodel TME. (J) Modulation of TIME in 4T1/NIH3T3 tumors after treatments. Reprinted from Zuo T, Zhang J, Yang J, et al. On-demand responsive nanoplatform mediated targeting of CAFs and down-regulating mtROS-PYK2 signaling for antitumor metastasis. Biomater Sci. 2021;9(5):1872–1885. 2021 © Royal Society of Chemistry.¹⁶⁵

Figure 8 Prodrug polymeric micelles integrating CAFs and synergistic chemotherapy for gastric cancer (GCs). (A) Schematic overview of the composition and synergistic mechanisms. (B) TEM images of PSN38 and PSN38@TPL-nsa NPs. (C) Low dose of TPL inactivated CAFs and inhibited CAFs. (D) Apoptotic analysis of BGC-823 and MKN45 cells after the treatment of TPL, SN38 or a combination of SN38 and TPL for 24 h in the co-culture and mono-culture model respectively. (E) The antitumor efficiency of PSN38@TPL-nsa in GC PDX model. (F) PSN38@TPL-nsa remodeled GC microenvironment in vivo. Reprinted from Zheng S, Wang J, Ding N, et al. Prodrug polymeric micelles integrating cancer-associated fibroblasts deactivation and synergistic chemotherapy for gastric cancer. J Nanobiotechnology. 2021;19(1):381. Creative Commons.¹⁶⁸

Figure 9 Targeting CAFs by dual-responsive lipid-albumin NPs to enhance drug perfusion for pancreatic tumor therapy. (A) Diagram of dual-responsive lipid-albumin NPs (HSA-PTX@CAP-ITSL) (B) TEM images of HSA-PTX, CAP-ITSL and HSA-PTX@CAP-ITSL. (C) The PTX release profiles of different formulations incubated with FAP-α. (D) cellular uptake after TGF-β activated NIH 3T3 cells incubated with different formulations. (E) Rhodamine B distribution of different treatment groups. (F) IR thermal images of subcutaneous tumor-bearing mice in different treatment groups.(G) H&E staining, α-SMA staining and Caspase-3 staining of tumor tissues. Reprinted from J Control Release, volume 321, Yu Q, Qiu Y, Li J, et al. Targeting cancer-associated fibroblasts by dual-responsive lipid-albumin nanoparticles to enhance drug perfusion for pancreatic tumor therapy. 564–575, Copyright 2020, with permission from Elsevier.¹⁸⁴

Figure 10 Metabolic Reprogramming by Dual-targeting Biomimetic NPs for Enhanced Tumor Chemo-Immunotherapy. (A) Scheme of PTX/PFK15-SLN@[4T1-3T3] NPs. (B) Western blot assay of 4T1 membrane (4T1m), 3T3 membrane (3T3m), 4T1-3T3 membrane (4T1m-3T3m), and SLN@[4T1-3T3] NPs for 4T1 membrane marker CD44and 3T3 membrane marker FAP-α. (C) CLSM images of the SLN@[4T1-3T3] NPs and a physical mixture of SLN@4T1 NPs and SLN@3T3 NPs. (D) Representative TEM images of PTX/PFK15-SLN and PTX/PFK15-SLN@[4T1-3T3] NPs. (E) CLSM images of 4T1, 3T3, B16F10, Pan02 and C166 cells stained with DAPI and cultured with DiD-labeled SLN@[4T1-3T3] NPs. (F) Representative CLSM images in tumor sites. The dotted line inside indicated CAFs. (G) Antitumor effect evaluation in vivo. (H) Representative flow cytometric images of the tumor CD4+ T cells, CD8+ T cells and Treg cells (gated by CD25). Reprinted from Acta Biomater, volume 148, Zang S, Huang K, Li J, et al. Metabolic reprogramming by dual-targeting biomimetic nanoparticles for enhanced tumor chemo-immunotherapy. 181–193, Copyright 2022, with permission from Elsevier.²¹⁵

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