Design strategy and research progress of multifunctional nanoparticles in lung cancer therapy

Figures & data

Table 1. FDA-approved nanoparticle formulations for lung cancer treatment and clinical trials.

Nano drug type	Drug	Manufacturers	Commodity Name	Indications	Drug delivery method	Role characteristics	Clinical Translation Phase
Liposomes	DDP	Regulon	Lipolatin	NSCLC	Intravenous	Extends the in vivo half-life of DDP significantly; substantially increases the drug content in tumor tissue	Phase III clinical
Polymeric micelles	PTX	Lupin	Genexol-PM	Lung cancer	Intravenous	Improves drug solubility, stability and targeting	Phase I Clinical
Nanoparticles	PTX	Bind	BIND-014	NSCLC	Intravenous	Targeted and specific killing of tumor cells without affecting normal cells around the tumor tissue	Phase II Clinical
	Camptoth-ecin	Cerulean	CRLX101	NSCLC	Intravenous	Extend the half-life of camptothecin in vivo; increase the drug content in tumor tissues; after drug release, the nanomaterials depolymerize into chain-like polymers and are excreted in the urine	Phase II Clinical
	siRNA	Silence	CALAA-01	Solid tumors	Intravenous	Extend in vivo half-life	Phase I
	siRNA	Silence	AUT-027	Solid tumors	Intravenous	Extend in vivo half-life and block PKN3 to inhibit tumor progression	Phase I
	Albumin-bound paclitaxel	Celgene	Abraxane	Breast Cancer,NSCLC and Pancreatic Cancer	Intravenous	Promote and stabilize microtubule aggregation into clusters and bundles, thus inhibiting the normal reorganization of microtubule network	Approval
Polymer-drug couples	Camptoth-ecin polymerization pre-drug	Mersana	XMT-1001	NSCLC	Intravenous	Enhance tolerability and efficacy, longer plasma half-life and higher concentrations in tumor tissue	Phase I
Inorganic nanoparticles	Hafnium oxide	NANOBIOTIX	NBTXR3	NSCLC, Head and Neck Cancer	Intravenous	Induce differential immunogenicity, triggering adaptive immune responses and long-term anti-cancer memory	Phase III
	Silicon Dioxide-Gold	Nanospectra	AuroLase	Lung cancer	Intravenous	Maximize treatment outcomes while reducing side effects associated with surgery, radiation and alternative focal therapies	Preclinical
Others	/	Coordination	CPI-200	Lung cancer	Intravenous drip	Degeneration/elimination of tumors	Preclinical

Figure 1. General schematic diagram of a novel nanoliposome for lung cancer therapy.

Table 2. Merits and demerits of various liposomes for lung cancer treatment.

Liposome type	Merits	Demerits	References
Active targeting of liposomes	Enhance tumor-specific drug delivery and avoid off-target effects	During in vitro modification of liposomes, many targeting ligands are prone to denaturation and inactivation, and the stability of their targeting functions cannot be guaranteed. Also, after liposome modification and arrival in vivo through drug delivery, changes in the size and surface charge of the drug carrier may make it susceptible to phagocytosis by the reticuloendothelial system, making it difficult to reach tumor cells.·Preparation process is difficult to industrialize	[22]
pH-sensitive liposomes	Highly targeted and pH-dependent drug release	Challenging for stability during drug loading, processing and storage	[24]
Cationic liposomes	Intracellular targeting·High load capacity·Significant enhancement of intracellular chemistry through adsorptive interactions with tumor cell membranes·Extending the circulation time of nanoparticles in the blood	Blocking the release of cytosolic siRNA due to electrostatic interactions	[25,26]
Magnetic liposomes	With magnetic fluid properties	In the presence of a magnetic field, magnetic liposomes coalesce into larger particles that interfere with blood flow	[27]
Thermosensitive liposomes	sustained drug release·temperature-responsive of drug	Excessive heating time can cause normal tissue damage·Weak targeting and difficulty in evading the action of mononuclear phagocytic system·Cannot be used for delivery of fat-soluble drugs	[28,29]

Figure 2. Passive, active, and physicochemical targeted nanoparticles.

Table 3. Cationic liposomes currently developed for the treatment of lung cancer.

Loading drugs	Liposomal materials	Object of action	Liposome action	References
Unmethylated oligodeoxynucleo −tides containing CpG motifs (CpG)	1,2-dioleoyl-3-trimethylammonium-propane; 1,2-dipalmitoylpHospHatidylcholine	B16F10 model of metastatic lung cancer in mice	Protect drugs from rapid extracellular degradation and increase their uptake by lung phagocytes.	[52]
PTX	Cholesterol, stearylamine and DSPE-PEG2000 and Lipo-Cat	A549 and LLC cell	Improve PTX biocompatibility, antitumor activity against cancer stem cells, and enhance the in vitro and in vivo antitumor effects of PTX free activity, but also protect against PTX-induced painful peripheral neuropathy.	[44]
miR-143 plasmid	Avanti Polar Lipids and cholesterol	A549 cell, naked mouse	Ensure formulation stability and safety, and accumulate mainly in the lungs after systemic administration.	[41]
VRB bitartrate and Quinacrine	L-alpha-Dipalmitoyl phosphatidylcholine, DC-Chol and DSPE-PEG2000	A549 cell, BALB/c mice	Significantly enhance cellular uptake and selective accumulation in A549 cells, thus exhibiting the strongest antitumor efficacy against tumor cells and tumor-bearing mice.	[53]
Hydroxycampto -thecin and 5-aminolevulinic acid	Soybean lecithin, cholesterol, octadecylamine and medical ultrasound gels	BALB/c mice	Increase the water solubility of drugs and protect them from rapid degradation to improve antitumor drug efficacy.	[54]
FUS1 and IL-12	1,2-Dioleoyl-3-trimethylammonium propane, cholesterol	A549 cell, NOD/SCID mice	Stable formulation with higher antitumor activity and lower toxicity in pulmonary metastases.	[55]
siRNA	1,2-dioleoyl-sn-glycero-3-ethylphosphocholine and cholesterol	LLC cells, BALB/c mice	High efficiency of in vivo drug delivery to lung cells, higher antitumor activity and lower toxicity in lung metastasis models.	[56]
Pemetrexed disodium	Egg yolk lecithin cholesterol and stearylamine	NSCLC cell, Kunming mice	The slow release of the drug prolongs the retention time in the body, increase the value of AUC, improve the accumulation and relative uptake rate of the drug in the lung, and enhance the anti-tumor efficacy of the drug.	[57]
PTX	1,2-Dioleyloxy-N, N-dimethyl-3-aminopropane, DOTAP, 1,2-dioleoyl-sn-glycero-3-phosphocholine, Cholesterol, N- (Carbonyl-methoxy-polyethylene glycol 2000)-1,2-dipalmitoylsn-glycero-3-pHospHoethanolamine	A549 cell, female athymic nude mice	Induce upregulation of miR-21 targets, including PTEN and DDAH1, in A549 cells, while increasing their sensitivity to PTX; achieve tumor regression, prolong survival and upregulation of miR-21 targets in an A549 xenograft mouse model.	[58]
PTX	Soybean lecithin, mPEG2000-DSPE, and Mal-PEG2000-DSPE, Cholesterol, T7 peptide and TAT peptide	A549 cell, BALB/c mice	Enhance in vitro cellular uptake with highest accumulation capacity; improve in vivo inhibition of tumor growth.	[59]
Cisplatin and metformin	2, 3-Dioleoyloxy-propyl)- trimethylammonium DSPE-PEG2000, DSPE-PEG-aminoethyl anisamide, cholesterol	H460 cells, Female nude mice	Significantly increase tumor accumulation of the drug and inhibit tumor growth through apoptosis without nephrotoxicity.	[60]

Table 4. Polymer-based nanocarriers currently developed for the treatment of lung cancer.

Classification	Loading drugs	Materials	Functions	References
Natural polymer- based nanocarriers	PTX, QUE	Cs, cetuximab, Sodium tripolyphosphate	Improving drug bioavailability	[76]
	PTX	Poly(lactide-co-glycolide), 2-HP-β-CD, Polyvinyl alcohol	Prolong PTX release, enhance drug transport efficiency	[77]
Synthetic and hybrid polymer-based nanocarriers	Cisplatin caprylate and ABCC3-siRNA	PEG-PLA, 1, 2-Dipalmitoyl-sn- glycero-3-phosphocholine, DOTAP	Imparting long circulation characteristics to the carrier	[78]
	Nucleic acid	PBAEs	Protect their nucleic acid cargo while promoting cellular uptake and endosomal escape	[79]
Polymeric micelles		Polycaprolactone, NAD(P)H: quinone oxidoreductase-1, PEG	Enhanced drug accumulation in the tumor	[80]
	DOX	PEG-b- poly(dithiolane trimethylene carbonate)	Favorable features of superb stability, minimal drug leakage, long circulation time	[81]
Polymersomes	MTX	PEG-b-poly (trimethylene carbonate-co- dithiolane trimethylene carbonate)- b-polyethylenimine	Show potent anti-tumor activity, depth of tumor penetration	[82]
	Granzyme B	Anisamide end-capped PEG-b-poly(2,4,6- trimethoxybenzylidene- 1,1,1-tris(hydroxymethyl)ethane methacrylate)-b-poly(acrylic acid)	Accelerated drug release in an acidic environment	[83]
Nanogel	DDP	Carboxymethyl chitosan, diallyl disulfide, valproate	Reactivate DDP and enhance early apoptosis, and has the ability to improve DDP resistance in NSCLC and enhance anti-tumor efficacy.	[84]

Figure 3. Inorganic rice granule formulations with different functional coatings.

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