Lipid Nanocarrier-Based Drug Delivery Systems: Therapeutic Advances in the Treatment of Lung Cancer

Figures & data

Figure 1 Schematic illustration of liposome-mediated lung cancer (LC) treatment.

Table 1 FDA-Approved Drugs Used in Different Stages and Types of Lung Cancer (LC) Treatments

Drug	Cancer Stage	Target	Date of Approval	Company
Atezolizumab	II to IIIA NSCLC	PD-L1 expression	10/15/2021	TECENTRIQ^®, Genentech Inc.
Atezolizumab	Metastatic NSCLC	PD-L1 expression	05/18/2020	TECENTRIQ^®, Genentech Inc.
Brigatinib	Adult patients with Anaplastic lymphoma kinase (ALK)-positive metastatic NSCLC	Anaplastic lymphoma kinase	05/22/2020	ALUNBRIG, ARIAD Pharmaceuticals Inc.
Cemiplimab	Advanced NSCLC	Tumors with PD-L1 expression	02/22/2021	Libtayo, Regeneron Pharmaceuticals Inc.
Durvalumab in combination with carboplatin/cisplatin	Extensive-stage SCLC (ES-SCLC).	-	03/30/2020	IMFINZI, AstraZeneca
Lorlatinib	Metastatic NSCLC	ALK-positive	03/03/2021	Lorbrena, Pfizer Inc.
Nivolumab + Ipilimumab	Metastatic NSCLC	First-line treatment for EGFR or ALK genomic tumor abnormalities	05/26/2020	OPDIVO, Bristol-Myers Squibb Co. YERVOY, Bristol-Myers Squibb Co.
Osimertinib for adjuvant therapy	NSCLC	Tumors have mutated EGFR	12/18/2020	TAGRISSO, AstraZeneca Pharmaceuticals LP
Ramucirumab + Erlotinib	Metastatic NSCLC	Tumors with mutated EGFR	05/29/2020	CYRAMZA, Eli Lilly and Company
Amivantamab-vmjw	Metastatic NSCLC	With EGFR exon 20 insertion mutations	05/21/2021	Rybrevant, Janssen Biotech Inc.
Capmatinib	Metastatic NSCLC	Tumors had a mutation that caused exon 14 of the mesenchymal-epithelial transition (MET) to be skipped.	05/06/2020	TABRECTA, Novartis
Lurbinectedin	Metastatic NSCLC	On or after platinum-based chemotherapy	06/15/2020	ZEPZELCA, Pharma Mar S.A.
Mobocertinib	Advanced or metastatic NSCLC	EGFR exon 20 insertion mutations	09/15/2021	Exkivity, Takeda Pharmaceuticals Inc.
Sotorasib	Locally advanced or metastatic NSCLC	RAS GTPase family inhibitor, for adult patients with KRAS G12C mutated	05/28/2021	Lumakras^™, Amgen Inc.
Tepotinib	Metastatic NSCLC	Harboring mesenchymal-epithelial transition (MET) exon 14 skipping alterations.	02/03/2021	Tepmetko, EMD Serono Inc.

Note: The data used in this table were retrieved from the FDA.

Table 2 Lipid-Based Nanocarriers Used in Drug Delivery Systems for LC Treatment

Lipid-Based Nanocarriers	Pros	Cons	Drug; Target Cancer; Phase; Status (Source-FDA)
Liposomes	Improved drug-target selectivity; improved pharmacokinetics and pharmacodynamics; lowered toxicity; improved therapeutic efficacy against pathogens^Citation37,Citation38	Expensive to produce; short shelf life and low stability^Citation37	Irinotecan Hydrochloride Liposome Injection (LY01610); SCLC; Phase 2; Recruiting
Lipid Micelles	Extends the circulation time of drug in blood; solubilizes hydrophobic drugs; has defined sizes and particle sizes^Citation39	Dilution might induce shift in the equilibrium towards the unimer state that leads to their dissociation^Citation39	Paclitaxel (Genexol^®) Drug: Paclitaxel-loaded polymeric micelle (Genexol-PM^®); NSCLC; Phase 2; Completed
Solid lipid nanoparticle (SLN)	Protects drug against harsh environmental conditions; high biocompatibility, and biodegradability^Citation40,Citation41	Crystalline structure; low drug loading efficiency; and drug expulsion due to storage conditions^Citation40	Not available
Lipid nanoparticle (LNP)	Easy synthesis using microfluidic techniques; improved charge-dependent drug loading such as nucleic acid	Few reports of side effects such as hepatotoxicity due to the use of polyethylene glycol^Citation42,Citation43	Not available

Abbreviation: FDA, US Food and Drug Administration.

Figure 2 Various types of modifications and conjugations on lipid-based nanocarriers for drug delivery.

Figure 3 LC treatment via nasal inhalation of anticancer drug-loaded liposome.

Table 3 Recent Studies Presenting Different Liposome-Based Bioformulations for Drug Delivery in LC Treatment

Liposome	Drug	Formulation Name	In vitro or in vivo/Model	Cancer Type	Result	References
Liposome	Doxorubicin (Dox)	SA-5-Dox-LP	In vivo/mice with lung tumors In vitro/BT-474, A549, Calu-3, and MCF-7 cells	NSCLC	Targeted SA-5-Dox-LP showed better anti-proliferative activity	[94]
Chitosan oligosaccharide-modified liposomes	Paclitaxel (PTX)	PTX-loaded CP50-LSs	In vitro/A549 In vivo/mice	LC	CSO modification provides promising applicability for nanomedicine	[95]
RGD-modified liposomes	DOX	DOX-RGD-LPs	In vitro/A549 In vivo/Balb/c nude mice	LC	The DOX-loaded pH-sensitive liposome, which has been modified with 5% cRGD-lipid, could be used to enhance cancer therapy	[96]
Liposome	Lonidamine or Epirubicin	-	In vitro/A549 cells In vivo/Female BALB/c mice	NSCLC	The formulation used as an anticancer agent to treat drug-resistant LC	[97]
Folate-modified submicron-sized liposome (ssLip)	Rapamycin (RM)	RM/FA-ssLip	In vitro/KB and LL2 cells and A549 cells In vivo/Male C57BL/6NCr mice	LC	Administration of this formulation extended the survival of LL2 cell tumor-bearing mice	[98]
pH-sensitive liposomes (PSL)	Thymoquinone (TQ)	TQPSL	In vivo/Swiss Albino Mice	LC	It shows potential of TQPSL as a LC therapeutic agent	[99]
PEGylated liposome	Lycobetaine Olic acid RGD	LBT-OA-PEG-Lipo + nRGD	In vivo/ mice xenograft	Lung carcinoma	Improved tumor penetration, and increased extravasation of formulations and antitumor efficacy	[93]
PSL	Afatinib (tyrosine kinase inhibitor)	AFT loaded PSL	In vitro/human LC cells (H-1975)	NSCLC cells	AFT loaded-PSL prompted apoptosis in H-1975 cells	[100]
Liposome	Betulinic parthenolide, honokiol and ginsenoside Rh2	Drug-loaded liposome	In vivo/mice In vitro/A549 cells	LC	Cocktail liposome systems could offer a more efficient and safer treatment for LC	[101]
PEGylated cationic liposomes	PTX	MLV-PEG-PTX	In vivo/Female C57BL/6 mice In vitro/A549 and the murine lung carcinoma cell line LL/2	LC	MLV-PEG-PTX exhibited biocompatibility and anticancer activity against CSCs	[53]
DSPE-PEG2000-PFV	Daunorubicin and Dioscin	Daunorubicin and dioscin co-delivery liposomes	In vitro/A549 cells In vivo/Male BALB/c nude mice	NSCLC	Increased the cellular uptake facilitated by PFV cell-penetrating peptide; augmented inhibitory effects on vasculogenic mimicry formation and tumor metastasis from the inclusion of dioscin	[102]
Liposome	Docetaxel and CD133 aptamers	CD133-DTX LP	In vitro/A549 tumor mice In vivo/mice xenograft	LC	CD133-DTX LP significantly decreased cell proliferation and improved the therapeutic efficiency	[103]
Folate-modified liposomes	Metallothionein 1D pseudogene (MT1DP) Erastin	Erastin/MT1DP@FA-LPs (E/M@FA-LPs)	In vitro/A549 and H1299 cells In vivo/BALB/c nude mice	NSCLS	The combination increased the bioavailability and effectiveness of the drug/gene	[104]
Folate-modified liposome (F-PLP)	Plasmid BIM	F-PLP/pBIM	In vitro/LL/2 and A549 LC In vivo/Female C57BL/6 mice	NSCLS	Developed formulation considerably blocked tumor growth by inducing apoptosis in tumor cells, and inhibited proliferation and angiogenesis	[105]
Liposome	Curcumin	Liposomal curcumin dry powder inhaler (LCD)	In vitro/A549 cells	Primary LC	Formulation having notable anticancer effects compared with the other two medications with reference to the pathology	[90]
Liposome	Inhalable Pirfenidone (PFD)	PFD-loaded liposomes	In vitro/H4006, A549 cell lines	NSCLC	PFD-loaded liposomes induced cell migration, apoptosis, and angiogenesis assays	[92]
Cationic liposome	PTX and Survivin siRNA	L-PTX-PSur	In vitro/NCI-H460 LC cells	LC	Developed formulation synergistically inhibits cancer cell growth	[106]
Liposome	PTX Curcumin (CUR) RGD	RGD- PTX-CUR LPs	In vitro/A549 LC cell lines In vivo/BALB/c nude mice	LC	The present formulation shows the antitumor effect in vivo, compared with the non-modified LPs	[52]
Liposome	PTX	LP (liposomal paclitaxel)-in-E. coli (LPE)	In vitro/A549 LC cell lines	LC	LPE significantly down-regulated the VEGF and HIF-1α in rat primary LC, and exacerbated apoptosis in the same cells	[107]

Figure 4 Limitations and challenges with DDSs using lipid-based nanocarriers.

Yadav D, Sandeep K, Pandey D, Dutta RK. Liposomes for drug delivery. J Biotechnol Biomater. 2017;7(4):276. doi:10.4172/2155-952X.1000276

 Google Scholar

Rommasi F, Esfandiari N. Liposomal nanomedicine: applications for drug delivery in cancer therapy. Nanoscale Res Lett. 2021;16(1):95. doi:10.1186/s11671-021-03553-8

 PubMed Web of Science ®Google Scholar

Wakaskar RR. General overview of lipid-polymer hybrid nanoparticles, dendrimers, micelles, liposomes, spongosomes and cubosomes. J Drug Target. 2018;26(4):311–318. doi:10.1080/1061186X.2017.1367006

 PubMed Web of Science ®Google Scholar

Ghasemiyeh P, Mohammadi-Samani S. Solid lipid nanoparticles and nanostructured lipid carriers as novel drug delivery systems: applications, advantages and disadvantages. Res Pharm Sci. 2018;13(4):288–303. doi:10.4103/1735-5362.235156

 PubMed Web of Science ®Google Scholar

Yoon G, Park JW, Yoon I-S. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs): recent advances in drug delivery. J Pharma Investig. 2013;43(5):353–362. doi:10.1007/s40005-013-0087-y

 Google Scholar

Shiraishi K, Yokoyama M. Toxicity and immunogenicity concerns related to PEGylated-micelle carrier systems: a review. Sci Technol Adv Mater. 2019;20(1):324–336. doi:10.1080/14686996.2019.1590126

 PubMed Web of Science ®Google Scholar

Chen B-M, Cheng T-L, Roffler SR. Polyethylene glycol immunogenicity: theoretical, clinical, and practical aspects of anti-polyethylene glycol antibodies. ACS Nano. 2021;15(9):14022–14048. doi:10.1021/acsnano.1c05922

 PubMed Web of Science ®Google Scholar

Naik H, Sonju JJ, Singh S, et al. Lipidated peptidomimetic ligand-functionalized HER2 targeted liposome as nano-carrier designed for doxorubicin delivery in cancer therapy. Pharmaceuticals. 2021;14(3):221. doi:10.3390/ph14030221

 Web of Science ®Google Scholar

Miao YQ, Chen MS, Zhou X, et al. Chitosan oligosaccharide modified liposomes enhance lung cancer delivery of paclitaxel. Acta Pharmacol Sin. 2021;42(10):1714–1722. doi:10.1038/s41401-020-00594-0

 PubMed Web of Science ®Google Scholar

Fu S, Zhao Y, Sun J, et al. Integrin α(v)β(3)-targeted liposomal drug delivery system for enhanced lung cancer therapy. Colloids Surf B Biointerfaces. 2021;201:111623. doi:10.1016/j.colsurfb.2021.111623

 PubMed Web of Science ®Google Scholar

Ying X. Dequalinium-mediated mitochondria-targeting drug liposomes for the treatment of drug-resistant lung cancer. In: Liposome-Based Drug Delivery Systems. Springer; 2021:345–364.

 Google Scholar

Onodera R, Morioka S, Unida S, Motoyama K, Tahara K, Takeuchi H. Design and evaluation of folate-modified liposomes for pulmonary administration in lung cancer therapy. Eur J Pharma Sci. 2022;168:106081. doi:10.1016/j.ejps.2021.106081

 PubMed Web of Science ®Google Scholar

Khan A, Alsahli MA, Aljasir MA, et al. Experimental and theoretical insights on chemopreventive effect of the liposomal thymoquinone against benzo [a] pyrene-induced lung cancer in Swiss albino mice. J Inflamm Res. 2022;15:2263. doi:10.2147/JIR.S358632

 PubMed Web of Science ®Google Scholar

Chen T, Gong T, Zhao T, Fu Y, Zhang Z, Gong T. A comparison study between lycobetaine-loaded nanoemulsion and liposome using nRGD as therapeutic adjuvant for lung cancer therapy. Eur J Pharm Sci. 2018;111:293–302. doi:10.1016/j.ejps.2017.09.041

 PubMed Web of Science ®Google Scholar

Almurshedi AS, Radwan M, Omar S, et al. A novel pH-sensitive liposome to trigger delivery of Afatinib to cancer cells: impact on lung cancer therapy. J Mol Liq. 2018;259:154–166. doi:10.1016/j.molliq.2018.03.024

 Web of Science ®Google Scholar

Jin X, Yang Q, Cai N, Zhang Z. A cocktail of betulinic acid, parthenolide, honokiol and ginsenoside Rh2 in liposome systems for lung cancer treatment. Nanomedicine. 2020;15(1):41–54. doi:10.2217/nnm-2018-0479

 PubMed Web of Science ®Google Scholar

Jiménez-López J, Bravo-Caparrós I, Cabeza L, et al. Paclitaxel antitumor effect improvement in lung cancer and prevention of the painful neuropathy using large pegylated cationic liposomes. Biomed Pharmacother. 2021;133:111059. doi:10.1016/j.biopha.2020.111059

 PubMed Web of Science ®Google Scholar

Wang Y, Fu M, Liu J, et al. Inhibition of tumor metastasis by targeted daunorubicin and dioscin codelivery liposomes modified with PFV for the treatment of non-small-cell lung cancer. Int J Nanomedicine. 2019;14:4071. doi:10.2147/IJN.S194304

 PubMed Web of Science ®Google Scholar

Ma J, Zhuang H, Zhuang Z, et al. Development of docetaxel liposome surface modified with CD133 aptamers for lung cancer targeting. Artif Cells, Nanomed Biotechnol. 2018;46(8):1864–1871. doi:10.1080/21691401.2017.1394874

 PubMed Web of Science ®Google Scholar

Gai C, Liu C, Wu X, et al. MT1DP loaded by folate-modified liposomes sensitizes erastin-induced ferroptosis via regulating miR-365a-3p/NRF2 axis in non-small cell lung cancer cells. Cell Death Dis. 2020;11(9):1–11. doi:10.1038/s41419-020-02939-3

 PubMed Web of Science ®Google Scholar

Tie Y, Zheng H, He Z, et al. Targeting folate receptor β positive tumor-associated macrophages in lung cancer with a folate-modified liposomal complex. Signal Transduct Target Ther. 2020;5(1):1–15. doi:10.1038/s41392-020-0115-0

 PubMed Web of Science ®Google Scholar

Zhang T, Chen Y, Ge Y, Hu Y, Li M, Jin Y. Inhalation treatment of primary lung cancer using liposomal curcumin dry powder inhalers. Acta Pharm Sin B. 2018;8(3):440–448. doi:10.1016/j.apsb.2018.03.004

 PubMed Web of Science ®Google Scholar

Parvathaneni V, Kulkarni NS, Shukla SK, et al. Systematic development and optimization of inhalable pirfenidone liposomes for non-small cell lung cancer treatment. Pharmaceutics. 2020;12(3):206. doi:10.3390/pharmaceutics12030206

 PubMed Web of Science ®Google Scholar

Zhang C, Zhang S, Zhi D, Zhao Y, Cui S, Cui J. Co-delivery of paclitaxel and survivin siRNA with cationic liposome for lung cancer therapy. Colloids Surf A. 2020;585:124054. doi:10.1016/j.colsurfa.2019.124054

 Google Scholar

Jiang K, Shen M, Xu W. Arginine, glycine, aspartic acid peptide-modified paclitaxel and curcumin co-loaded liposome for the treatment of lung cancer: in vitro/vivo evaluation. Int J Nanomedicine. 2018;13:2561. doi:10.2147/IJN.S157746

 PubMed Web of Science ®Google Scholar

Zhang M, Li M, Du L, Zeng J, Yao T, Jin Y. Paclitaxel-in-liposome-in-bacteria for inhalation treatment of primary lung cancer. Int J Pharm. 2020;578:119177. doi:10.1016/j.ijpharm.2020.119177

 PubMed Web of Science ®Google Scholar