Herein, we will focus on the clinical trials of developed vaccines, summarized in Table 5. Immunomodulation strategies to improve cancer immunotherapy in nanomedicines: Nanomedicine was designed to induce immunogenic cell death, to promote antitumor immunity cancer vaccination , to modulate immune cells, to activate innate immunity, to inhibit soluble immunosuppressive factors, to alternate tumor matrix, to engineer lymphocyte and normalize vessel [ ].
This vaccine is indicated for patients with resected solid tumors including bladder carcinoma, melanoma and non-small cell lung carcinoma NSCLC. In addition, mRNA is also used in combination with pembrolizumab for patients with advanced or metastatic cancers.
After administration, this LNP is uptaken and translated by antigen presenting cells, thereby inducing both cytotoxic T-lymphocyte and memory T-cell-dependent immune responses to destroy the cancer cells. This therapeutic vaccine provides immunity to kill the cancer cells expressing a glycoprotein antigen of Mucin 1 MUC The trial for patients with advanced non-small cell lung cancer NSCLC , but the results were disappointing and did not meet the primary endpoint [ ]. As a result, L-BLP was terminated.
In March , more than Concurrently, COVID has a high probability of becoming a seasonal disease with high infection rates and a long incubation period [ ]. Consequently, developing COVID vaccines has been a necessity for the global population [ ], for which numerous platforms have been investigated. There are 12 vaccines approved by the FDA. Others are in clinical trials, 93 vaccines are listed with trials [ , ], of which, 29 vaccines in Phase 1, 39 vaccines in Phase 2, and 25 vaccines in Phase 3 [ ].
The activating mechanisms in most of those vaccine candidates are based on the induction of neutralizing antibodies against the spike S protein to prevent the uptake into human cells via the human angiotensin-converting enzyme-2 ACE2 receptor [ ].
The BNTb2 candidate has finished phase 3 clinical trials with promising results of a safe and effective vaccine. The S protein of SARS-CoV-2 viruses mediates cell attachment, receptor recognition, and fusion for viral penetration and infection [ ].
McKay et al. These self-amplifying RNA constructs have been proposed because any antigen of interest can be encoded and formulated at a lower dose than conventional mRNA. The age groups for this study are healthy people from 18—80 years, with the exception of pregnant and breast-feeding women.
Preliminary data for ARCT showed a favourable safety profile at a relatively low dose [ ]. This trial will evaluate the safety, tolerance and immunogenicity of multiple doses in the population above 18 year olds [ ]. The LNPs under development for the COVID vaccines do not only include the aforementioned approved products or those still in the clinical trials, but also include numerous others that are continuously being developed in pre-clinical stage Table 6 [ ].
Globe Biotech Ltd. It was expected to get interim results in the third quarter of [ ]. Daiichi-Sankyo Co. For next clinical studies, Daiichi-Sankyo Co. DPX is the lipid-based delivery system in which peptide antigens are dissolved in lipids with the final formulation stored in dry form [ ]. After dissolution, this vaccine is injected intramuscularly. There is no releasing mechanism at the injection site, but the peptide antigens act as adjuvant and the formulated DPX can then recruit the antigen presenting cells that induce an immune response from the lymph nodes [ ].
Na-Na Zhang et al. Additionally, this vaccine candidate can be stored at room temperature for at least one week. Depending on these preliminary tests, it can be concluded that mRNA vaccines can act as a flexible platform to design effective candidates [ ]. Besides, the developing strategy of vaccines has still studied for other diseases. Shirai et al. This was confirmed through the results about the immune-stimulatory effects on dendritic cells in mice and the protection ability of LNPs encapsulating the conventional seasonal split vaccine SV in comparison with bare SVs and SVs combined Alum.
The LNP was made of 1,2-dioleoyltrimethylammonium- propane, 1,2-dipalmitoyl-sn-glycerophosphocholine, N- carbonyl-methoxypolyethyleneglycol -1,2-distearoyl-sn-glycerophosphoethanolamine and cholesterol. Alum induced a high inflammatory response, which is considered a limitation of traditional adjuvants. Swaminathan et al. Surprisingly, the LNP without adjuvant was able to induce B-cell responses against HbsAg hepatitis B virus surface antigen and ovalbumin sub-unit antigens at a comparable level than in the presence of other adjuvants including IMO, 3-O-deactytaled monophosphoryl lipid and aluminum-based adjuvants.
The LNP not only induced a significant enhancement of immune responses but also elicited a higher Th1-type response compared to IMO alone. So the combination of LNPs and immune-modulatory oligonucleotide adjuvants led to have the synergistic effects for immune responses and to manipulate those immune qualities that is quite different from the inorganic adjuvants. The clinical development of lipid-based nanoparticle technologies with chemo- and nucleic acid therapeutics have demonstrated the potential of lipid-based carriers in the treatment of a range of diseases.
However, the number of successful products that have reached the market does not accurately represent the number of formulations in pre clinical trials, indicating that the development of these nanoparticles still suffers from difficulties and challenges in the translation from animals to humans.
Recently, several strategies have been developed to overcome these limitations. To improve the stability of nanoparticles and prevent drug leakage, lipid structures have been designed that efficiently complex by ionic attraction with the encapsulated therapeutic.
Cholesterol, on the other hand, is essential in providing stability to the liposomal structures resulting in tight packing of the drugs. Stability of the LNPs in physiological media and systemic circulation is achieved by modifying the particle surface with a PEG-lipid, thereby reducing the recognization by the reticuloendothelial system. The quest for PEG alternatives has, therefore, become necessary to enable repeated injections.
The selective association of LNPs with target cells remains a challenge. Nucleic acid vaccines for example cannot be injected directly into our lymph nodes or spleen, which are tissues that are home to immune cells responsible for making antibodies and killing cancer cells. The targeted delivery of nucleic acids from injection sites to immune cells in lymph nodes or the spleen is therefore critical to maximising the production of antibody or long-lived antigen-specific cytotoxic T cells.
Such delivery systems need the ability to target lymph nodes but also cross the barrier cells in the lymph nodes to interact with immune cells.
Additionally, after internalization, the controlled release of therapeutics to aberrant cells has to be initiated effectively. These mechanisms that facilitate cell uptake, internalization, and payload release have not yet achieved the expected results. The success of LNPs with selective ligands in the market have not been completed yet. Therefore, with various cell type-specific ligands and stimulus agents, it is expected that studies related efficacy of modified LNPs for different diseases will enter clinical trials soon.
The co-delivery or drug co-encapsulating with adjuvants are of interest in this field to improve efficacy and immune modulation.
Additionally, the manufacturing and scaling up process of LNPs, has been challenging. New methodologies of LNP preparation based on microfluidics have been considered as the most robust to date, but it exhibits limitations in formulating multifunctional LNPs. These vaccines are not limited to infectious diseases but have also been developed for other disease types such as cancer and hyperlipidemia.
Some clinical trials are almost at the final phase. Numerous studies are at early stages and will increase in the future, which forecasts a range of products to be launched on the market.
A long road to optimizing LNP formulations for small molecule drugs and nucleic acid delivery has been paid off, and LNPs have become, once again, a frontrunner in nano drug delivery system. This review highlights key lessons learnt from this long road and serves as a reference for designing LNPs. Further development of LNPs is still urgently needed to address current global health challenges, which requires collaborative efforts of scientists in different fields.
Conceptualization, N. All authors have read and agreed to the published version of the manuscript. National Center for Biotechnology Information , U. Journal List Vaccines Basel v. Vaccines Basel. Published online Apr 8. Estelle J. Nghia P. Tripp, Academic Editor. Author information Article notes Copyright and License information Disclaimer. Received Mar 23; Accepted Apr 6. This article has been cited by other articles in PMC.
Abstract COVID vaccines have been developed with unprecedented speed which would not have been possible without decades of fundamental research on delivery nanotechnology. Introduction Nanomedicine is the convergence of nanotechnology, pharmaceutical, and biomedical sciences and has developed rapidly with the design of new nanoformulations for therapeutic purposes, imaging agents and theragnostic applications.
Open in a separate window. Figure 1. Lipid-Based Nanoparticles 2. Overview of Lipid-Based Nanoparticles Lipid-based nanoparticles are classified into 5 categories depending on the fabrication method and on the physicochemical properties of the formulations. Figure 2. Table 1 Summary of main characteristics of common lipid-based nanoparticles. The Properties of Lipid-Based Nanoparticles Governing Their Efficiencies For the delivery of oligonucleotides, nanoparticles need to encapsulate sufficient amounts of nucleic acid and have specific tissues targeting properties [ 12 , 13 ].
Figure 3. Figure 4. Lipid-Based Nanoparticles for Drug Delivery For almost 30 years, liposomes have been blossoming in clinical applications. Table 3 Liposomal formulations in clinical trials. Figure 5. Lipid-Based Nanoparticles for Therapeutic Vaccines LNPs and liposomes showed their best suitability for RNA-based vaccines in protective ability, pharmacokinetics, tissue distribution and targeted delivery dendritic cells and macrophages [ 12 , , , , ]. Figure 6.
Table 5 Clinical trial information of LNPs for cancer vaccines. Conclusions and Future Directions The clinical development of lipid-based nanoparticle technologies with chemo- and nucleic acid therapeutics have demonstrated the potential of lipid-based carriers in the treatment of a range of diseases. Author Contributions Conceptualization, N. Institutional Review Board Statement Not applicable. Informed Consent Statement Not applicable. Data Availability Statement Not applicable. Conflicts of Interest The authors declare no conflict of interest.
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Hemagglutinin functionalized liposomal vaccines enhance germinal center and follicular helper T cell immunity. Kedmi R. A modular platform for targeted RNAi therapeutics. Cell specific delivery of modified mRNA expressing therapeutic proteins to leukocytes. For this study, the researchers coated the nanoparticles with targeting molecules that recognize a protein called PSMA prostate-specific membrane antigen , found abundantly on the surface of most prostate tumor cells as well as many other types of tumors.
The BIND nanoparticles have three components: one that carries the drug, one that targets PSMA, and one that helps evade macrophages and other immune-system cells. A few years ago, Langer and Farokhzad developed a way to manipulate these properties very precisely, creating large collections of diverse particles that could then be tested for the ideal composition.
Food and Drug Administration. Clinical results The Phase I clinical trial involved 17 patients with advanced or metastatic tumors who had already gone through traditional chemotherapy.
To determine safe dosages, patients were given escalating doses of the nanoparticles. So far, doses of BIND have reached the amount of docetaxel usually given without nanoparticles, with no new side effects. The known side effects of docetaxel have also been milder. Higher blood concentration of BIND facilitated tumor targeting resulting in tumor shrinkage in patients, in some cases with doses of BIND that correspond to as low as 20 percent of the amount of docetaxel normally given.
The nanoparticles were also effective in cancers in which docetaxel usually has little activity, including cervical cancer and cancer of the bile ducts. The researchers also found that in animals treated with the nanoparticles, the concentration of docetaxel in the tumors was up to tenfold higher than in animals treated with conventional docetaxel injection for the first 24 hours, and that nanoparticle treatment resulted in enhanced tumor reduction.
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Patients should have clinical, radiographical, cytological, or histological confirmation of NSCLC or lung or nodal metastases from another primary cancer defined as within or touching the zone of the proximal bronchial tree, defined as a volume 2 cm in all directions around the trachea and proximal bronchial tree carina, right and left main bronchi, right and left upper lobe bronchi, intermedius bronchus, right middle lobe bronchus, lingular bronchus right and left lower lobe bronchi.
OR Histologically or cytologically confirmed pancreatic ductal adenocarcinoma of the pancreatic head, body or tail.
Eligible NSCLC patients must have no evidence of nodal involvement N0 , and disease has to be determined unresectable by a thoracic oncologist or the patient is medically inoperable. Participants must have normal organ and marrow function as defined below:.
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Read our disclaimer for details. Last Update Posted : November 1, See Contacts and Locations. Study Description. This research study is being done to help determine the safety and efficacy of gadolinium based nanoparticle, Activation and Guidance of Irradiation X AGuIX , used in conjunction with MR-guided stereotactic body radiation therapy SBRT in the treatment of pancreatic cancer and lung tumors.
Detailed Description:. The phase II part of the study is a randomized controlled trial that tests, for each disease group, the treatment efficacy of stereotactic body radiation therapy SBRT in combination with AGuIX gadolinium-chelated polysiloxane based nanoparticles compared to treatment with stereotactic magnetic resonance MR -guided adaptive radiation therapy SMART alone The U. FDA Resources.
Arms and Interventions. Central lung tumor cohort will receive: five fractions of stereotactic body radiation therapy SBRT AGuIX Nanoparticle given on -7 or day prior to radiation treatment, then with 1st fraction of radiation and for patients receiving radiation over a two 2 week period with the 4th fraction of radiation. Stereotactic magnetic resonance-guided adaptive radiation therapy. Outcome Measures. Local control at 12 months is defined as the treated tumor is equal to or less than the tumor volume at start of SMART.
Changes in the largest diameter unidimensional measurement of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. Bayesian hierarchical two-sample test for binary outcomes.
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