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Pharmaceutics
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Functionalized Nanoparticles in Cancer Therapeutics, 2nd Edition
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Functionalized Nanoparticles in Cancer Therapeutics, 2nd Edition

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Nanomedicine and Nanotechnology".

Deadline for manuscript submissions: 20 February 2025 | Viewed by 8197

Special Issue Editors

Prof. Dr. R. Jayachandra Babu

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Guest Editor
Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA
Interests: nanoparticles; liposomes; solubility improvement; chemotherapeutic delivery
Special Issues, Collections and Topics in MDPI journals
Dr. Amit K. Tiwari

E-Mail Website
Guest Editor
College of Pharmacy, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA
Interests: drug resistance; chemotherapy failure; drug–drug interaction; anticancer drug discovery; novel mechanisms
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer is a leading cause of death, accounting for millions of lives lost worldwide. Drug discovery and development efforts have provided highly potent chemotherapeutic drug molecules for the treatment of various cancers. However, many cancer mortalities are due to high systemic exposures from conventional chemotherapeutic drugs to various organs and inadequate delivery to the tumor sites. Targeted delivery of drugs, via functional nanomedicines to cancer tumors in a “magic bullet” approach, selectively kills the tumor cells without harming the benign cells. Current clinical practice for cancer treatment is based on many functional nanomedicines for tumor targeting with minimal exposure to “normal” cells, thus avoiding toxicity to the patient.

This Special Issue covers the following nanomedicines:

  • Protein, polymer, and lipid-based nanomedicines with multi functionalities such as targeted moieties, triggered stimuli responses, immunoevasion (pegylation), prolonged release, and protection of the drug from degradation;
  • Inorganic nanomedicines with unique electromagnetic properties for tumor site-specific delivery and diagnostic and imaging capabilities;
  • Nanomedicines prepared with various functional biomaterials with unique transport properties for tumor targeting via enhanced permeability and retention (EPR) effect.

Prof. Dr. R. Jayachandra Babu
Dr. Amit K. Tiwari
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • liposomes
  • polymeric nanoparticles
  • dendrimer-based nanoparticles
  • micellar nanoparticles
  • inorganic nanoparticles
  • small interfering RNA-based nanoparticles
  • protein-based nanoparticles
  • functional nanomaterials

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Published Papers (3 papers)

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Research

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15 pages, 1916 KiB  
Article
Efficient Gene Editing for Heart Disease via ELIP-Based CRISPR Delivery System
by Xing Yin, Romain Harmancey, Brion Frierson, Jean G. Wu, Melanie R. Moody, David D. McPherson and Shao-Ling Huang
Pharmaceutics 2024, 16(3), 343; https://doi.org/10.3390/pharmaceutics16030343 - 29 Feb 2024
Cited by 1 | Viewed by 1910
Abstract
Liposomes as carriers for CRISPR/Cas9 complexes represent an attractive approach for cardiovascular gene therapy. A critical barrier to this approach remains the efficient delivery of CRISPR-based genetic materials into cardiomyocytes. Echogenic liposomes (ELIP) containing a fluorescein isothiocyanate-labeled decoy oligodeoxynucleotide against nuclear factor kappa [...] Read more.
Liposomes as carriers for CRISPR/Cas9 complexes represent an attractive approach for cardiovascular gene therapy. A critical barrier to this approach remains the efficient delivery of CRISPR-based genetic materials into cardiomyocytes. Echogenic liposomes (ELIP) containing a fluorescein isothiocyanate-labeled decoy oligodeoxynucleotide against nuclear factor kappa B (ELIP-NF-κB-FITC) were used both in vitro on mouse neonatal ventricular myocytes and in vivo on rat hearts to assess gene delivery efficacy with or without ultrasound. In vitro analysis was then repeated with ELIP containing Cas9-sg-IL1RL1 (interleukin 1 receptor-like 1) RNA to determine the efficiency of gene knockdown. ELIP-NF-κB-FITC without ultrasound showed limited gene delivery in vitro and in vivo, but ultrasound combined with ELIP notably improved penetration into heart cells and tissues. When ELIP was used to deliver Cas9-sg-IL1RL1 RNA, gene editing was successful and enhanced by ultrasound. This innovative approach shows promise for heart disease gene therapy using CRISPR technology. Full article
(This article belongs to the Special Issue Functionalized Nanoparticles in Cancer Therapeutics, 2nd Edition)
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Figure 1

Figure 1
<p>Proposed structure of gas-containing echogenic liposomes (ELIP) and experimental setup for ELIP applications. (<b>A</b>) The ELIP loaded with payloads is typically composed of three main lipid components, including ionizable cationic/anionic lipids, helper lipids, and cholesterol. (<b>B</b>) In vitro, the setup comprises a Costar transwell insert with a 0.4 μm pore polyester membrane placed on Rho-C rubber. The polyester membrane enables 100% ultrasound wave transmission, while the Rho-C rubber prevents wave reflection. To prevent air interference, a water layer separates the membrane and rubber.</p> Full article ">Figure 2
<p>Representative images and echogenicity of liposomes at 4 μg/mL with/without gas. (<b>A</b>) PBS only; (<b>B</b>) liposomes only; (<b>C</b>) air-containing ELIP loaded with CRISPR complex. (<b>D</b>) Octafluoropropane (OFP)-containing ELIP loaded with CRISPR complex.</p> Full article ">Figure 3
<p>Dose–response (<b>A</b>) and fluorescent imaging (<b>B</b>) of Ultrasound/NFκB-FITC-ELIP enhanced transfection efficiency into neonatal C57BL/6J mouse cardiomyocytes in vitro. Cardiomyocytes were cultured and then split. (<b>A</b>) Following, the cardiomyocytes suspended with PBS were treated with ELIP-NF-κB-FITC (final concentration 10 nM) with different ultrasound parameters, and then the cardiomyocytes were washed with PBS. The fluorescent intensity of the cardiomyocytes was measured using a Synergy microplate reader. Excitation and emission monochromators were set at 490 and 520 nm, respectively. (<b>B</b>) Representative fluorescent images of the cardiomyocytes were shown. US: ultrasound.</p> Full article ">Figure 4
<p>Representative images (<b>A</b>) and quantitation (<b>B</b>) of fluorescent intensity were shown in rats in vivo. DAPI nuclear staining (blue), FITC immunofluorescence, and a merged image are shown in panels, respectively, using the Nikon H600L imaging System. US: ultrasound.</p> Full article ">Figure 5
<p>Characterization of OFP-ELIP-CRISPR complex. (<b>A</b>). Dose-dependent response in echogenicity (maximum mean grayscale value). Dashed line: trendline (logarithmic). (<b>B</b>). Loading efficiency and ultrasound-triggered release of Cas9 and sg-IL1RL1 RNA from OFP-ELIP at 4 μg/mL of ELIP. US: Ultrasound (1 MHz, 1 W/cm<sup>2</sup>, 100%, 15″ for loading or 120″ for release). * <span class="html-italic">p</span> &lt; 0.001, as compared to no-US. <span>$</span> <span class="html-italic">p</span> &lt; 0.01, as compared to baseline. Mean ± SD (<span class="html-italic">n</span>).</p> Full article ">Figure 6
<p>Efficiency of Cas9/sg-IL1RL1 RNA components for gene disruption in mouse neonatal cardiomyocytes using the ELIP-CRISPR delivery platform. Cardiomyocytes were transfected with GeneArt<sup>®</sup> CRISPR All-In-One vectors targeting <span class="html-italic">Mus musculus</span> IL1RL1 locus regions using ELIP. PCR amplification with flanking primers was followed by re-annealing, treatment with Detection Enzyme, and electrophoresis on a 2% agarose gel. (<b>A</b>) Representative gel images from the Genomic Cleavage Detection Assay. (<b>B</b>) Significance was determined using one-way analysis of variance (ANOVA) with Tukey’s posthoc test (* <span class="html-italic">p</span> &lt; 0.0001). <span>$</span> <span class="html-italic">p</span> &lt; 0.0001 compared to ELIP + RNP without ultrasound (US). RNP: Cas9/sg-IL1RL1 RNA ribonucleoprotein complex. PB: Parental Band, PB-1: 516 bp, PB-2: 976 bp. CBs: Cleaved Bands, CBs-1: 225 bp and 291 bp, CBs-2: 478 bp and 498 bp. PCR kit control: Control Template and Primers. DNA Ladder: 1 Kb Plus DNA Ladder (Accuris SmartCheck).</p> Full article ">Figure 7
<p>Schematic illustration of the ELIP-based CRISPR delivery platform designed for gene therapy targeting heart disease. In this study, we developed this platform to efficiently deliver Cas9-sg-IL1RL1 RNA RNP to cardiomyocytes, demonstrating an effective approach for CRISPR-based gene editing.</p> Full article ">

Review

Jump to: Research

18 pages, 1449 KiB  
Review
Role of Biofunctionalized Nanoparticles in Digestive Cancer Vaccine Development
by Razvan Zdrehus, Cristian Delcea and Lucian Mocan
Pharmaceutics 2024, 16(3), 410; https://doi.org/10.3390/pharmaceutics16030410 - 16 Mar 2024
Viewed by 1918
Abstract
Nanotechnology has provided an opportunity for unparalleled development of the treatment of various severe diseases. The unique properties of nanoparticles offer a promising strategy for enhancing antitumor immunity by enhancing immunogenicity and presentation of tumor autoantigens for cancer immunotherapy. Polymeric, liposomal, carbon or [...] Read more.
Nanotechnology has provided an opportunity for unparalleled development of the treatment of various severe diseases. The unique properties of nanoparticles offer a promising strategy for enhancing antitumor immunity by enhancing immunogenicity and presentation of tumor autoantigens for cancer immunotherapy. Polymeric, liposomal, carbon or silica-based nanoparticles are among those with major immunomodulatory roles in various cancer treatments. Cancer vaccines, in particular digestive cancer vaccines, have been researched and developed on nanotechnological platforms. Due to their safety, controlled release, targeting of dendritic cells (DCs) and improved antigen uptake, as well as enhanced immunogenicity, nanoparticles have been used as carriers, as adjuvants for increased effect at the tumor level, for their immunomodulating effect, or for targeting the tumor microenvironment, thereby increasing tumor immunogenicity and reducing tumor inflammatory response. This review looks at digestive cancer vaccines developed on nanoparticle platforms and the impact nanoparticles have on the effects of these vaccines. Full article
(This article belongs to the Special Issue Functionalized Nanoparticles in Cancer Therapeutics, 2nd Edition)
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Figure 1

Figure 1
<p>Cancer vaccines can be composed of various platforms to deliver specific tumor antigens. These platforms offer advantages such as simpler manufacturing and flexibility in vaccine delivery. Cell-based vaccines, like dendritic cell (DC) vaccines, allow targeted loading of antigens and manipulation in vivo. However, standardizing manufacturing and quality assessment poses challenges. As our understanding of the immune system grows, there is potential for more efficient and intelligent design of cancer vaccine platforms. These vaccines can be used alone or in combination with other cancer therapies, expanding the scope of cancer immunotherapy as the fourth pillar in oncology, alongside surgery, chemotherapy, and radiation. Reproduced with permission from [<a href="#B4-pharmaceutics-16-00410" class="html-bibr">4</a>].</p> Full article ">Figure 2
<p>The role of DCs in tumor immunity. DCs present antigens to naïve T cells, leading to T-cell activation and transformation into cytotoxic T lymphocytes (CTLs). CTLs then attack tumor cells through direct killing or IFN-γ-dependent pathways. Nanoparticles (NPs) modified with antigens and adjuvants have two main functions: they specifically deliver antigens to DCs, and they promote DC maturation and CTL activation, either by antigen presentation or with the help of adjuvants. This results in the activation and expansion of CD4+ and CD8+ T cells, granting them cytotoxic abilities or helper functions, such as IFN-γ secretion.</p> Full article ">Figure 3
<p>Schematic illustration of the endogenous antigen-carrying nanoparticles (EAC-NPs), EAC-NP formation and the mechanisms of EAC-NP-induced cancer immunotherapy. (<b>A</b>) Schematic illustration of the preparation of HSP70-chaperoned polypeptides HCP+CpG@NPs-CD80 Ab vesicles and induction of T-cell immune responses. (<b>B</b>) Partial magnification of (<b>A</b>). Once phagocytosis occurs, antigen-presenting cells are activated through two signaling pathways: antigen signaling and TLR signaling. After activation, APCs deliver antigen signaling to T lymphocytes, which differentiate into helper T (Th) cells and CTLs and even produce memory T cells. Reproduced with permission from [<a href="#B13-pharmaceutics-16-00410" class="html-bibr">13</a>].</p> Full article ">Figure 4
<p>(<b>a</b>) Fluorescent images of mouse injected with RITC-labeled XL-MSNs subcutaneously on abdomen region, showing targeting of XL-MSNs to the draining lymph node (white dotted circle). (<b>b</b>) OVA-specific and (<b>c</b>) intracellular cytokine-secreting CTLs in the spleens of vaccinated mice measured in flow cytometry (<span class="html-italic">n</span> = 6). Error bars, mean ± s.d. * <span class="html-italic">p</span> &lt; 0.05. (<b>d</b>) Proliferation of CFSE-labeled OVA-specific CD8+ T cells in the lymph node (red line: XL-MSN + OVA + CpG, black line: control), reproduced with permission from [<a href="#B29-pharmaceutics-16-00410" class="html-bibr">29</a>].</p> Full article ">
28 pages, 3710 KiB  
Review
Tumor-Associated Macrophage Targeting of Nanomedicines in Cancer Therapy
by Xuejia Kang, Yongzhuo Huang, Huiyuan Wang, Sanika Jadhav, Zongliang Yue, Amit K. Tiwari and R. Jayachandra Babu
Pharmaceutics 2024, 16(1), 61; https://doi.org/10.3390/pharmaceutics16010061 - 29 Dec 2023
Cited by 6 | Viewed by 3675
Abstract
The tumor microenvironment (TME) is pivotal in tumor growth and metastasis, aligning with the “Seed and Soil” theory. Within the TME, tumor-associated macrophages (TAMs) play a central role, profoundly influencing tumor progression. Strategies targeting TAMs have surfaced as potential therapeutic avenues, encompassing interventions [...] Read more.
The tumor microenvironment (TME) is pivotal in tumor growth and metastasis, aligning with the “Seed and Soil” theory. Within the TME, tumor-associated macrophages (TAMs) play a central role, profoundly influencing tumor progression. Strategies targeting TAMs have surfaced as potential therapeutic avenues, encompassing interventions to block TAM recruitment, eliminate TAMs, reprogram M2 TAMs, or bolster their phagocytic capabilities via specific pathways. Nanomaterials including inorganic materials, organic materials for small molecules and large molecules stand at the forefront, presenting significant opportunities for precise targeting and modulation of TAMs to enhance therapeutic efficacy in cancer treatment. This review provides an overview of the progress in designing nanoparticles for interacting with and influencing the TAMs as a significant strategy in cancer therapy. This comprehensive review presents the role of TAMs in the TME and various targeting strategies as a promising frontier in the ever-evolving field of cancer therapy. The current trends and challenges associated with TAM-based therapy in cancer are presented. Full article
(This article belongs to the Special Issue Functionalized Nanoparticles in Cancer Therapeutics, 2nd Edition)
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Figure 1

Figure 1
<p>In the tumor niche, tumor cells release MCSF, IL4, and IL10, etc., to attract macrophage; then, tumor-associated macrophages engage in intricate interactions with cancer-associated fibroblasts (CAFs), T regulatory cells, natural killer cells to form an immunosuppressive tumor microenvironment (TME). Understanding these interactions is crucial for developing targeted therapies to overcome immunosuppression in the TME. (Images created with <a href="http://biorender.com" target="_blank">biorender.com</a>, accessed on 17 July 2023).</p> Full article ">Figure 2
<p>The role of macrophages in TME: In the context of tumor progression, neoplastic cells and stromal cells release specific molecules that act as chemoattractants, such as CCL2 and MCSF-1, to recruit circulating monocytes to the tumor site. Once recruited, monocytes significantly differentiate into M2 TAMs. The predominant M2 TAMs promote the downregulation of tumor immunity, angiogenesis, as well as therapeutic resistance (↓ suggesting decrease) (created with <a href="http://biorender.com" target="_blank">biorender.com</a>, accessed on 17 July 2023).</p> Full article ">Figure 3
<p>Schematic representation of a variety of therapeutic approaches targeting TAM. Targeting TAMs therapeutic strategies involve inhibiting TAM recruitment and differentiation, depleting or impairing their function, reprogramming M2 TAMs, and promoting their phagocytic activity. Inhibiting TAM recruitment entails blocking chemokine and growth factor signaling while inhibiting TAM differentiation involves targeting factors like IL-4 and IL-13. Depleting TAMs can be achieved through selective elimination using specific markers or immunotherapies. Impairing TAM function targets signaling pathways involved in immunosuppression and angiogenesis. Reprogramming M2 TAMs toward an anti-tumoral M1-like phenotype enhances their anti-tumor activity. Promoting TAM phagocytosis enhances their ability to eliminate tumor cells. Combination therapies, integrating TAM-targeting approaches with other modalities, hold promise for synergistic effects (Created with <a href="http://biorender.com" target="_blank">biorender.com</a>, accessed on 17 July 2023).</p> Full article ">Figure 4
<p>Represenative of therapeutic modality for metabolism in TAM. (<b>A</b>) Schematic illustration of biomimetic targeting codelivery of Shikonin/JQ1 for reprogramming TME via regulation of metabolism (↑ suggesting increase, ↓ suggesting decrease) [<a href="#B180-pharmaceutics-16-00061" class="html-bibr">180</a>]. Copyright © 2019 American Chemical Society. (<b>B</b>) Schematic illustration of anti-alcoholism drug disulfiram for targeting glioma energy metabolism [<a href="#B178-pharmaceutics-16-00061" class="html-bibr">178</a>]. Copyright © 2022 Published by Elsevier Ltd. (<b>C</b>) Schematic illustration of using a PD-L1-targeting system loaded with rapamycin and regorafenib for metabolic modulation in TME [<a href="#B182-pharmaceutics-16-00061" class="html-bibr">182</a>]. Copyright © 2020 Elsevier Ltd.</p> Full article ">Figure 5
<p>Representative work of inorganic nanomaterials for TAM modality. (<b>A</b>) Schematic illustration of AuNC-based in situ vaccination: the photothermal tumor ablation of AuNC cut the source of TAM differentiation; the combination of AuNCs with the JQ1 (PD-L1 suppressor) dramatically inhibit the function of M2 TAM that overexpress PD-L1 [<a href="#B197-pharmaceutics-16-00061" class="html-bibr">197</a>]. Copyright © 2022 American Chemical Society. (<b>B</b>) Graphdiyne oxide nanosheets reprogram immunosuppressive macrophages for cancer immunotherapy (↑ suggesting the increase, ↓ suggesting the decrease) [<a href="#B204-pharmaceutics-16-00061" class="html-bibr">204</a>]. Copyright © 2022 Elsevier Ltd.</p> Full article ">Figure 6
<p>Representative work of inorganic nanomaterials for TAM modality. (<b>A</b>) Schematic representation of recombinant cell-penetrating trichosanthin synergizes anti-PD-1 therapy in colorectal tumor [<a href="#B208-pharmaceutics-16-00061" class="html-bibr">208</a>]. This is an open-access article distributed under the terms of the Creative Commons Attribution License. (<b>B</b>) Schematic representation of using mannose-modified system for mRNA delivery. Reproduced from reference [<a href="#B210-pharmaceutics-16-00061" class="html-bibr">210</a>]. Open-access article distributed under the terms of the Creative Commons CC BY license. (<b>C</b>) Schematic representation of using erythrocyte membrane-coated virus-mimicking nanogel for miRNA delivery [<a href="#B210-pharmaceutics-16-00061" class="html-bibr">210</a>]. Copyright © 2021 John Wiley and Sons.</p> Full article ">Figure 7
<p>Nanotechnology-based strategies for reprogramming tumor microenvironment. (<b>A</b>) Remodeling tumor-associated macrophages and neovascularization overcomes EGFRT790M-associated drug resistance by PD-L1 nanobody-mediated codelivery of Gefitinib and Simvastatin [<a href="#B224-pharmaceutics-16-00061" class="html-bibr">224</a>]. Copyright © 2018 WILEY-VCH Verlag GmbH &amp; Co. KGaA, Weinheim, Germany. (<b>B</b>) Reprogramming tumor-associated macrophages to reverse EGFRT790M resistance by dual-targeting codelivery of gefitinib/vorinostat [<a href="#B239-pharmaceutics-16-00061" class="html-bibr">239</a>]. Copyright © 2017 American Chemical Society (↑ suggesting the increase, ↓ suggest the decrease). (<b>C</b>) Targeting lipid metabolism to overcome EMT-associated drug resistance via integrin β3/FAK pathway and tumor-associated macrophage repolarization using legumain-activatable delivery [<a href="#B249-pharmaceutics-16-00061" class="html-bibr">249</a>]. This is an open-access article distributed under the terms of the Creative Commons Attribution License.</p> Full article ">
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