Bacteria from Infectious Particles to Cell Based Anticancer Targeted Drug Delivery Systems
Abstract
:1. Introduction
2. Targeted Drug Delivery System
2.1. The Development of a Targeted DDS
2.2. Advantage of DDS
2.3. Classification and Types of Targeted DDSs
2.4. Challenges of Targeted DDSs
2.5. Biological Targeted DDSs
3. Bacterial Ghosts (BGs)
3.1. The Concept and Production
3.2. Structure of BGs
4. Application
- i.
- BGs as a drug delivery system
- ii.
- BGs for proteins and peptides delivery
- iii.
- Delivery of nucleic acid via BGs
- iv.
- Immunization by BGs
- v.
- As a delivery system for anticancer drugs (PK/PD)
Ghost Bacteria | Active Compound | Target Cells | Proof of Principle | Findings/Outcomes | Ref. |
---|---|---|---|---|---|
Escherichia coli NM522 | DNA | Human melanoma cells | Tissue culture | BGs exhibit a high transfection efficiency; up to 82% of melanoma cells expressed the plasmid-encoded reporter gene delivered by BGs. | [17] |
Mannheimia haemolytica | DOX | Caco-2 cells | Tissue culture | Higher antiproliferative effects of DOX on Caco-2 cells were mediated by the specific drug targeting properties of the BGs. | [56] |
E. coli | 5-FU | Caco-2 cells | Tissue culture | 69.2% of the ghost-associated 5-FU was released with a significant antiproliferative effect. | [42] |
Salmonella typhimurium | DOX | HepG2 | Tissue culture | The death rate of HepG2 reached 64.5% by using of 4 μg/mL while it was about 51% using the same concentration of the free DOX. The proliferative inhibitory concentration of the DOX-loaded BG was about one third of the IC50 of the free DOX. Combined DOX showed more accumulation in early and late apoptosis than that of free DOX. | [57] |
E. coli BL21 (DE3) | DOX | HT-29 cells | Tissue culture | DOX loaded in BG showed more apoptosis (55%) than the control and DOX solution. | [58] |
Lactobacillus acidophilus | PG | HCT116 CRC cells | Tissue culture | PG was highly bound to LAGs cell wall with a stable bioactive entity (PG-LAGs) active against HCT116 CRC cells at the cellular and molecular levels. | [59] |
E. coli NM522 & M. haemolytica A23 | plasmid pEGFP-N1 | SK-Mel-28 & A-375 cells | Tissue culture | High capability of cell lines to bind BGs was observed, and the Bowes cells exhibited a high expression level of GFP and the incubation of cells with plasmid-loaded BGs led up to 82% transfection efficiency. | [17] |
E. coli Nissle1917 | 5-FU & zoledronic acid | 4T1 tumor cells and RAW264.7 macrophages | Tissue culture & Animal studies | High loading levels of 5FU (8.8%) and ZOL (10.5%) are achieved, as well as high retention rates of bacterial viability (87%) and motion velocity (88%), leading to the accumulation of 5-FU and increases in its chemotherapeutic effect on tumors inhibition. | [22] |
E. coli Nissle1917 | Oxaliplatin | CT26 murine colon carcinoma cells (CRL-2638) | Tissue culture & Animal studies | The combination treatment has showed strong synergistic anticancer activity against the CT26 allograft, resulting in prolonged survival with complete remission in a murine model of CRC carcinomatosis. | [60] |
Ghost Bacteria | Active Compound | Target Cells | Proof of Principle | Finding/Outcomes | Ref. |
---|---|---|---|---|---|
Helicobacter pylori | Plain BGs | Immune cells | Oral vaccination | Coadministration of ghosts with cholera toxin as a mucosal adjuvant resulted in a complete protection of 10 of 10 and 8 of 8 mice against H. pylori challenge, with three animals showing sterile immunity. | [61] |
E. coli | OmpA-HbcAg-149 Protein | Immune cells | Subcutaneous immunizations | Induced significant immune responses against HBcAg-149 in mice were observed, indicating that BGs provide an excellent carrier system for antigen delivery. | [62] |
Salmonella typhimurium–LTB | MontanideTM ISA 70VG | Immune cells | Intramuscular immunization | Injection of S. typhimurium-LTB ghost with or without Montanide(TM) ISA70VG adjuvant is capable of inducing protective immunity against the virulent S. typhimurium infection in chickens. | [63] |
E. coli O157:H7 | staphylococcal nuclease A | Immune cells | Oral immunization | Immunized mice showed 86% protection against lethal challenge with a heterologous EHEC strain after single-dose oral immunization and 93.3% protection after one booster at day 28, whereas the controls showed 26.7% and 30% survival, respectively. These results indicate that it is possible to develop an efficacious single-dose oral EHEC BG vaccine. | [64] |
Salmonella enteritidis | flagellin (FliC) antigen | Immune cells | Intramuscular immunization | pJHL184:fliC ghost can generate significantly high antigen-specific IgY and cell-mediated immune responses and cytokine responses elicited by stimulated splenic T-cells. The elimination of both SE and ST in chicken organs ensures the immunization of the present SE. The ghost vaccine be beneficial in preventing enteric infections in humans. | [65] |
Salmonella enteritidis | pVAX1-nspA plasmid | Immune cells | Oral immunization | Coadministration of SE ghosts (pVAX1-nspA) and SE ghosts (pVAX1-porB) elicited significant specific humoral and cellular immune responses. | [66] |
Streptococcus suis | Plain BGs | Immune cells | Subcutaneous immunization | S.suis ghosts as candidate vaccine showed the excellent immunogenicity and provided protection against S.suis challenge in mice model. | [67] |
Streptococcus iniae | Plain BGs | Immune cells | Intraperitoneal immunization | Immunization with S. iniae ghosts induces immune responses and provides protection against a virulent S. iniae challenge. | [68] |
E. coli O157:EDL 933 | pOEVP1 and pOCVP1 plasmids | Immune cells | Intraperitoneal immunization | The VP1 chimeric antigens of BGs are target candidates for a new type of vaccine against hand-foot-and-mouth disease. This vaccine strategy also elicited a stronger immune response against E. coli O157:EDL 933. | [69] |
E. coli O78:K80 | pmET32b plasmid | Immune cells | Subcutaneous immunization | The O78:K80 BGs vaccine triggered higher proinflammatory cytokine expression including IL-6, IL-1β and TNFSF15; a higher level of antibody-dependent humoral (IgY and IgA) and cellular immune responses (IFNγ and lymphocyte proliferation). | [70] |
Brucella abortus | GEM-7Zf+-gntR-SacB-λE | Immune cells | Subcutaneous immunization | The 2308ΔgntR ghost induced high protective immunity in BALB/c mice against challenge with S2308, and elicited an anti-Brucella-specific immunoglobulin G (IgG) response and induced the secretion of interferon gamma (IFN-γ) and interleukin-4 (IL-4). Additionally, 2308ΔgntR ghosts demonstrated strong spleen CD4+ and CD8+ T cell responses. | [71] |
Salmonella typhimurium | DENV-EDIII protein | Immune cells | Oral immunization | Significantly elevated titers of EDIII-specific IgG, IgG1 and IgG2a were observed in the immunized mice. Furthermore, lymphocyte proliferative activity and CD3+CD4+ T-cell subpopulations increased significantly in vitro in re-pulsed splenic T cells compared with those from non-immunized mice. | [72] |
Salmonella enteritidis (JOL2114) | HA1 protein | Immune cells | Intramuscular & Oral immunization | Protective humoral and cell-mediated immune responses were effectively elicited against both Salmonella and influenza challenge. | [73] |
Neisseria gonorrhoeae | pVAX1-porB | Immune cells | Oral immunization | Oral immunization with the BGs vaccine candidate elicited greater CD4+ and CD8+ T cell responses and induced higher IgG responses than N. gonorrhoeae DNA vaccine alone. | [74] |
Actinobacillus pleuropneumoniae | Plain BGs | Immune cells | Intramuscular immunization | A significant systemic increase of IgM, IgA, IgG(Fc’), or IgG(H+L) antibodies reactive with A. pleuropneumoniae was measured in GVPs and BVPs. | [75] |
Vibrio cholera | V. cholerae ghosts expressing rVCG-MOMP | Immune cells | Intramuscular immunization | rVCG-MOMP vaccine induced increased local genital mucosal, as well as systemic, Th1 responses. Moreover, T cells from immunized mice could transfer partial protection against C. trachomatis. | [76] |
5. Clinical Trials
6. Uniqueness of BGs as Delivery System
6.1. Structural Integrity
6.2. Bioadhesive and Attachments for Targeted Colonization
6.3. Immunogenicity
6.4. Compartmentalization and Placement of Antigens and/or Medications within BGs
7. Cell, Tissue Uptake and Cellular Inflammatory Response
8. Ideal Drugs to Be Loaded into BGs
9. Safety Issues of Using BGs
9.1. Human Risk of BGs as DNA Vaccine Carriers
9.2. Controlling the Risk
10. Stability Aspects of Using BGs as Delivery Systems
11. Generation vs. Species
12. Future Prospective
13. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Classes | General Classification | Site of Action | Based on Mechanism |
---|---|---|---|
Subclasses | 1. Active targeting | 1. Organ (colonic targeted DDS) | 1. Chemical targeted DDS |
2. Passive targeting | 2. Therapeutic material (gene carrier) | 2. Physical targeted DDS | |
3. Cellular uptake (endocytosis, macropinocytosis, and phagocytosis DS) | 3. Biological targeted DDS |
Bacterial Ghosts | Disease | Target Cells | Outcomes/Conferred Protection | Developer/ Pharm. Company |
---|---|---|---|---|
Edwardsiella tarda | Edwardsiellosis | Fish | E. tarda BGs showed a significant systemic and mucosal Ag-specific humoral immune response. | BIRD-C |
Actinobacillus pleuropneumoniae | Porcine pleuropneumonia | Pig | Ag-specific humoral immune response; increased T helper cytotoxic T cell ratio; complete protection against clinical disease | BIRD-C |
Pasteurella multocida, Mannheimia haemolytica | Bovine respiratory disease | Cattle | Protective immunity against homologous challenge; cross-reactivity to various Pasteurella serotypes. | BIRD-C |
Salmonella enteritidis | Salmonellosis/Enteritis and systemic disease | Chicken | Double-immunized chickens showed protection against the intestinal, liver, splenic and ovarian colonization of S. enteritidis; Ag-specific lymphocyte proliferative response in immunized chickens. | BIRD-C |
Aeromonas hydrophila | Hemorrhagic septicemia | Fish | Oral immunization with A. hydrophila BGs elicits systemic and mucosal immune responses. | BIRD-C |
E. coli 0157:H7 | EHEC carrier status Diarrhea | Cattle | Induction of EHEC specific antibodies, significant reduction of both duration and total shedding of EHEC offer oral challenge | BIRD-C |
Heamophilus parasuis | Glässer’s disease | Pig | Piglets immunized with H. parasuis BGs exhibited higher levels of T helper cells relevant for protection. | BIRD-C |
Escherichia coli | Hemorrhagic septicemia | Fish | Ag-specific immune response; protection after challenge (>80%) | BIRD-C |
Bordetella bronchiseptica | Kennel cough | Dog | BbBG vaccine showed equivalent results when compared to the positive control vaccine (Bronchicine CAe) in terms of safety and efficacy. | BIRD-C |
Flavobacterium columnare | Columnaris disease | Fish | Ctenopharyngodon idellus immunized with F. columnare BGs showed a significantly higher Ag-specific immune response. | BIRD-C |
Salmonella typhimurium | E. coli colibacillosis | Pig | Oral immunization of piglets with S. typhimurium BGs ETEC fimbriae provides protection to E. coli colibacillosis. | BIRD-C |
Salmonella gallinarium | Fowl typhoid | Chicken | Significant Ag-specific systemic IgG response; increased mRNA level of Th1 cytokines (IFNγ and IL-2). | BIRD-C |
Klebsiella pneumoniae | Mastitis | Pig | Cross reactivity to related subspecies and clear protection against virulent bacteria | BIRD-C |
Streptococcus iniae | Streptococcosis | Fish | Tilapia (Oreochromis niloticus) immunized with S. iniae BGs showed better protection and higher bactericidal activity as compared to formalin-killed vaccines. | BIRD-C |
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Salem-Bekhit, M.M.; Youssof, A.M.E.; Alanazi, F.K.; Aleanizy, F.S.; Abdulaziz, A.; Taha, E.I.; Amara, A.A.A.F. Bacteria from Infectious Particles to Cell Based Anticancer Targeted Drug Delivery Systems. Pharmaceutics 2021, 13, 1984. https://doi.org/10.3390/pharmaceutics13121984
Salem-Bekhit MM, Youssof AME, Alanazi FK, Aleanizy FS, Abdulaziz A, Taha EI, Amara AAAF. Bacteria from Infectious Particles to Cell Based Anticancer Targeted Drug Delivery Systems. Pharmaceutics. 2021; 13(12):1984. https://doi.org/10.3390/pharmaceutics13121984
Chicago/Turabian StyleSalem-Bekhit, Mounir M., Abdullah M. E. Youssof, Fars K. Alanazi, Fadilah Sfouq Aleanizy, Alsuwyeh Abdulaziz, Ehab I. Taha, and Amro Abd Al Fattah Amara. 2021. "Bacteria from Infectious Particles to Cell Based Anticancer Targeted Drug Delivery Systems" Pharmaceutics 13, no. 12: 1984. https://doi.org/10.3390/pharmaceutics13121984