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Review

Controlled Drug Delivery Vehicles in Veterinary Oncology: State-of-the-Art and Future Directions

by
Patricia de Faria Lainetti
1,
Fernanda Zuliani
1,
Antonio Fernando Leis-Filho
1,
Ricardo Henrique Fonseca Alves
2 and
Carlos Eduardo Fonseca-Alves
1,3,*
1
Department of Veterinary Surgery and Animal Reproduction, School of Veterinary Medicine and Animal Science, São Paulo State University—UNESP, Botucatu 18618-681, Brazil
2
John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA
3
Institute of Health Sciences, Universidade Paulista—UNIP, Bauru 17048-290, Brazil
*
Author to whom correspondence should be addressed.
Processes 2020, 8(5), 541; https://doi.org/10.3390/pr8050541
Submission received: 30 March 2020 / Revised: 23 April 2020 / Accepted: 28 April 2020 / Published: 5 May 2020
(This article belongs to the Special Issue Application of Nanoparticles in Cancer Therapy)

Abstract

:
Controlled drug delivery systems can be used to carry several anticancer agents, including classical chemotherapeutic agents such as doxorubicin, paclitaxel or cisplatin, and are also used for the encapsulation of tyrosine kinase inhibitors and monoclonal antibodies. Usually, the controlled systems are used to decrease drug toxicity, increase local drug concentration or target specific organs or systems. In dogs, liposomal doxorubicin is the most known controlled drug delivery vehicle in veterinary medicine. However, several antitumor drugs can be encapsulated within these systems. Since the delivery vehicles are a relatively new topic in veterinary oncology, this review aims to discuss the current knowledge regarding the controlled drug delivery vehicles and discuss the current challenges and future direction of its use in veterinary oncology.

1. Introduction

In the past years, veterinary medicine has been experiencing an increased life expectancy associated with the appearance of several aging-related diseases in pets [1]. Among these diseases, cancer is one of the most prevalent in older dogs [1]. The treatment options in veterinary oncology include surgical procedure [2], radiation therapy [3], conventional chemotherapy [4], target therapies [5], electrochemotherapy [6] or a combination of these modalities. Although all these therapies have been used in veterinary oncology, we still have poor prognosis when compared with human patients. For this reason, new antitumor therapies are required. Different from humans, cytoreductive chemotherapy is poorly explored for solid tumors in veterinary oncology and tumors as prostatic carcinomas [7], soft tissue sarcoma [8], osteosarcomas [9], hemangiosarcomas [10] and mammary gland tumors [1] show poor antitumor response. While conventional chemotherapy has been used in veterinary oncology, some drawbacks of chemotherapy are low therapeutic indices, lack of targets predicting antitumor response, development of drug resistance and low specificity for neoplastic cells.
Performing a critical review of the manuscripts published on PubMed about drug delivery systems in dogs, we identified 2338 publications and most of them, were performed in healthy dogs to evaluated pharmacological properties. Therefore, the current knowledge on drug delivery system in veterinary medicine is focused on the understanding of drug pharmacokinetics and pharmacodynamics, mainly focused on the human health [11,12,13,14,15]. Regarding the canine tumors, a high number of articles were on brain tumors [16,17,18,19,20]. The use of dogs as models for human brain tumors has been increasing in the last years and these studies usually use controlled drug delivered vehicles in the experimental approach [16,17,18,19,20]. Although these studies have the human health as a primary focus, positive antitumor response can benefit dogs and humans. Different studies have used different drug delivered vehicles, including gold particles, liposomes and polymer-based nanoparticles [16,17,18,19,20,21].
There are a high number of studies evaluating drug delivery vehicles in healthy dogs, aiming to increase drug concentration in specific organs [22], drug bioavailability [13,21] or decrease drug toxicity [13,14]. Although a high number of studies have investigated pharmacokinetics of different drug delivery vehicles in healthy dogs, a limited number of studies have investigated drugs with anticancer properties in healthy dogs [11,12,13,14,21,22,23]. More intriguing, the translation rate of the studies performed in healthy dogs to dogs with cancer is very low. Most likely, because these studies in its majority aim to stablish drug pharmacokinetics with focus on human diseases [11,12]. Among the studies aiming to decrease drug toxicity through drug encapsulation, cisplatin [11,23], paclitaxel [14] and doxorubicin [12,24] were the most studied. Since the use of drug delivery vehicles is a relatively new topic in veterinary oncology, this review aimed to discuss the current knowledge regarding the controlled drug delivery vehicles and discuss the current challenges and future direction of its use in veterinary oncology.

2. Paclitaxel

Paclitaxel it is widely used in human medicine for treating different cancer subtypes, including metastatic breast cancer in the lungs [25,26]. Paclitaxel is an insoluble drug and should be combined with dehydrated alcohol and polyoxyethylated castor oil [27]. Unfortunately, this combination administrated intravenously have proved to induce severe and acute hypersensitivity in dogs and cats [28]. Due to its high hypersensitivity reaction during intravenous administration, Silva et al. [28] evaluated the paclitaxel subcutaneous administration expecting to find a lower rate of side effects. The results showed that even using subcutaneous administration, dogs presented several side effects and a low number of patients received more than one paclitaxel injection. Therefore, authors were not able to establish maximum tolerated dosage and no further studies have used this protocol.
Since one of the side effects of paclitaxel is associated to the hypersensitivity induced by the drug adjuvant, paclitaxel encapsulation in different controlled drug delivery vehicles were previously tested [14,29,30,31]. Axiak et al. [14] evaluated the safety of paclitaxel nanoparticles (CTI 52010) administration in healthy dogs. These authors showed that paclitaxel nanoparticles (CTI 52010), with a starting dosage of 80 mg/m2, was well tolerated after intravenous administration and presented liver, kidney and spleen toxicity (evaluated by histopathology). On the other hand, Zhao et al. [30] evaluated paclitaxel liposomes for a lung target delivered system. Their liposomes were composed of Tween-80/HSPC/cholesterol (0.03:3.84:3.84, mol/mol), containing paclitaxel and lipids (1:40, mol/mol) [30]. These authors evaluated the pharmacokinetics of their preparation in 25 healthy dogs and demonstrated high lung concentration of the paclitaxel liposomes [30]. However, authors did not describe side effects of this administration.
Based on preliminary studies on paclitaxel nanoparticles (CTI 52010) [29], Selting et al. [29] evaluated the paclitaxel nanoparticles (CTI 52010) in tumor bearing dogs. In their study, paclitaxel nanoparticles (CTI 52010) was used in an increasing dosage raging to 80 mg/m2 up to 136 mg/m2. Fifteen dogs with different tumor subtypes were included and the maximum tolerated dosage could not be determined due the highly variable toxicity among all fifteen dogs [29]. Although it presents some preliminary results, the paclitaxel nanoparticles (CTI 52010) pharmacokinetics was similar in both health (N = 3) and tumor-bearing dogs (N = 15) and this formulation did not induce hypersensitivity. Thus, could be a promising treatment option.

3. Doxorubicin

Doxorubicin is an anthracycline antitumor drug originated as a product from Streptomyces classified as a chemotherapeutic from the antibiotic class [32]. It is widely used in veterinary medicine for dogs with lymphoma [33], osteosarcoma [34], hemangiosarcoma [35] and mammary gland tumors [1]. However, in dogs [36] and in cats, relevant clinical cardiotoxicity can be highly nephrotoxic [37]. Therefore, new strategies to decrease doxorubicin toxicity has been studied [12]. In this scenario, doxorubicin liposomal encapsulation has been providing promising results [38,39,40]. Using domestic pigs as an experimental model to evaluate the potential of liposomal doxorubicin to induce cardiotoxicity, it was demonstrated a cardiotoxicity attenuation via induction of interferon-related DNA damage resistance [39]. Since the first description of liposomal doxorubicin, several manuscripts were published showing its efficacy in the clinical practice [12,41,42,43,44,45,46,47,48]. In a previous randomized controlled study evaluating both efficacy and toxicity of encapsulated doxorubicin into pegylated liposome compared to free doxorubicin, there was no statistical difference of overall survival in patients treated with free doxorubicin versus liposomal doxorubicin [42]. Besides that, in the studied group no patients developed cardiotoxicity (even treated with free doxorubicin) [42]. In their study, two dogs treated with liposomal doxorubicin experienced desquamating dermatitis like palmar-plantar erythrodysesthesia and other three presented anaphylactic reactions [42].
After the first studies, liposome-encapsulated doxorubicin has proved to decrease toxicity; however, the clinical efficacy has showed no improvement or only a modest improvement [12,41,42,43,44,45,46,47,48]. Thus, increased the search for different approaches aiming to increase antitumor response of liposome encapsulated chemotherapy [45]. Hauck et al. [45] evaluated the safety of a low temperature sensitive liposome-encapsulated doxorubicin related with local hyperthermia in dogs with sarcomas or carcinomas. The protocol was well tolerated with acceptable side effects and with favorable antitumor response [45]. Recently, Bredlau et al. [12] evaluated the pharmacokinetics of temperature sensitive liposomes containing doxorubicin associated with hyperthermia across the canine blood–brain barrier [12]. Their protocol was effective and showed high concentration temperature sensitive liposomes in the central nervous system and the normal tissue presented a very low toxicity [12]. Therefore, this therapy could be promising treating patients with primary brain tumors.

4. Cisplatin

Cisplatin is a well-known platinum-based anti-cancer chemotherapy drug used to treat different cancer subtypes [49]. Usually show high nephrotoxicity and should be administrated with a diuresis protocol [49]. However, a newer platin-derived drug was developed with similar mechanism of action and lower nephrotoxicity [50]. Thus, since carboplatin is less toxic than cisplatin and do not need a diuretic protocol, it is a Food and Drug Administration (FDA) approved treatment [51].
Currently, carboplatin is a widely used chemotherapeutic drug, including in the treatment of ovarian, bladder, breast and esophageal cancers [50]. When compared to antitumor effects of carboplatin and cisplatin, for some tumor subtypes, cisplatin still shows a better antitumor response than carboplatin. As a result, new strategies for the cisplatin safety use was required [52]. Aiming to reduce cisplatin toxicity and increase the drug concentration, cisplatin encapsulation in a liposomal formulation (SPI-77) was previously evaluated [14,53]. The cisplatin liposomal encapsulation allows delivered drug concentration five times more the maximum tolerated dosage when compared to free cisplatin [14,53]. The same research group published the evaluation of SPI-77 cisplatin formulation in healthy dogs [14] and dogs with osteosarcoma [53]. First, this research group evaluated SPI-77 formulation in liposomes containing a pegylated lipid [N-(carbamoyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero3-phosphoethanolamine sodium salt, MPEG-DSPE] in osteosarcoma-affected dogs [53]. In their previous study, dogs were treated with SPI-77 formulation containing cisplatin (STEALTH) versus dogs treated with maximum tolerated dosage of carboplatin and they demonstrated no increased toxicity of STEALTH formulation and identified five times higher concentration of drug delivered when compared to free cisplatin. However, their study did not show the difference in overall survival between both treatments [53].
Then, this research group published a manuscript evaluating the efficacy of the liposome encapsulate cisplatin in healthy dogs [14]. The liposome formulation was composed by dipalmitoyl phosphatidyl glycerol, soy phosphatidyl choline, cholesterol, and methoxy-polyethylene glycol-distearoyl phosphatidylethanolamine. Four different dosages were tested, including 70, 100, 125, and 150 mg/m2 in a small group of dogs (N = 4). As expected, the side effects were more frequently in the group treated with higher dosage; however, being acceptable. Thus, authors concluded that the dosage of 150 mg/m2 can be used without association of hydration protocols [53]. However, no further studies evaluated this formulation in tumor-bearing dogs.
Based on the systemic toxicity using free-cisplatin, Venable et al. [54] used a natural polysaccharide (Hyaluronan) nanocarrier to conjugate with cisplatin and treat dogs with soft tissue sarcomas. After hyaluronan metabolization, the lymphatic system is responsible for its metabolites elimination via lysosomal and endocytosis degradation [54]. Thus, can be promising in intratumoral formulations. These authors tested their hyaluronan-cisplatin nanoconjugate intratumorally in five client-owned dogs and found no local reaction related to drug administration. Besides that, authors found a higher concentration of cisplatin (1000×) intratumorally compared to serum concentrations. Since it was the first manuscript using this formulation in dogs with soft tissue sarcomas, they did not focus on antitumor response. Therefore, in 2016 a phase I/II clinical trial in dogs with spontaneous cancers treated with Hyaluronan-Cisplatin Nanoconjugate was performed [52]. In this clinical trial, 16 dogs with different tumors subtyped were used, including anal sac carcinoma, oral squamous cell carcinoma, oral melanoma, nasal carcinoma and digital squamous cell carcinoma. A complete response was observed in three dogs (3/16), one experienced partial response (1/16) and other one stable disease (1/16). Thus, the formulation failed in show antitumor response in 69% of the patients (11/16). Interestingly, three patients with complete response had carcinomas from head and neck (oral or nasal carcinomas). Consequently, this formulation could be promising for carcinomas in this location. However, a new clinical trial should be performed to clarify if this formulation can benefit dogs with head and neck carcinomas. Overall, the current information does not support the use of Hyaluronan-Cisplatin Nanoconjugate in tumor-bearing dogs.

5. Small-Molecule Inhibitors and Monoclonal Antibodies

The delivered systems can be used to carrier several anticancer agents, including tyrosine kinase inhibitors and monoclonal antibodies (Figure 1) [55]. Among the small-molecule inhibitors tested in dogs, masitinib [56,57], toceranib [58,59] and sorafenib [5,60] has been most studied in vitro and in vivo. Although these drugs can be promising in the treatment of dogs with cancer, one of the most important limitation of these drugs is the high toxicity. Toceranib [58,59], one of the most studied small-molecule inhibitors, usually cannot be used at the maximum tolerated dosage (3.25 mg/kg) due to its high toxicity. In this scenario, the controlled drug vehicles can be used to minimize toxicity and increase tissue concentration.
Sorafenib is an important tyrosine kinase inhibitor in human medicine, usually used to patients with hepatocellular carcinoma [21]. This tyrosine kinase inhibitor has been studied recently in veterinary medicine [5,60], with sorafenib safety in dogs evaluated by Foskett et al. [60] and its in vitro efficacy against canine mammary gland tumors demonstrated by Prado et al. [5]. Due to sorafenib low aqueous solubility, Park et al. [21] loaded sorafenib in nanoparticles containing fat and supercritical fluid (NUFS™) to improve sorafenib absorption. Among the evaluated studies in this review, this is the only one using nanoparticles in a tablet formulation for oral administration [21]. The in vivo experiments using Beagle dogs (N = 21) demonstrated sorafenib optimization, exhibiting higher serum profiles. Thus, indicating that this formulation increased sorafenib solubilization. Since it is a recently published paper, no further studies have addressed antitumor effect.
Cetuximab is a human-mouse chimeric monoclonal antibody, primarily used to treat patients with non-small cell lung carcinoma and other tumors with EGFR overexpression [61]. Since cetuximab is a humanized monoclonal antibody, it is predicted to be specific to human proteins. However, Singer et al. [62] demonstrated a homology over than 90% among EGFR proteins family and demonstrated that cetuximab binds canine mammary carcinoma cells. Therefore, cetuximab demonstrated antitumor activity through inhibition canine mammary gland tumor cell proliferation, being a promising option in canine tumors [62]. Freeman et al. [19] developed a cetuximab conjugated iron-oxide nanoparticles (cetuximab-IONPs) aiming to increase cetuximab concentration in central nervous system. These authors performed a pilot study in dogs with gliomas (N = 8) implanting two FDA-approved catheters (Medtronic intrathecal catheters Indura 8709SC and Ascenda 8780) after surgery in the remaining tumor region. These authors confirmed that IONPs target tumor area through resonance magnetic image magnetic resonance imaging and is safe and effective against canine gliomas.

6. Tumor Microenvironment and Drug-Delivered Systems

Tumor microenvironment (TME) is widely studied in human oncology, and it is well accepted that TME is pivotal to determine tumor aggressiveness, prognosis and response to antitumor therapies [63,64]. TME consists in the interaction among extracellular matrix components, such as collagen, stromal fibroblasts, macrophages, lymphocytes and endothelial cells [63]. These cellular and non-cellular components are remodeled according to each tumor characteristics providing a network’s formation benefiting cancer cells. In this scenario, TME can directly modify antitumor response against different drugs and delivered systems [63]. In relation to dogs, TME is poorly understood and few studies have investigated interaction between microenvironment and tumor cells [65,66,67,68]. In canine prostate cancer, higher expression of elastic fibers associated with decreased Col-IV expression were previously associated with high tumor grade [67]. The lack of Col-IV is strongly correlated with tumor invasion through stroma and the high expression of elastic fibers, can be related with a stroma reaction against the invasive cells. This interaction between tumor cells and stroma reinforce the impact of TME in therapeutic strategies. In this concept, nano drug delivery systems targeting TME has been studied [69].
The preexisting tumor stroma can represent a physical barrier for proper drug delivery and the use of different systems can induce therapeutic resistance due TME [69]. Among the cellular components, few studies have investigated TME canine tumors. The lymphocytes, macrophages, fibroblast and T-regulatory cells were previously investigated, mainly in mammary gland tumors [66,68,70]. Overall, these studies demonstrated similarities between canine mammary gland tumors and human breast cancer, with tumor associated macrophages and lymphocytes presenting a correlation with patients’ overall survival. Besides these cellular components, Ettlin et al. [71] performed a comparative analysis of Col-1, αSMA, Cavelolin-1, MMP2 and other matrix components of canine mammary gland tumors and human breast cancer. In their comprehensive analysis, they identified similarities in TME, proposing dogs as a model for the breast cancer TME study.

7. Development of Controlled Drug Delivery Systems and Future Perspectives

In veterinary oncology, we lack standardization of the drug delivered systems with studies testing the different systems in small group of animals. Liposomes and nanoparticles are the most used carriers in veterinary oncology [72,73,74,75] and more recently, gold nanoparticles have been introduced in vitro [76,77,78]. In dogs, liposomal doxorubicin is commercially available (Doxil/Caelyx), presenting an effective antitumor response and lack of cardiotoxicity [72]. However, its clinical use is limited due the commercial price. Thus, conventional doxorrubicina still remains the most used in veterinary oncology. However, since dogs are pharmacokinetics model to human drugs, the tested nano-carriers canine preclinical models represent an opportunity to benefit dogs. Since the liposomes are the most studied nanocarrier in both humans and dogs represents a promising method for cytostatic drug encapsulation [72]. Liposomes are artificial and spherical nanocarrier with size varying of 30 nm until micrometers [73]. Thus, based on the previous results using liposomal doxorubicin, liposomal vehicles can be considered promising in veterinary oncology.
Zabielska-Koczywas and Lechowski [72] reviewed liposomes and nanoparticles as drug delivery systems to improve cancer treatment in dogs and cats in 2017. Based on their description, we performed a Table showing all studies describing use of drug delivery vehicles in dogs (Table 1). At that time, these authors identified six clinical trials registered at American Veterinary Medical Association (AVMA) involving drug delivery vehicles in veterinary oncology. Currently, three clinical studies are registered at AVMA website in oncology section being one study for the use of iron nanoparticles for the investigation of metastatic lymph nodes (AAHSD004735), one pilot study of AuroLase® Therapy for the Treatment of Solid Tumors in Canine and Feline Patients (AAHSD000007) and one study in phase I/II, evaluating Cisplatin Hyaluronate Nanoparticles in Tumor-bearing Dogs (AAHSD000024) (search performed on 12th March 2020).
One limitation for the use of controlled drug delivery systems in veterinary medicine, is the final price of the treatment for the owner. Overall, drugs using the different systems show a higher price compared to free chemotherapeutic agents. However, since the use of small-molecule inhibitors and monoclonal antibodies has growing in the past years, the encapsulation of these drugs can decrease toxicity of small-molecule inhibitors and enhance drug concentration in specific sites.

Author Contributions

Conceptualization, P.d.F.L.; F.Z.; A.F.L.-F.; R.H.F.A.; and C.E.F.-A.; data curation, P.d.F.L.; F.Z.; A.F.L.-F.; R.H.F.A.; and C.E.F.-A.; writing—Original draft preparation, P.d.F.L.; A.F.L.-F. and C.E.F.-A.; writing—Review and editing, F.Z.; R.H.F.A.; and C.E.F.-A.; supervision, C.E.F.-A. All authors have read and agreed to the published version of the manuscript.

Funding

The correspondence author from this review article received post-doc scholarship during the conceptualization of this literature review. The scholarship was founded by São Paulo Research Foundation—FAPESP (#2015/25400-7 and #2020/06278-4). R.H.F.A thanks the financial support given by CAPES (PDSE - Call No. 41/2018).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Dos Anjos, D.S.; Vital, A.F.; Lainetti, P.F.; Leis-Filho, A.F.; Dalmolin, F.; Elias, F.; Calazans, S.G.; Fonseca-Alves, C.E. Deregulation of VEGFR-2 and PDGFR Expression and Microvascular Density in a Triple-Negative Model of Canine Malignant Mammary Tumors with Lymph Node or Lung Metastasis. Vet. Sci. 2019, 6, 3. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Boston, S.; Henderson, R.A., Jr. Role of surgery in multimodal cancer therapy for small animals. Vet. Clin. Small Anim. Pract. 2014, 44, 855–870. [Google Scholar] [CrossRef] [PubMed]
  3. Meier, V.S.; Beatrice, L.; Turek, M.; Poirier, V.J.; Cancedda, S.; Stiborova, K.; Körner, M.; Marconato, L.; Weyland, M.S.; Rohrer Bley, C. Outcome and failure patterns of localized sinonasal lymphoma in cats treated with first-line single-modality radiation therapy: A retrospective study. Vet. Comp. Oncol. 2019, 17, 528–536. [Google Scholar] [CrossRef] [PubMed]
  4. Kent, M.S. Cats and chemotherapy: Treat as ‘small dogs’ at your peril. J. Feline Med. Surg. 2013, 15, 419–424. [Google Scholar] [CrossRef]
  5. Prado, M.C.M.; Macedo, S.A.L.; Guiraldelli, G.G.; de Faria Lainetti, P.; Leis-Filho, A.F.; Kobayashi, P.E.; Laufer-Amorim, R.; Fonseca-Alves, C.E. Investigation of the Prognostic Significance of Vasculogenic Mimicry and Its Inhibition by Sorafenib in Canine Mammary Gland Tumors. Front. Oncol. 2019, 9, 1445. [Google Scholar] [CrossRef] [Green Version]
  6. Dos Anjos, D.S.; Bueno, C.; Magalhães, L.F.; Magalhães, G.M.; Mattos-Junior, E.; Pinto, M.M.R.; De Nardi, A.B.; Brunner, C.H.M.; Leis-Filho, A.F.; Calazans, S.G.; et al. Electrochemotherapy induces tumor regression and decreases the proliferative index in canine cutaneous squamous cell carcinoma. Sci. Rep. 2019, 9, 15819. [Google Scholar] [CrossRef]
  7. Fonseca-Alves, C.E.; Kobayashi, P.E.; Leis-Filho, A.F.; Lainetti, P.F.; Grieco, V.; Kuasne, H.; Rogatto, S.R.; Laufer-Amorim, R. E-Cadherin Downregulation is Mediated by Promoter Methylation in Canine Prostate Cancer. Front. Genet. 2019, 10, 1242. [Google Scholar] [CrossRef]
  8. Hohenhaus, A.E.; Kelsey, J.L.; Haddad, J.; Barber, L.; Palmisano, M.; Farrelly, J.; Soucy, A. Canine Cutaneous and Subcutaneous Soft Tissue Sarcoma: An Evidence-Based Review of Case Management. J. Am. Anim. Hosp. Assoc. 2016, 52, 77–89. [Google Scholar] [CrossRef]
  9. Turner, H.; Séguin, B.; Worley, D.R.; Ehrhart, N.P.; Lafferty, M.H.; Withrow, S.J.; Selmic, L.E. Prognosis for dogs with stage III osteosarcoma following treatment with amputation and chemotherapy with and without metastasectomy. J. Am. Vet. Med. Assoc. 2017, 251, 1293–1305. [Google Scholar] [CrossRef]
  10. Wendelburg, K.M.; Price, L.L.; Burgess, K.E.; Lyons, J.A.; Lew, F.H.; Berg, J. Survival time of dogs with splenic hemangiosarcoma treated by splenectomy with or without adjuvant chemotherapy: 208 cases (2001–2012). J. Am. Vet. Med. Assoc. 2015, 247, 393–403. [Google Scholar] [CrossRef]
  11. Axiak, S.M.; Selting, K.A.; Decedue, C.J.; Henry, C.J.; Tate, D.; Howell, J.; Bilof, K.J.; Kim, D.Y. Phase I dose escalation safety study of nanoparticulate paclitaxel (CTI 52010) in normal dogs. Int. J. Nanomed. 2011, 6, 2205–2212. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Bredlau, A.L.; Motamarry, A.; Chen, C.; McCrackin, M.A.; Helke, K.; Armeson, K.E.; Bynum, K.; Broome, A.M.; Haemmerich, D. Localized delivery of therapeutic doxorubicin dose across the canine blood-brain barrier with hyperthermia and temperature sensitive liposomes. Drug Deliv. 2018, 25, 973–984. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Kesisoglou, F.; Wang, M.; Galipeau, K.; Harmon, P.; Okoh, G.; Xu, W. Effect of Amorphous Nanoparticle Size on Bioavailability of Anacetrapib in Dogs. J. Pharm. Sci. 2019, 108, 2917–2925. [Google Scholar] [CrossRef] [PubMed]
  14. Marr, A.K.; Kurzman, I.D.; Vail, D.M. Preclinical evaluation of a liposome-encapsulated formulation of cisplatin in clinically normal dogs. Am. J. Vet. Res. 2004, 65, 1474–1478. [Google Scholar] [CrossRef]
  15. Prélaud, A.R.; Fuchs, S.; Weber, K.; Winter, G.; Coester, C.; Mueller, R.S. In vitro effects of CpG oligodeoxynucleotides delivered by gelatin nanoparticles on canine peripheral blood mononuclear cells of atopic and healthy dogs—a pilot study. Vet. Dermatol. 2013, 24, 494-e117. [Google Scholar] [CrossRef]
  16. Arami, H.; Patel, C.B.; Madsen, S.J.; Dickinson, P.J.; Davis, R.M.; Zeng, Y.; Sturges, B.K.; Woolard, K.D.; Habte, F.G.; Akin, D.; et al. Nanomedicine for Spontaneous Brain Tumors: A Companion Clinical Trial. ACS Nano 2019, 13, 2858–2869. [Google Scholar] [CrossRef]
  17. Lee, J.; Cho, H.R.; Cha, G.D.; Seo, H.; Lee, S.; Park, C.K.; Kim, J.W.; Qiao, S.; Wang, L.; Kang, D.; et al. Flexible, sticky, and biodegradable wireless device for drug delivery to brain tumors. Nat. Commun. 2019, 10, 5205. [Google Scholar] [CrossRef]
  18. Young, J.S.; Bernal, G.; Polster, S.P.; Nunez, L.; Larsen, G.F.; Mansour, N.; Podell, M.; Yamini, B. Convection-Enhanced Delivery of Polymeric Nanoparticles Encapsulating Chemotherapy in Canines with Spontaneous Supratentorial Tumors. World Neurosurg. 2018, 117, e698–e704. [Google Scholar] [CrossRef]
  19. Freeman, A.C.; Platt, S.R.; Holmes, S.; Kent, M.; Robinson, K.; Howerth, E.; Eagleson, J.; Bouras, A.; Kaluzova, M.; Hadjipanayis, C.G. Convection-enhanced delivery of cetuximab conjugated iron-oxide nanoparticles for treatment of spontaneous canine intracranial gliomas. J. Neurooncol. 2018, 137, 653–663. [Google Scholar] [CrossRef]
  20. Rossmeisl, J. Maximizing Local Access to Therapeutic Deliveries in Glioblastoma. Part V: Clinically Relevant Model for Testing New Therapeutic Approaches. In Glioblastoma [Internet]; De Vleeschouwer, S., Ed.; Codon Publications: Brisbane, Australia, 2017. Available online: http://www.ncbi.nlm.nih.gov/books/NBK470000 (accessed on 20 April 2020).
  21. Park, S.Y.; Kang, Z.; Thapa, P.; Jin, Y.S.; Park, J.W.; Lim, H.J.; Lee, J.Y.; Lee, S.W.; Seo, M.H.; Kim, M.S.; et al. Development of sorafenib loaded nanoparticles to improve oral bioavailability using a quality by design approach. Int. J. Pharm. 2019, 566, 229–238. [Google Scholar] [CrossRef]
  22. Grabtchak, S.; Montgomery, L.G.; Whelan, W.M. Feasibility of interstitial near-infrared radiance spectroscopy platform for ex vivo canine prostate studies: Optical properties extraction, hemoglobin and water concentration, and gold nanoparticles detection. J. Biomed. Opt. 2014, 19, 057003. [Google Scholar] [CrossRef] [PubMed]
  23. Feldhaeusser, B.; Platt, S.R.; Marrache, S.; Kolishetti, N.; Pathak, R.K.; Montgomery, D.J.; Reno, L.R.; Howerth, E.; Dhar, S. Evaluation of nanoparticle delivered cisplatin in beagles. Nanoscale 2015, 7, 13822–13830. [Google Scholar] [CrossRef] [PubMed]
  24. Xie, Y.; Shao, N.; Jin, Y.; Zhang, L.; Jiang, H.; Xiong, N.; Su, F.; Xu, H. Determination of non-liposomal and liposomal doxorubicin in plasma by LC-MS/MS coupled with an effective solid phase extraction: In comparison with ultrafiltration technique and application to a pharmacokinetic study. J. Chromatogr. B 2018, 1072, 149–160. [Google Scholar] [CrossRef] [PubMed]
  25. Aktas, B.Y.; Taban, H.; Aksoy, S. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N. Engl. J. Med. 2019, 380, 985–986. [Google Scholar] [CrossRef]
  26. Wardhani, B.W.; Puteri, M.U.; Watanabe, Y.; Louisa, M.; Setiabudy, R.; Kato, M. TGF-β-Induced TMEPAI Attenuates the Response of Triple-Negative Breast Cancer Cells to Doxorubicin and Paclitaxel. J. Exp. Pharmacol. 2020, 12, 17–26. [Google Scholar] [CrossRef] [Green Version]
  27. Poirier, V.J.; Hershey, A.E.; Burgess, K.E.; Phillips, B.; Turek, M.M.; Forrest, L.J.; Beaver, L.; Vail, D.M. Efficacy and toxicity of paclitaxel (Taxol) for the treatment of canine malignant tumors. J. Vet. Intern. Med. 2004, 18, 219–222. [Google Scholar] [CrossRef]
  28. Silva, D.M.; Franciosi, A.I.; Pezzini, P.C.; Guérios, S.D. Subcutaneous administration of paclitaxel in dogs with cancer: A preliminary study. Can. Vet. J. 2015, 56, 823–830. [Google Scholar]
  29. Selting, K.A.; Bechtel, S.M.; Espinosa, J.; Henry, C.J.; Tate, D.; Bryan, J.N.; Rajewski, L.; Flesner, B.K.; Decedue, C.; Baltezor, M. Evaluation of intravenous and subcutaneous administration of a novel, excipient-free, nanoparticulate formulation of paclitaxel in dogs with spontaneously occurring neoplasia. Vet. Comp. Oncol. 2018, 16, 650–657. [Google Scholar] [CrossRef]
  30. Zhao, L.; Ye, Y.; Li, J.; Wei, Y.M. Preparation and the in-vivo evaluation of paclitaxel liposomes for lung targeting delivery in dogs. J. Pharm. Pharmacol. 2011, 63, 80–86. [Google Scholar] [CrossRef]
  31. Axiak-Bechtel, S.M.; Kumar, S.R.; Dank, K.K.; Clarkson, N.A.; Selting, K.A.; Bryan, J.N.; Rosol, T.J.; Espinosa, J.; Decedue, C.J. Nanoparticulate paclitaxel demonstrates antitumor activity in PC3 and Ace-1 aggressive prostate cancer cell lines. Invest. New Drugs 2013, 31, 1609–1615. [Google Scholar] [CrossRef]
  32. Young, R.C.; Ozols, R.F.; Myers, C.E. The anthracycline antineoplastic drugs. N. Engl. J. Med. 1981, 305, 139–153. [Google Scholar] [CrossRef] [PubMed]
  33. Ogilvie, G.K.; Fettman, M.J.; Mallinckrodt, C.H.; Walton, J.A.; Hansen, R.A.; Davenport, D.J.; Gross, K.L.; Richardson, K.L.; Rogers, Q.; Hand, M.S. Effect of fish oil, arginine, and doxorubicin chemotherapy on remission and survival time for dogs with lymphoma: A double-blind, randomized placebo-controlled study. Cancer 2000, 88, 1916–1928. [Google Scholar] [CrossRef]
  34. Mauldin, G.N.; Matus, R.E.; Withrow, S.J.; Patnaik, A.K. Canine osteosarcoma. Treatment by amputation versus amputation and adjuvant chemotherapy using doxorubicin and cisplatin. J. Vet. Intern. Med. 1988, 2, 177–180. [Google Scholar] [CrossRef] [PubMed]
  35. Sorenmo, K.U.; Jeglum, K.A.; Helfand, S.C. Chemotherapy of canine hemangiosarcoma with doxorubicin and cyclophosphamide. J. Vet. Intern. Med. 1993, 7, 370–376. [Google Scholar] [CrossRef]
  36. Withers, S.S.; Kass, P.H.; Rodriguez, C.O., Jr.; Skorupski, K.A.; O’Brien, D.; Guerrero, T.A.; Sein, K.D.; Rebhun, R.B. Fasting reduces the incidence of delayed-type vomiting associated with doxorubicin treatment in dogs with lymphoma. Transl. Oncol. 2014, 7, 377–383. [Google Scholar] [CrossRef] [Green Version]
  37. O’Keefe, D.A.; Sisson, D.D.; Gelberg, H.B.; Schaeffer, D.J.; Krawiec, D.R. Systemic toxicity associated with doxorubicin administration in cats. J. Vet. Intern. Med. 1993, 7, 309–317. [Google Scholar] [CrossRef]
  38. Vail, D.M.; Kravis, L.D.; Cooley, A.J.; Chun, R.; MacEwen, E.G. Preclinical trial of doxorubicin entrapped in sterically stabilized liposomes in dogs with spontaneously arising malignant tumors. Cancer Chemother. Pharmacol. 1997, 39, 410–416. [Google Scholar] [CrossRef]
  39. Gyöngyösi, M.; Lukovic, D.; Zlabinger, K.; Spannbauer, A.; Gugerell, A.; Pavo, N.; Traxler, D.; Pils, D.; Maurer, G.; Jakab, A.; et al. Liposomal doxorubicin attenuates cardiotoxicity via induction of interferon-related DNA damage resistance. Cardiovasc. Res. 2019, 116, cvz192. [Google Scholar] [CrossRef]
  40. Working, P.K.; Newman, M.S.; Sullivan, T.; Yarrington, J. Reduction of the cardiotoxicity of doxorubicin in rabbits and dogs by encapsulation in long-circulating, pegylated liposomes. J. Pharmacol. Exp. Ther. 1999, 289, 1128–1133. [Google Scholar]
  41. Sorenmo, K.; Samluk, M.; Clifford, C.; Baez, J.; Barrett, J.S.; Poppenga, R.; Overley, B.; Skorupski, K.; Oberthaler, K.; Van Winkle, T.; et al. Clinical and pharmacokinetic characteristics of intracavitary administration of pegylated liposomal encapsulated doxorubicin in dogs with splenic hemangiosarcoma. J. Vet. Intern. Med. 2007, 21, 1347–1354. [Google Scholar] [CrossRef]
  42. Teske, E.; Rutteman, G.R.; Kirpenstein, J.; Hirschberger, J. A randomized controlled study into the efficacy and toxicity of pegylated liposome encapsulated doxorubicin as an adjuvant therapy in dogs with splenic haemangiosarcoma. Vet. Comp. Oncol. 2011, 9, 283–289. [Google Scholar] [CrossRef] [PubMed]
  43. Wójcik, M.; Lewandowski, W.; Król, M.; Pawłowski, K.; Mieczkowski, J.; Lechowski, R.; Zabielska, K. Enhancing anti-tumor efficacy of Doxorubicin by non-covalent conjugation to gold nanoparticles—in vitro studies on feline fibrosarcoma cell lines. PLoS ONE 2015, 10, e0124955. [Google Scholar] [CrossRef] [PubMed]
  44. Yin, Q.; Tang, L.; Cai, K.; Tong, R.; Sternberg, R.; Yang, X.; Dobrucki, L.W.; Borst, L.B.; Kamstock, D.; Song, Z.; et al. Pamidronate functionalized nanoconjugates for targeted therapy of focal skeletal malignant osteolysis. Proc. Natl. Acad. Sci. USA 2016, 113, E4601–E4609. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Hauck, M.L.; LaRue, S.M.; Petros, W.P.; Poulson, J.M.; Yu, D.; Spasojevic, I.; Pruitt, A.F.; Klein, A.; Case, B.; Thrall, D.E.; et al. Phase I trial of doxorubicin-containing low temperature sensitive liposomes in spontaneous canine tumors. Clin. Cancer Res. 2006, 12, 4004–4010. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Kisseberth, W.C.; MacEwen, E.G.; Helfand, S.C.; Vail, D.M.; London, C.L.; Keller, E. Response to liposome-encapsulated doxorubicin (TLC D-99) in a dog with myeloma. J. Vet. Intern. Med. 1995, 9, 425–428. [Google Scholar] [CrossRef] [PubMed]
  47. Kleiter, M.; Tichy, A.; Willmann, M.; Pagitz, M.; Wolfesberger, B. Concomitant liposomal doxorubicin and daily palliative radiotherapy in advanced feline soft tissue sarcomas. Vet. Radiol. Ultrasound 2010, 51, 349–355. [Google Scholar] [CrossRef]
  48. Griffin, L.; Frank, C.B.; Seguin, B. Pilot study to evaluate the efficacy of lymphotropic nanoparticle enhanced MRI for diagnosis of metastatic disease in canine head and neck tumours. Vet. Comp. Oncol. 2019. [Google Scholar] [CrossRef]
  49. Dasari, S.; Tchounwou, P.B. Cisplatin in cancer therapy: Molecular mechanisms of action. Eur. J. Pharmacol. 2014, 740, 364–378. [Google Scholar] [CrossRef] [Green Version]
  50. Sousa, G.F.; Wlodarczyk, S.R.; Monteiro, G. Carboplatin: Molecular mechanisms of action associated with chemoresistance. Braz. J. Pharm. Sci. 2014, 50, 693–701. [Google Scholar] [CrossRef]
  51. Food and Drug Administration—FDA. PARAPLATIN®. 2004. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/20452scs001_paraplatin_lbl.pdf (accessed on 20 April 2020).
  52. Cai, S.; Zhang, T.; Forrest, W.C.; Yang, Q.; Groer, C.; Mohr, E.; Aires, D.J.; Axiak-Bechtel, S.M.; Flesner, B.K.; Henry, C.J.; et al. Phase I-II clinical trial of hyaluronan-cisplatin nanoconjugate in dogs with naturally occurring malignant tumors. Am. J. Vet. Res. 2016, 77, 1005–1016. [Google Scholar] [CrossRef] [Green Version]
  53. Vail, D.M.; Kurzman, I.D.; Glawe, P.C.; O’Brien, M.G.; Chun, R.; Garrett, L.D.; Obradovich, J.E.; Fred, R.M., 3rd; Khanna, C.; Colbern, G.T.; et al. STEALTH liposome-encapsulated cisplatin (SPI-77) versus carboplatin as adjuvant therapy for spontaneously arising osteosarcoma (OSA) in the dog: A randomized multicenter clinical trial. Cancer Chemother. Pharmacol. 2002, 50, 131–136. [Google Scholar] [CrossRef] [PubMed]
  54. Venable, R.O.; Worley, D.R.; Gustafson, D.L.; Hansen, R.J.; Ehrhart, E.J., 3rd; Cai, S.; Cohen, M.S.; Forrest, M.L. Effects of intratumoral administration of a hyaluronan-cisplatin nanoconjugate to five dogs with soft tissue sarcomas. Am. J. Vet. Res. 2012, 73, 1969–1976. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Fonseca-Alves, C.E.; Calazans, S.G. Metronomic Chemotherapy in Small Animal Practice: An Update. Asian J. Anim. Vet. Adv. 2016, 11, 17–23. [Google Scholar] [CrossRef] [Green Version]
  56. Holtermann, N.; Kiupel, M.; Kessler, M.; Teske, E.; Betz, D.; Hirschberger, J. Masitinib monotherapy in canine epitheliotropic lymphoma. Vet. Comp. Oncol. 2016, 14 (Suppl. 1), 127–135. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Giuliano, A.; Dobson, J. Prospective clinical trial of masitinib mesylate treatment for advanced stage III and IV canine malignant melanoma. J. Small Anim. Pract. 2020, 61, 190–194. [Google Scholar] [CrossRef] [PubMed]
  58. Berger, E.P.; Johannes, C.M.; Jergens, A.E.; Allenspach, K.; Powers, B.E.; Du, Y.; Mochel, J.P.; Fox, L.E.; Musser, M.L. Retrospective evaluation of toceranib phosphate (Palladia®) use in the treatment of gastrointestinal stromal tumors of dogs. J. Vet. Intern. Med. 2018, 32, 2045–2053. [Google Scholar] [CrossRef] [Green Version]
  59. Piscoya, S.L.; Hume, K.R.; Balkman, C.E. A retrospective study of proteinuria in dogs receiving toceranib phosphate. Can. Vet. J. 2018, 59, 611–616. [Google Scholar]
  60. Foskett, A.; Manley, C.; Naramore, R.; Gordon, I.K.; Stewart, B.M.; Khanna, C. Tolerability of oral sorafenib in pet dogs with a diagnosis of cancer. Vet. Med. 2017, 8, 97–102. [Google Scholar] [CrossRef] [Green Version]
  61. Mazzarella, L.; Guida, A.; Curigliano, G. Cetuximab for treating non-small cell lung cancer. Expert Opin. Biol. Ther. 2018, 18, 483–493. [Google Scholar] [CrossRef]
  62. Singer, J.; Weichselbaumer, M.; Stockner, T.; Mechtcheriakova, D.; Sobanov, Y.; Bajna, E.; Wrba, F.; Horvat, R.; Thalhammer, J.G.; Willmann, M.; et al. Comparative oncology: ErbB-1 and ErbB-2 homologues in canine cancer are susceptible to cetuximab and trastuzumab targeting. Mol. Immunol. 2012, 50, 200–209. [Google Scholar] [CrossRef]
  63. Baghban, R.; Roshangar, L.; Jahanban-Esfahlan, R.; Seidi, K.; Ebrahimi-Kalan, A.; Jaymand, M.; Kolahian, S.; Javaheri, T.; Zare, P. Tumor microenvironment complexity and therapeutic implications at a glance. Cell Commun. Signal. 2020, 18, 59. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Pi Castro, D.; José-López, R.; Fernández Flores, F.; Rabanal Prados, R.M.; Mandara, M.T.; Arús, C.; Pumarola Batlle, M. Expression of FOXP3 in Canine Gliomas: Immunohistochemical Study of Tumor-Infiltrating Regulatory Lymphocytes. J. Neuropathol. Exp. Neurol. 2020, 79, 184–193. [Google Scholar] [CrossRef] [PubMed]
  65. Fonseca-Alves, C.E.; Rodrigues, M.M.; de Moura, V.M.; Rogatto, S.R.; Laufer-Amorim, R. Alterations of C-MYC, NKX3.1, and E-cadherin expression in canine prostate carcinogenesis. Microsc. Res Tech. 2013, 76, 1250–1256. [Google Scholar] [CrossRef] [PubMed]
  66. Franzoni, M.S.; Brandi, A.; de Oliveira Matos Prado, J.K.; Elias, F.; Dalmolin, F.; de Faria Lainetti, P.; Prado, M.C.M.; Leis-Filho, A.F.; Fonseca-Alves, C.E. Tumor-infiltrating CD4(+) and CD8(+) lymphocytes and macrophages are associated with prognostic factors in triple-negative canine mammary complex type carcinoma. Res. Vet. Sci. 2019, 126, 29–36. [Google Scholar] [CrossRef] [PubMed]
  67. Calderón, L.G.R.; Kobayashi, P.E.; Vasconcelos, R.O.; Fonseca-Alves, C.E.; Laufer-Amorim, R. Characterization of Collagen Fibers (I, III, IV) and Elastin of Normal and Neoplastic Canine Prostatic Tissues. Vet. Sci. 2019, 6, 22. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  68. De Souza, T.A.; de Campos, C.B.; De Biasi Bassani Gonçalves, A.; Nunes, F.C.; Monteiro, L.N.; de Oliveira Vasconcelos, R.; Cassali, G.D. Relationship between the inflammatory tumor microenvironment and different histologic types of canine mammary tumors. Res. Vet. Sci. 2018, 119, 209–214. [Google Scholar] [CrossRef] [Green Version]
  69. Guo, J.; Zeng, H.; Chen, Y. Emerging Nano Drug Delivery Systems Targeting Cancer-Associated Fibroblasts for Improved Antitumor Effect and Tumor Drug Penetration. Mol. Pharm. 2020, 17, 1028–1048. [Google Scholar] [CrossRef]
  70. Matiz, O.R.S.; Santili, J.; Almeida, M.A.M.; Magalhaes, L.F.; Magalhaes, G.M.; Fonseca-Alves, C.E.; Nardi, A.B.; Calazans, S.G. Loss of Tumor-Associated Macrophages and Vascular Endothelial Growth Factor Immunoexpression in Solid Mammary Carcinoma in Dogs. Pak. Vet. J. 2019, 40. [Google Scholar] [CrossRef]
  71. Ettlin, J.; Clementi, E.; Amini, P.; Malbon, A.; Markkanen, E. Analysis of gene expression signatures in cancer-associated stroma from canine mammary tumours reveals molecular homology to human breast carcinomas. Int. J. Mol. Sci. 2017, 18, 1101. [Google Scholar] [CrossRef]
  72. Zabielska-Koczywąs, K.; Lechowski, R. The Use of Liposomes and Nanoparticles as Drug Delivery Systems to Improve Cancer Treatment in Dogs and Cats. Molecules 2017, 22, 2167. [Google Scholar] [CrossRef] [Green Version]
  73. Akbarzadeh, A.; Rezaei-Sadabady, R.; Davaran, S.; Joo, S.W.; Zarghami, N.; Hanifehpour, Y.; Samiei, M.; Kouhi, M.; Nejati-Koshki, K. Liposome: Classification, preparation, and applications. Nanoscale Res. Lett. 2013, 8, 102. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Hoopes, P.J.; Wagner, R.J.; Duval, K.; Kang, K.; Gladstone, D.J.; Moodie, K.L.; Crary-Burney, M.; Ariaspulido, H.; Veliz, F.A.; Steinmetz, N.F.; et al. Treatment of Canine Oral Melanoma with Nanotechnology-Based Immunotherapy and Radiation. Mol. Pharm. 2018, 15, 3717–3722. [Google Scholar] [CrossRef] [PubMed]
  75. Lucas, S.R.; Maranhão, R.C.; Guerra, J.L.; Coelho, B.M.; Barboza, R.; Pozzi, D.H. Pilot clinical study of carmustine associated with a lipid nanoemulsion in combination with vincristine and prednisone for the treatment of canine lymphoma. Vet. Comp. Oncol. 2015, 13, 184–193. [Google Scholar] [CrossRef] [PubMed]
  76. Raposo, L.R.; Roma-Rodrigues, C.; Jesus, J.; Martins, L.M.D.R.S.; Pombeiro, A.J.; Baptista, P.V.; Fernandes, A.R. Targeting canine mammary tumours via gold nanoparticles functionalized with promising Co(II) and Zn(II) compounds. Vet. Comp. Oncol. 2017, 15, 1537–1542. [Google Scholar] [CrossRef]
  77. Hansen, A.E.; Petersen, A.L.; Henriksen, J.R.; Boerresen, B.; Rasmussen, P.; Elema, D.R.; af Rosenschöld, P.M.; Kristensen, A.T.; Kjær, A.; Andresen, T.L. Positron Emission Tomography Based Elucidation of the Enhanced Permeability and Retention Effect in Dogs with Cancer Using Copper-64 Liposomes. ACS Nano 2015, 9, 6985–6995. [Google Scholar] [CrossRef] [Green Version]
  78. Axiak-Bechtel, S.M.; Upendran, A.; Lattimer, J.C.; Kelsey, J.; Cutler, C.S.; Selting, K.A.; Bryan, J.N.; Henry, C.J.; Boote, E.; Tate, D.J.; et al. Gum arabic-coated radioactive gold nanoparticles cause no short-term local or systemic toxicity in the clinically relevant canine model of prostate cancer. Int. J. Nanomed. 2014, 9, 5001–5011. [Google Scholar] [CrossRef] [Green Version]
  79. Benhabbour, S.R.; Luft, J.C.; Kim, D.; Jain, A.; Wadhwa, S.; Parrott, M.C.; Liu, R.; DeSimone, J.M.; Mumper, R.J. In vitro and in vivo assessment of targeting lipid-based nanoparticles to the epidermal growth factor-receptor (EGFR) using a novel Heptameric ZEGFR domain. J. Control. Release 2012, 158, 63–71. [Google Scholar] [CrossRef] [Green Version]
  80. Mili, B.; Das, K.; Kumar, A.; Saxena, A.C.; Singh, P.; Ghosh, S.; Bag, S. Preparation of NGF encapsulated chitosan nanoparticles and its evaluation on neuronal differentiation potentiality of canine mesenchymal stem cells. J. Mater. Sci. Mater. Med. 2017, 29, 4. [Google Scholar] [CrossRef]
  81. Zhong, J.; Mao, W.; Shi, R.; Jiang, P.; Wang, Q.; Zhu, R.; Wang, T.; Ma, Y. Pharmacokinetics of liposomal-encapsulated and un-encapsulated vincristine after injection of liposomal vincristine sulfate in beagle dogs. Cancer Chemother. Pharmacol. 2014, 73, 459–466. [Google Scholar] [CrossRef]
Figure 1. Representation of some controlled drug delivery vehicles, including liposome (A), gold Nanoparticles (B), polymeric particle (C) and micelle (D). Using the different systems, it is possible to encapsulate classical antitumor agents, small-molecule inhibitors, monoclonal antibodies, gene target therapies and RNA interference. Created by Biorender (https://app.biorender.com/).
Figure 1. Representation of some controlled drug delivery vehicles, including liposome (A), gold Nanoparticles (B), polymeric particle (C) and micelle (D). Using the different systems, it is possible to encapsulate classical antitumor agents, small-molecule inhibitors, monoclonal antibodies, gene target therapies and RNA interference. Created by Biorender (https://app.biorender.com/).
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Table 1. Studies describing use of drug delivery vehicles in dogs depending on the chosen substance.
Table 1. Studies describing use of drug delivery vehicles in dogs depending on the chosen substance.
SubstanceNanomaterialTumour SubtypeStudy ResultsOutcomeReference
-Silica- coated gold nanoparticles (GNPs)Brain tumorsGNPs were more frequently found in tissue areas closer to blood vessel walls and had heterogeneous extravasation into spontaneous brain tumors.Nanoparticles’ EPR and its variations foreshadow clinical applications of nanomedicine in management of brain tumorsArami et al. [16]
-Colloidal solution of Gold nanorods (Nanopartz)ProstateOptical detection of Au NPs via the proportional absorption of the product (NP concentration and the individual absorption cross-section).Gold nanoparticles can be used for ex vivo systematic study of canine and, potentially, human prostate; comprehensive diagnostic markers in determining the state of the prostate healthGrabtchak et al. [22]
Plant-based virus-like nanoparticle (VLP)Magnetic iron oxide nanoparticle (mNPH)Oral melanomaImmunological reaction in the tumor correlated with the clinical response and significant increase in immune cell infiltration of tumors receiving radiotherapy with VLP treatment.The study successfully demonstrates the feasibility, safety and promising efficacy of VLP + radiotherapy treatment in a highly translatable spontaneous preclinical modelHoopes et al. [74]
CarmustineLipid nanoemulsion (LDE)LymphomaLDE-carmustine showed non-hematologic toxicity or hepatic function commitment; LDE- carmustine and commercial carmustine were equivalent in terms of toxicity, tumor remission and survival time.LDE- carmustine is safe for administration in a combined chemotherapeutic protocol with vincristine and prednisoneLucas et al. [75]
CetuximabIron-oxide nanoparticles (cetuximab-IONPs)Spontaneous intracranial gliomasVolume of distribution was proportional to infusion volume and dispersion of the cetuximab-IONPs and infusion can be delivered in awake dogs safely and effectively over 3 days.Cetuximab-IONP CED is a safe and effective adjuvant therapy for spontaneous canine glioma patients at the time of their initial tumor surgery.Freeman et al. [19]
CisplatinHyaluronan-cisplatin nanoconjugate (HA-Pt)Spontaneous cancersCisplatin and HA-Pt inhibited cell growth over 80% compared to control and cisplatin treatment showed similar levels of creatinine excretion. HA-Pt did not cause nephrotoxicity.The HA-Pt formulation demonstrated positive response in spontaneous canine squamous cell carcinomasCai et al. [52]
CisplatinPlatin-M nano- particles (T-Platin-M-NPs)Canine J3TBG glioma and SDT3G glioblastoma cell linesT-Platin-M-NPs can be effective in glial cell canine tumors and its activity is better than cisplatin and carboplatin which are currently used as chemotherapeutic agents.There is potential to use T-Platin-M-NPs as an effective injectable chemotherapeutic agent in dogsFeldhaeusser et al. [23]
CisplatinLiposome-encapsulatedHealthy animalsToxic effects commonly associated with unencapsulated cisplatin, were not observed in dogs treated with liposome-encapsulated cisplatin at dosages equivalent to twice the known maximally tolerated dose of unencapsulated cisplatin.Liposome- encapsulated cisplatin can be safely administered to clinically normal dogs at dosages of up to 150 mg/m2 without the need for concurrent hydration protocolsMarr et al. [14]
CisplatinSTEALH Liposome-encapsulated cisplatin (SPI-77)OsteosarcomaThe 11-month overall median survival found for SPI-77-treated dogs was nearly identical to that reported using native cisplatin. The systemic delivery of these escalated doses did not translate into enhanced efficacy.Liposome encapsulation of cisplatin allows the safe and repeated delivery of doses up to five times the maximally tolerated dose of native cisplatin in tumor bearing dogsVail et al. [53]
CisplatinHyaluronan nanocarrierSoft tissue sarcomasNo tissue reactions were detected after hyaluronan-cisplatin injection; intratumoral administration of hyaluronan-cisplatin resulted in higher concentrations in the tumor and sentinel lymph nodes than in plasma or serum.Intratumoral injection of the hyaluronan-cisplatin nanoconjugate was well tolerated in treated dogs and may be a safe and effective method for the administration of maintenance chemotherapyVenable et al. [54]
Co(II)-NanoTS265 and Zn(II)-NanoTS262 compoundsGold nanoparticles (AuNPs)Mammary tumours (FR37-CMT) cellsBoth compounds induced a reduction of viable cell. AuNPs can act as promising carriers for drug delivery; increased cytotoxic activity; metal compounds displayed lower IC50 than cisplatin and doxorubicin against cells.NanoTS262 and NanoTS265 are promising chemotherapeutic formulations for mammary carcinomas and targeting anti-bodies or peptides, may further improve efficacyRaposo et al. [76]
Cu-64PEGylated liposomes with copper-64Spontaneous solid tumorsNew and highly efficient method for loading copper-64 PET isotopes into liposomes; moderate to high nanocarrier tumor accumulation levels were achieved in spontaneous carcinomas based on the EPR-effect.Radiolabeled liposomes may serve as theragnostic imaging agent guiding both diagnostic and therapeutic intervention for several malignancies in future clinical practiceHansen et al. [77]
DoxorrubicinPEGylated liposomes with Copper-64Splenic HaemangiosarcomaIntraperitoneal treated dogs had fewer serosal, mesenteric, and omental metastases than historical controls treated with systemic doxorubicin. Pegylated liposomal doxorubicin was absorbed relatively quickly from the abdominal cavity.Intraperitoneal pegylated liposomal encapsulated doxorubicin administration did not prevent intraabdominal recurrence of HSA in dogsSorenmo et al. [41]
DoxorrubicinPL-DOX (Doxil®, Sequus Pharmaceuticals, Menlo Park, CA, USA)Splenic HaemangiosarcomaThe median disease-free period for dogs treated with PL-DOX and free doxorubicin was equivalent. No significant differences in toxicity between PL-DOX and free doxorubicin were noticed.PL-DOX was easily administered to dogs and did not lead to significant toxicities and significant difference in survival was not observedTeske et al. [42]
DoxorrubicinPL-DOX (Doxil®, Sequus Pharmaceuticals, Menlo Park, CA, USA)Different tumors typeThe dose-limiting toxicities are different for Doxil when compared to free doxorubicin and o significant myelosuppression or cardiotoxicity was noted in Doxil treatment.Although the results of this study must be evaluated with care owing to the small number in each tumor group, it appears that Doxil as a single agent may have a broad spectrum of activityVail et al. [38]
DoxorrubicinColloid gold nanoparticlesFeline fibrossarcomaA higher cytotoxic effect of Au-GSH-Dox than that of free doxorubicin has been observed. GSH coated Au NPs are good doxorubicin nanocarriers for feline fibrosarcoma cell lines with high P-gp activity.Au-GSH-Dox may be a potent new therapeutic agent to increase the efficacy of the drug by overcoming the resistance to doxorubicin in feline fibrosarcoma cell linesWójcik et al. [43]
DoxorrubicinPolylactide nanoparticles (NPs) loaded with doxorubicin (Doxo) and coated with bone-seeking pamidronate (Pam)
Pam-Doxo-NPs
OsteosarcomaEnhanced bone tumor accumulation and prolonged retention compared with nontargeted NPs. The therapeutic was well tolerated without toxicities and attenuated localized osteosarcoma progression compared with nontargeted Doxo-NPs.Pam-Doxo-NPs were capable of minimizing systemic off target toxicities and enhance localized antitumor activities in a preclinical murine tumor model and canine modelYin et al. [44]
DoxorubicinTemperature sensitive liposomes (TSL)High-grade gliomasHigher temperatures resulted in increased area of cerebral damage and TSL combined with hyperthermia allows potentially therapeutic doses of Dox across the blood–brain barrier.The study demonstrates that localized doxorubicin delivery to the brain can be facilitated by TSL-Dox with localized hyperthermia with no significant neurological deficitsBredlau et al. [12]
DoxorubicinLow temperature sensitive liposome (LTSL-doxorubicin)Solid tumors (carcinomas or sarcomas)The dose of LTSL doxorubicin was suboptimal in many patients and had a 30% response rate and cutaneous toxicity typically observed with LTSL-doxorubicin.LTSL-doxorubicin offers a novel approach to improving drug delivery to solid tumors; it was well tolerated and resulted in favorable response profiles in these patientsHauck et al. [45]
DoxorubicinLiposome-encapsulated Doxorubicin (L-DOX)Multiple MyelomaLiposome encapsulation of doxorubicin decreases its cardiotoxicity; the remission induced with L-DOX was complete and durable; L-DOX has a decreased toxicity compared with free doxorubicin even with a high doseL-DOX has greater efficacy in the treatment of some tumors and decreased toxicity compared with free doxorubicin, without cardiotoxicityKisseberth et al. [46]
DoxorubicinPegylated Liposomal DoxorubicinFeline soft tissues sarcomasMedian overall survival was 324 days and all cats developed some degree of leukotrichia. The liposomal doxorubicin and daily fractionated palliative radiotherapy were well tolerated by the cats.The administration of pegylated liposomal doxorubicin in combination with daily palliative radiotherapy was feasible, generally well tolerateKleiter et al. [47]
FerumoxytolUltra-small superparamagnetic iron oxide nanoparticle (USPIOs) lymphotropic nanoparticle enhanced MRI (LNMRI)Metastatic lymph nodes in Canine Head and Neck TumorsThere were no negative side effects to the USPIOs noted and LNMRI was successful in identifying metastatic lymph nodes with 100% sensitivity and an 88% specificity.LNMRI has the potential to be a sensitive and specific method of diagnosing lymph node metastasisGriffin et al. [48]
GoldGum arabic-coated 198AuNP (GA-198AuNP)Prostate cancerGA-198AuNPs have more homogenous dose distribution and higher emission of energy compared to current brachytherapy seeds used to treat prostate cancer and the gum arabic glycoprotein provided a nontoxic coating on NPs and is highly stable in vivoThis study provides evidence that intralesional injection of GA-198AuNP is safe with minimal short-term systemic toxicity in the naturally occurring large animal model of prostatic cancerAxiak-Bechte et al. [78]
High affinity histidine×6-tagged EGFR-binding Z domain (heptameric ZEGFR domain).Lipid-based oil-filled nanoparticles (NPs) with a high concentration of surface-chelated nickel (Ni-NPs)A431 epidermoid carcinoma cellsSuperior cell uptake achieved in EGFR overexpressing cells with these Ni-NPs with ZEGFR target; successfully target EGFR overexpressing cancer cells; targeting efficiency of the novel heptameric ZEGFR domain was also demonstrated in vivoNi-NPs could be a very useful tool for targeting and drug delivery to a wide range of EGFR positive cancersBenhabbour et al. [79]
Nerve growth factor (NGF)Encapsulated chitosan nanoparticles (CNPs)Mesenchymal Stem CellsNGF had 61% efficiency in vitro and these nanoparticles were found to be cytocompatible to Mesenchymal Stem Cells; NGF- CNPs were able to transdifferentiate cBM-MSCs without any chemical based reinduction.NGF-CNPs are capable of releasing bioactive NGF with the ability to transdifferentiate mesenchymal stem cells into neuronsMili et al. [80]
PaclitaxelNanoparticule paclitaxel (CTI 52010)Healthy animals. focused on spontaneously occurring tumorsNo evidence of hypersensitivity or gastrointestinal toxicity. The dose-limiting toxicity was grade 4 neutropenia and the maximum tolerated dosage was 120 mg/m2.CTI 52010 was well tolerated when administered intravenously to normal dogsAxiak et al. [11]
Paclitaxel Nanoparticulate paclitaxel (nPX) formulation (CTI52010, Crititax®) Prostate cancer cell lines (human and dogs)nPX was as effective as PX in decreasing cell viability, increasing apoptosis, inhibiting clonogenic potential, and modifying microtubule dynamics; it could be an effective alternate for PX Nanoparticulate paclitaxel is as effective as paclitaxel in both human and canine castration-resistant prostate cancer Axiak-Bechtel et al. [31]
PaclitaxelNanoparticulate, excipient-free formulation of paclitaxel (CTI52010)Different tumors typeThe lack of systemic absorption after subcutaneous administration; side effects were well tolerated at dosages up to 118 mg/m2; no unique toxicity or hypersensitivity was notedCTI52010 was administered safely to tumor-bearing dogs and is an attractive chemotherapeutic to be considered in intratumoral administrationSelting et al. [29]
PaclitaxelLiposomes composed of Tween-80/HSPC/cholesterolHealthy animalsThe paclitaxel liposomes showed excellent lung targeting properties in comparison with paclitaxel injection; liposome carrier was associated with a lung-targeting effect; didn’t cause hemolysisThe liposomes are a promising carrier for a lung-targeting drug delivery system for the treatment of lung diseases, such as lung cancerZhao et al. [30]
SorafenibNanoparticulation using fat and supercritical fluid (NUFs)Healthy animalsEncapsulated sorafenib exhibited higher blood drug profiles indicating better absorption; concentration of PVP should be kept at low level to achieve the maximum absorption of sorafenibNanoparticle formulation could enhance the bioavailability and therapeutic efficacy of sorafenibPark et al. [21]
Temozolomide (TMZ)Polymeric magnetite nanoparticles (PMNPs)Intracranial tumorsIn 70% of the cases, the infusion accurately targeted the tumor mass was determined by the presence of PMNP signal in the tumor on immediate postoperative MRI; PMNP was enough to induce an observable decrease in tumor volumeT convection-based drug delivery using PMNPs can be safely performed in a canine model of gliomaYoung et al. [18]
VincristineLiposomesHealthy animalsEncapsulated vincristine showed a higher plasmatic concentration then un-encapsulated vincristine after intravenous injection of both forms of vincristine; enhanced anti-tumor activity and lower toxicity of liposomeThe increased therapeutic index of encapsulated vincristine is demonstrated by the pharmacokinetic featuresZhong et al. [81]

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Lainetti, P.d.F.; Zuliani, F.; Leis-Filho, A.F.; Fonseca Alves, R.H.; Fonseca-Alves, C.E. Controlled Drug Delivery Vehicles in Veterinary Oncology: State-of-the-Art and Future Directions. Processes 2020, 8, 541. https://doi.org/10.3390/pr8050541

AMA Style

Lainetti PdF, Zuliani F, Leis-Filho AF, Fonseca Alves RH, Fonseca-Alves CE. Controlled Drug Delivery Vehicles in Veterinary Oncology: State-of-the-Art and Future Directions. Processes. 2020; 8(5):541. https://doi.org/10.3390/pr8050541

Chicago/Turabian Style

Lainetti, Patricia de Faria, Fernanda Zuliani, Antonio Fernando Leis-Filho, Ricardo Henrique Fonseca Alves, and Carlos Eduardo Fonseca-Alves. 2020. "Controlled Drug Delivery Vehicles in Veterinary Oncology: State-of-the-Art and Future Directions" Processes 8, no. 5: 541. https://doi.org/10.3390/pr8050541

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