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Nanocarriers as Magic Bullets in the Treatment of Leukemia.

ABSTRACT: Leukemia is a type of hematopoietic stem/progenitor cell malignancy characterized by the accumulation of immature cells in the blood and bone marrow. Treatment strategies mainly rely on the administration of chemotherapeutic agents, which, unfortunately, are known for their high toxicity and side effects. The concept of targeted therapy as magic bullet was introduced by Paul Erlich about 100 years ago, to inspire new therapies able to tackle the disadvantages of chemotherapeutic agents. Currently, nanoparticles are considered viable options in the treatment of different types of cancer, including leukemia. The main advantages associated with the use of these nanocarriers summarized as follows: i) they may be designed to target leukemic cells selectively; ii) they invariably enhance bioavailability and blood circulation half-life; iii) their mode of action is expected to reduce side effects. FDA approval of many nanocarriers for treatment of relapsed or refractory leukemia and the desired results extend their application in clinics. In the present review, different types of nanocarriers, their capability in targeting leukemic cells, and the latest preclinical and clinical data are discussed.

SUBMITTER: Houshmand M

PROVIDER: S-EPMC7075174 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Nanocarriers as Magic Bullets in the Treatment of Leukemia.

Houshmand Mohammad M Garello Francesca F Circosta Paola P Stefania Rachele R Aime Silvio S Saglio Giuseppe G Giachino Claudia C

Nanomaterials (Basel, Switzerland) 20200206 2

Leukemia is a type of hematopoietic stem/progenitor cell malignancy characterized by the accumulation of immature cells in the blood and bone marrow. Treatment strategies mainly rely on the administration of chemotherapeutic agents, which, unfortunately, are known for their high toxicity and side effects. The concept of targeted therapy as magic bullet was introduced by Paul Erlich about 100 years ago, to inspire new therapies able to tackle the disadvantages of chemotherapeutic agents. Currentl ...[more]

PMID: 32041219

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Project description:Introduction and importanceVulvar penetrating trauma is a rather uncommon occurrence (1). Firearm injuries caused by low-velocity gravitational bullets are a common cause of injuries in war-torn countries such as Somalia [2] (Campbell and Wilbert, 2022). These types of injuries are inflicted on by-standers by wayward bullets. No standard consensus on the appropriate management of vulvar penetrating trauma has been established (3). Here in, we report the successful management of an impacted bullet in the clitoris by a simple incision under local anesthesia. The principles of vulva and clitoris tired bullet trauma management are discussed. In our case, we thought it to be rare and interesting, considering its occurrence.Case presentationIn this report, a 24-year-old woman (gravida 2, para 2) suffered from a vulvar area penetrating bullet injury. Imaging revealed that the foreign body was confined to the clitoris, and no evidence of other parts of the body. Under local anesthesia, the bullet was accessed and removed from the clitoris by performing a minor incision. No complications were observed following the surgical removal of the bullet.Clinical discussionNon-obstetric vulva trauma is an extremely rare occurrence. Typically, the cause of non-obstetric vulvar trauma includes sports-related injuries, straddle injuries, and midline splitting injuries. To the best of our knowledge, this case is unique due to the bullet being retained in the clitoris. The treatment of the foreign body is mostly surgical removal. Under local anesthesia, this patient underwent complete surgical removal of the metallic foreign body. During surgical excision, care should be taken not to damage the urethra and other pelvic issues.ConclusionTo the best of our knowledge, this is the first wayward bullet (not intended for the patient) injury penetrating the vulvar area with a retained bullet in the clitoris. In our case, we thought it to be rare and interesting, considering its occurrence.

Project description:BackgroundAcute myeloid leukemia (AML) is a fatal clonal hematopoietic malignancy, which results from the accumulation of several genetic aberrations in myeloid progenitor cells, with a worldwide 5-year survival prognosis of about 30%. Therefore, the development of more effective therapeutics with novel mode of action is urgently demanded. One common mutated gene in the AML is the DNA-methyltransferase DNMT3A whose function in the development and maintenance of AML is still unclear. To specifically target "undruggable" oncogenes, we initially invented an RNAi-based targeted therapy option that uses the internalization capacity of a colorectal cancer specific anti-EGFR-antibody bound to cationic protamine and the anionic siRNA. Here, we present a new experimental platform technology of molecular oncogene targeting in AML.MethodsOur AML-targeting system consists of an internalizing anti-CD33-antibody-protamine conjugate, which together with anionic molecules such as siRNA or ibrutinib-Cy3.5 and cationic free protamine spontaneously assembles into vesicular nanocarriers in aqueous solution. These nanocarriers were analyzed concerning their physical properties and relevant characteristics in vitro in cell lines and in vivo in xenograft tumor models and patient-derived xenograft leukemia models with the aim to prepare them for translation into clinical application.ResultsThe nanocarriers formed depend on a balanced electrostatic combination of the positively charged cationic protamine-conjugated anti-CD33 antibody, unbound cationic protamine and the anionic cargo. This nanocarrier transports its cargo safely into the AML target cells and has therapeutic activity against AML in vitro and in vivo. siRNAs directed specifically against two common mutated genes in the AML, the DNA-methyltransferase DNMT3A and FLT3-ITD lead to a reduction of clonal growth in vitro in AML cell lines and inhibit tumor growth in vivo in xenotransplanted cell lines. Moreover, oncogene knockdown of DNMT3A leads to increased survival of mice carrying leukemia patient-derived xenografts. Furthermore, an anionic derivative of the approved Bruton's kinase (BTK) inhibitor ibrutinib, ibrutinib-Cy3.5, is also transported by this nanocarrier into AML cells and decreases colony formation.ConclusionsWe report important results toward innovative personalized, targeted treatment options via electrostatic nanocarrier therapy in AML.

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Nanocarriers as Magic Bullets in the Treatment of Leukemia.

Publications

Nanocarriers as Magic Bullets in the Treatment of Leukemia.

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