Development of a Small Molecule Tubulysin B Conjugate for Treatment of Carbonic Anhydrase IX Receptor Expressing Cancers

Marks, Isaac; Gardeen, Spencer S.; Kurdziel, Sarah J.; Nicolaou, Sonia T.; Woods, Jane; Kularatne, Sumith A.; Low, Philip S.

doi:10.1021/acs.molpharmaceut.8b00139

Cited by 25 publications

(23 citation statements)

References 49 publications

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“…However, reports from clinical trials are currently sparse. Given the potential for side effects due to the physiological importance of these proteins in all organ systems, much attention has focused on inhibiting those proteins, such as CAIX, which are specifically upregulated in cancer cells (in response to hypoxia) and not highly expressed elsewhere [426] . Another approach, the combinatorial use of blockers, allows for a lower dose of each and thus fewer undesired effects on non-tumor cells.…”

Section: Other Applications By Clinical Specialtymentioning

confidence: 99%

The therapeutic importance of acid-base balance

Quade

Parker

Occhipinti

2021

Biochemical Pharmacology

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Baking soda and vinegar have been used as home remedies for generations and today we are only a mouse-click away from claims that baking soda, lemon juice, and apple cider vinegar are miracles cures for everything from cancer to COVID-19. Despite these specious claims, the therapeutic value of controlling acid-base balance is indisputable and is the basis of Food and Drug Administration-approved treatments for constipation, epilepsy, metabolic acidosis, and peptic ulcers. In this narrative review, we present evidence in support of the current and potential therapeutic value of countering local and systemic acid-base imbalances, several of which do in fact involve the administration of baking soda (sodium bicarbonate). Furthermore, we discuss the side effects of pharmaceuticals on acid-base balance as well as the influence of acid-base status on pharmacokinetic properties of drugs. Our review considers all major organs systems as well as information relevant to several clinical specialties such as anesthesiology, infectious disease, oncology, dentistry, and surgery.

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Section: Other Applications By Clinical Specialtymentioning

confidence: 99%

The therapeutic importance of acid-base balance

Quade

Parker

Occhipinti

2021

Biochemical Pharmacology

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“…Currently, several approaches aimed at development of anti-cancer therapeutics targeting CAIX are under evaluation, including small molecule CAIX inhibitors 9,10 , small-molecule-drug conjugates 11,12 , anti-CAIX monoclonal antibodies 13,14 , anti-CAIX antibody-drug conjugates 15 , and anti-CAIX monoclonal antibodies labeled with cytotoxic radionuclides for targeted radionuclide therapy 16,17 . A sufficiently high expression of CAIX is a precondition for successful application of such therapeutics.…”

Section: Introductionmentioning

confidence: 99%

Comparative evaluation of affibody- and antibody fragments-based CAIX imaging probes in mice bearing renal cell carcinoma xenografts

Garousi

Huizing

Vorobyeva

et al. 2019

Sci Rep

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Carbonic anhydrase IX (CAIX) is a cancer-associated molecular target for several classes of therapeutics. CAIX is overexpressed in a large fraction of renal cell carcinomas (RCC). Radionuclide molecular imaging of CAIX-expression might offer a non-invasive methodology for stratification of patients with disseminated RCC for CAIX-targeting therapeutics. Radiolabeled monoclonal antibodies and their fragments are actively investigated for imaging of CAIX expression. Promising alternatives are small non-immunoglobulin scaffold proteins, such as affibody molecules. A CAIX-targeting affibody ZCAIX:2 was re-designed with the aim to decrease off-target interactions and increase imaging contrast. The new tracer, DOTA-HE3-ZCAIX:2, was labeled with 111In and characterized in vitro. Tumor-targeting properties of [111In]In-DOTA-HE3-ZCAIX:2 were compared head-to-head with properties of the parental variant, [99mTc]Tc(CO)3-HE3-ZCAIX:2, and the most promising antibody fragment-based tracer, [111In]In-DTPA-G250(Fab’)2, in the same batch of nude mice bearing CAIX-expressing RCC xenografts. Compared to the 99mTc-labeled parental variant, [111In]In-DOTA-HE3-ZCAIX:2 provides significantly higher tumor-to-lung, tumor-to-bone and tumor-to-liver ratios, which is essential for imaging of CAIX expression in the major metastatic sites of RCC. [111In]In-DOTA-HE3-ZCAIX:2 offers significantly higher tumor-to-organ ratios compared with [111In]In-G250(Fab’)2. In conclusion, [111In]In-DOTA-HE3-ZCAIX:2 can be considered as a highly promising tracer for imaging of CAIX expression in RCC metastases based on our results and literature data.

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“…Small molecule-mediated targeting represents advantages in terms of the straightforward organic synthesis of SMDCs and their uniform structure as compared to antibodies. Indeed, small molecule ligands have been used to efficiently target tumors expressing the folate receptor [7], prostate-specific membrane antigen (PSMA) [8], carbonic anhydrase IX (CAIX) [9,10,11], and somatostatin receptors (SSTRs) [12].…”

Section: Introductionmentioning

confidence: 99%

Octreotide Conjugates for Tumor Targeting and Imaging

et al. 2019

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Tumor targeting has emerged as an advantageous approach to improving the efficacy and safety of cytotoxic agents or radiolabeled ligands that do not preferentially accumulate in the tumor tissue. The somatostatin receptors (SSTRs) belong to the G-protein-coupled receptor superfamily and they are overexpressed in many neuroendocrine tumors (NETs). SSTRs can be efficiently targeted with octreotide, a cyclic octapeptide that is derived from native somatostatin. The conjugation of cargoes to octreotide represents an attractive approach for effective tumor targeting. In this study, we conjugated octreotide to cryptophycin, which is a highly cytotoxic depsipeptide, through the protease cleavable Val-Cit dipeptide linker using two different self-immolative moieties. The biological activity was investigated in vitro and the self-immolative part largely influenced the stability of the conjugates. Replacement of cryptophycin by the infrared cyanine dye Cy5.5 was exploited to elucidate the tumor targeting properties of the conjugates in vitro and in vivo. The compound efficiently and selectively internalized in cells overexpressing SSTR2 and accumulated in xenografts for a prolonged time. Our results on the in vivo properties indicate that octreotide may serve as an efficient delivery vehicle for tumor targeting.

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Development of a Small Molecule Tubulysin B Conjugate for Treatment of Carbonic Anhydrase IX Receptor Expressing Cancers

Cited by 25 publications

References 49 publications

The therapeutic importance of acid-base balance

The therapeutic importance of acid-base balance

Comparative evaluation of affibody- and antibody fragments-based CAIX imaging probes in mice bearing renal cell carcinoma xenografts

Octreotide Conjugates for Tumor Targeting and Imaging

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