light imide-diacids were synthesized from trimellitic anhydride, pyromellitic anhydride and aminoacids of the formula HOOC-(CH2)n-NH2, with n = 1,2,3,5. From them, polyanhydride-imides were obtained following a general method of formation of polyanhydrides in the presence of acetic anhydride',2.These co-polyimides have an aliphatic-aromatic structure and the relation between the general properties and the amount of the aliphatic part in the repeat unit was studied. IR spectroscopy, elemental analysis and viscosity measurements were used for the characterization. Studies of solubility, hydrolysis resistance and thermal properties were also made. ZUSAMMENFASSUNG:Acht Imid-dicarbonsauren wurden aus Trimellitsaureanhydrid, Pyromellitsaureanhydriti und verschiedenen aliphatischen Aminocarbonsauren (HOOC-(CH2)n-NH2r n = 1,2,3,5) synthetisiert.Die entsprechenden Copolyimid-anhydride wurden nach den iiblichen Methoden in Anwesenheit von Essigsaureanhydrid hergestellt I.*.Die Copolyimide haben eine aliphatisch-aromatische Struktur ; ihre Eigenschaften wurden in Abhlngigkeit der Struktur untersucht und durch IR-Spektren, Elementaranalyse und viskosimetrische Messungen charakterisiert. Loslichkeit, Hydrolysierbarkeit und Wirmestabilitat wurden bestimmt.
Background: Intra-operative identification of positive margins and lymph nodes continues to be a challenge for breast cancer surgeons. Current techniques such as frozen section or touch prep cytology are time consuming and vary in accuracy across institutions. Our study is the first part of a phase 2 trial of a systemically administered, ratiometric, activatable, cell-penetrating fluorescent peptide dye conjugate that visualizes breast cancer tumor tissue in vivo and ex vivo. We hypothesized that this method would be able to identify breast cancer close to the margin of lumpectomy specimens. Methods: AVB-620 is a cell penetrating peptide-fluorescent imaging agent which undergoes proteolytic cleavage by proteases in the matrix metalloproteinase family that have higher activity in cancerous tissue. After cleavage, the predominant fluorescent emission wavelength changes and fluorescent intensity increases, generating a ratiometric readout. AVB-620 was administered 3- 24 hours prior to operation via intravenous infusion to stage 0-III breast cancer patients. Patients were monitored for safety followed by primary breast surgery and either sentinel lymph node biopsy (SLNB) with radiotracer only or axillary lymph node dissection (ALND). Using a near-infrared camera system, fluorescent intensity of two wavelengths was measured intraoperatively both in vivo and ex vivo, including primary tumors, shave margins, and lymph nodes. The ratio of the intensity of these two wavelengths was utilized to distinguish between malignant and non-malignant tissues and visualized on a video monitor. Pathology reports were correlated to a computer-assisted human review of the fluorescent images. Results: Thirty-two patients were dosed without adverse events attributable to the agent; 31 were evaluable for fluorescent imaging. The average age of patients was 60 years (range 32-79). All patients underwent lumpectomy and axillary surgery. Two patients received neoadjuvant chemotherapy; 10% of patients had pure DCIS tumors. Among invasive tumors: 94% were ER+; 13% were high grade. All primary tumor images demonstrated fluorescent intensity and ratiometric changes that differentiated malignant and non-malignant tissue. 35% of patients had at least one positive margin (invasive tumor on ink or DCIS ≤2mm from ink). 61% of cases had at least one margin that was considered either close (≤2mm from ink for invasive tumor) or positive on H&E staining. 84% of patients with positive/close margins were identified utilizing fluorescent imaging. Four of the 5 patients with positive nodes had a positive fluorescent image. Discussion: These results demonstrate the ability of AVB-620 to identify and visualize malignant tumor and lymph nodes intraoperatively, illustrating the potential of such a tool to decrease reoperation rates. The second part of this phase II study is underway where intraoperative fluorescent imaging will be utilized to guide removal of additional shave margins. Citation Format: Chen SL, Baron PL, Lee MC, Feldman SM, McLaughlin SA, Terando AM, Harootunian A, Poonka P, Gonzalez JE. Use of an activatable cell penetrating peptide-fluorescent imaging agent (AVB-620) to identify positive and close margins intraoperatively [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-14-07.
Background: A continuing challenge in breast cancer surgery is the difficulty with intraoperative lymph node status determination and achieving negative surgical margins. Current techniques such as frozen section, touch prep and intraoperative radiographic imaging are time consuming and vary in accuracy from institution to institution. Our study is a first-in-human study of a novel ratiometric activatable cell penetrating fluorescent peptide dye conjugate that labels breast cancer tumor tissue in vivo. Methods: AVB-620 is a substrate for and activated by proteases in the matrix metalloproteinase family. It has two fluorophores moieties linked by a cleavable peptide. Upon cleavage, there is an increase in fluorescence intensity and a change in the predominant wavelength of fluorescence emission. AVB-620 was given preoperatively via intravenous infusion to stage 0-III breast cancer patients. Patients were monitored for safety and AVB-620 pharmacokinetic parameters determined. After 12-20 hours, patients underwent lumpectomy or mastectomy with either sentinel lymph node biopsy (SLNB) or axillary lymph nodes dissection (ALND). Using a customized near-infrared camera system, fluorescence intensity signals at two wavelengths were measured intraoperatively both in vivo and ex vivo of primary tumors, shave margins and lymph nodes. The intensity ratio of these two wavelengths was utilized to distinguish between malignant and non-malignant tissues. Images were correlated to pathology reports. Results: Fifteen patients with average age of 59 years were enrolled across 5 dose cohorts without any significant adverse events. All patients underwent definitive breast surgery (12 lumpectomy, 3 mastectomy) and axillary surgery (12 – SLNB, 3- ALND). Four patients that had tumor-positive lymph nodes confirmed pathologically which correlated with increased fluorescence intensity and ratio on imaging. Primary tumor images also demonstrated fluorescence intensity and ratiometric changes that distinguished cancerous and non-cancerous tissues. Discussion: The purpose of this phase 1 dose escalation was to determine safety profile and adequate dosing. This study demonstrated a proof of concept of the use of a protease-activatable ratiometric fluorescent peptide dye conjugate to identify malignant tissue intraoperatively. Increased fluorescent ratio correlated and resulted in fluorescent imaging of known tumor in the operating room, with images that directly correlated with position of tumor in the excised tissue. This approach has the potential to quickly and accurately visualize the pathologic status of tumor margins and lymph node intraoperatively. Further studies to optimize dose, timing of administration, and thresholds for ratiometric imaging are underway. Citation Format: Unkart JT, Chen SL, González JE, Harootunian A, Wallace AM. Intraoperative tumor detection using a ratiometric activatable fluorescent peptide: A first-in-human phase I study allows tumors to be visualized in the operating room [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD3-02.
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