Drug Dose Reduction Research Articles

Process optimization and in vivo performance of docetaxel loaded PHBV-TPGS therapeutic vesicles: A synergistic approach

This research was motivated due to substantial requirement of improved treatment for breast cancer which accounts for over 0.52 million deaths annually worldwide. Utilizing nanoparticles carrying active medicaments as targeted delivery carrier is emerging as a promising approach. For a drug to be clinically effective, it needs to be suitably protected in the biological fluid till it is delivered to the targeted site. Keeping above in mind, we prepared and optimized polymeric nanoparticles by polyhydroxybutyrate-co-hydroxyvalerate (PHBV) a biodegradable polymer utilizing modified emulsification solvent evaporation method. The optimized formulation had particle size of 349±3.51nm with entrapment efficiency of 69±1.28%. Nanoparticle formation and its surface morphology were confirmed by various electron microscopes. The in vitro and pharmacokinetic studies demonstrated a sustained release of drug in a non-biological system and into rat's bloodstream respectively. Also, the in vitro cytotoxicity and in vivo toxicological evaluation at the therapeutic dose demonstrated the safety and antitumor efficacy of the formulation. Due to formulation characteristic properties, it was found to be effective in enveloping and chaperoning the drug to the suitable site of action. The PHBV-TPGS combination causes the drug to be released in controlled and sustained modes, thereby reducing drug dose and toxicity.

MRI manifestations of immunosuppressive drugs associated encephalopathy after allogeneic hematopoietic stem cell transplantation in children with aplastic anemia

Objective To summarize the MRI manifestations of immunosuppressive drugs associated encephalopathy after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children with aplastic anemia. Methods Fifteen patients with immunosuppressive drugs associated encephalopathy after allogeneic hematopoietic stem cell transplantation for aplastic anemia during January 2014 to October 2016 were analyzed retrospectively. There were 7 males and 8 females, aged from 3 to15 years old, with the median age of 7 years old. Ten cases presented dizziness and headache while other 4 cases presented blurred vision, blind and gaze. Only one case suffered from seizure and loss of consciousness. MRI patterns including distribution, morphology and signal intensity were analyzed after treatment. Follow up MRI were performed after reducing drug dose and symptom remission. The duration of immunosuppressive drugs associated encephalopathy of the 15 cases were 1-14 months, with 6 months in 9 cases. Results Focal lesions were found in 11 cases, in which the deep nuclei were involved in one case and the white matter was involved in 10. Four patients showed both cerebral cortex and white matter lesions, including cerebellum and brainstem invasion in one patient. No corpus callosum lesions were found. Various degree of brain atrophy was found in all patients. Cortical lesions showed swelling and involved subcortical white matter presented as arc shape or strip-like lesions. Patchy patterns were found in deep white matter. Thin layer shaped lesions were found in the periventricular white matter. Small flake-like lesions were found in the brain stem and the cerebellum. The lesions showed hypointensity on T1WI, equal or high signal on T2WI. T2WI FLAIR showed equal or high signal;DWI in the cortex and subcortical white matter lesions showed iso-or high signal, while other lesions were isointense. Eight cases acquired clinical relief in short term without obvious improvement on MRI image. Both clinical symptoms and imaging findings improved in 6 cases. One case showed clinical relief but progression on MRI. Conclusions MRI is an effective way to find immunosuppressive drugs-related encephalopathy in children with aplastic anemia after allogeneic hematopoietic stem cell transplantation. It can help the diagnosis and provide the information for clinical treatment. Key words: Anemia, aplastic; Hematopoietic stem cell transplantation; Magnetic resonance imaging

Intracellular delivery of nano‐formulated antituberculosis drugs enhances bactericidal activity

AbstractTuberculosis kills more people worldwide than any other infectious disease. Treatment requires multiple drug therapy administered over long periods (6–24 months). The emergence of multidrug‐resistant strains is a major problem, and with few new drugs in the pipeline, a novel modus operandi is urgently required. Solid drug nanoparticles (SDNs), a new development in nanomedicine, offer a fresh therapeutic approach. Here, we show that SDNs are more effective (50‐fold) at killing pathogenic mycobacteria than aqueous forms of the same drug and can target mycobacteria internalised by macrophages, where bacilli reside. We demonstrate synthesis of dual and triple drug loaded SDNs, facilitating combination tuberculosis therapy. Our results suggest that by employing SDNs of existing antibiotics, it may be possible to improve drug delivery and therefore reduce drug dosage to lessen side effects and fight drug resistance.

Tumor response of temozolomide in combination with morphine in a xenograft model of human glioblastoma.

Despite multimodal treatments comprising, radiation therapy (RT) and chemotherapy with temozolomide (TMZ), the prognosis of glioblastoma multiforme (GBM) remains dismal and consolidated therapy yields a median survival of 14.6 months.Blood Brain Barrier (BBB) mediated chemoresistance and high dose related toxicity make necessary the development of new therapeutic approach to sensitize GBM to TMZ.The aim of the present study was to investigate the potential of the treatment morphine plus TMZ metronmic doses (1,77 and 0,9 mg/kg) in GBM therapy.The effect of morphine, on tumor cell growth and P-glycoprothein (P-gp) activity, was investigate in in vitro models.The results demonstrated that GBM cells growth is not influenced by morphine treatment and, for the first time, we show that morphine is an inhibitor of the activity of P-gp efflux transporter who is markedly expressed on BBB.In vivo, response to the treatments TMZ plus morphine was investigated in an orthotopic nude mice model of GBM.Animals treated with TMZ metronomic doses showed a significant tumor growth inhibition compared to untreated mice and association with morphine appears to improve TMZ efficacy.Moreover, the combination of morphine with lower dose of TMZ result in a cytostatic effect on tumor growth over the period of the pharmacological treatments.In conclusion this novel approach could be a successful strategy to overcome chemoresistance and side effects TMZ mediated, reducing drug dosage and improving long term response, in GBM therapy.

An Investigative Approach to Treatment Modalities for Squamous Cell Carcinoma of Skin.

Squamous cell carcinoma of skin has become an important matter of discussion worldwide due to high number of deaths. Treatment of such cancer involves use of drugs (chemotherapy) along with surgery or radiation therapy. The combination chemotherapy is preferred over single treatment modality may be due to synergistic effect of targeting agent resulting in reduced drug dose, reduced cytotoxic effect and improved efficacy and survival rate. The objective of this work is to provide insight into the squamous cell carcinoma of skin; the various approaches and challenges adapted to surmount the cancer malignancies. Research evidence shows that nanoparticle based therapeutic delivery to squamous cell carcinoma is equanimous to lead therapeutic approaches for intervention of cancer growth. Active chemotherapeutic approach is one of the leading therapies to such cancer cells due specific selectivity towards the EGFR-receptors over-expressed in tumor cells. Review of numerous research publications revealed innate toxicity of chemotherapeutic agents, and substantiated active receptor mediated drug targeting for therapeutic regime. These actively functionalized nanoparticles have been delivered to the targeted cells with higher selectivity, minimal toxicity and better retention in the cell. Numerous approaches and strategies have been designed till date for successful delivery of drug to cancer cells. The techniques have shown tremendous improvement in getting normalcy of carcinomas but a few have been marketed so far. Indeed, receptor based drug targeting approach through molecular signal transduction pathways involved in skin cancer development will provide insight into squamous carcinoma. Despite of these, other such challenges in drug delivery to squamous cell carcinoma need further clarification.

New FTY720-docetaxel nanoparticle therapy overcomes FTY720-induced lymphopenia and inhibits metastatic breast tumour growth

PurposeCombining molecular therapies with chemotherapy may offer an improved clinical outcome for chemoresistant tumours. Sphingosine-1-phosphate (S1P) receptor antagonist and sphingosine kinase 1 (SK1) inhibitor FTY720 (FTY) has promising anticancer properties, however, it causes systemic lymphopenia which impairs its use in cancer patients. In this study, we developed a nanoparticle (NP) combining docetaxel (DTX) and FTY for enhanced anticancer effect, targeted tumour delivery and reduced systemic toxicity.MethodsDocetaxel, FTY and glucosamine were covalently conjugated to poly(lactic-co-glycolic acid) (PLGA). NPs were characterised by dynamic light scattering and electron microscopy. The cellular uptake, cytotoxicity and in vivo antitumor efficacy of CNPs were evaluated.ResultsWe show for the first time that in triple negative breast cancer cells FTY provides chemosensitisation to DTX, allowing a four-fold reduction in the effective dose. We have encapsulated both drugs in PLGA complex NPs (CNPs), with narrow size distribution of ~ 100 nm and excellent cancer cell uptake providing sequential, sustained release of FTY and DTX. In triple negative breast cancer cells and mouse breast cancer models, CNPs had similar efficacy to systemic free therapies, but allowed an effective drug dose reduction. Application of CNPs has significantly reversed chemotherapy side effects such as weight loss, liver toxicity and, most notably, lymphopenia.ConclusionsWe show for the first time the DTX chemosensitising effects of FTY in triple negative breast cancer. We further demonstrate that encapsulation of free drugs in CNPs can improve targeting, provide low off-target toxicity and most importantly reduce FTY-induced lymphopenia, offering potential therapeutic use of FTY in clinical cancer treatment.

Simultaneous delivery of hydrophobic small molecules and siRNA using Sterosomes to direct mesenchymal stem cell differentiation for bone repair.

Application of phenamil, a small molecular bone morphogenetic protein (BMP) stimulator, combined with suppression of natural BMP antagonists such as noggin is a promising therapeutic strategy to enhance bone regeneration. Here, we present a novel strategy to co-deliver hydrophobic small molecule phenamil and noggin-targeted siRNA via cationic Sterosomes formed with stearylamine (SA) and high content of cholesterol (Chol) to enhance osteogenesis and bone repair. SA/Chol Sterosomes demonstrated high phenamil encapsulation efficiency, supported sustained release of encapsulated drugs, and significantly reduced drug dose requirements to induce osteogenic differentiation of mesenchymal stem cells (MSCs). Simultaneous deliver of phenamil and noggin siRNA in a single vehicle synergistically enhanced MSC osteogenesis and calvarial bone repair. This study suggests a new non-phospholipid liposomal formulation to simultaneously deliver small molecules and therapeutic genes for combined treatment.

Compliance of elderly head and neck squamous cell carcinoma (HNSCC) patients (pts) with concurrent chemoradiotherapy (CRT) in cetuximab versus cisplatin.

e17553 Background: Cisplatin toxicities substantially increased in elderly patients with head and neck cancer, when it is given as CRT. Bio-radiotherapy using cetuximab could offer a less toxic alternative. The purpose of this retrospective study is to evaluate the compliance of cetuximab versus cisplatin in CRT for HNSCC pts 70 years of age or old pts. Methods: We included over 70 years old patients treated by radio chemotherapy in head and neck cancer. Severity of AE was measured by the percentage of the drug dose reduction. Dose is considered reduced if patient did not receive 200mg/m² in cisplatin group, and if he did not receive the seven planned cycles in cetuximab group. We recalculated the dose reduction percentage including over 65 years old patientes. Results: We enrolled 37 over 70 years pts, middle age 74.5(from 70 to 88). 23 pts were treated by cetximab-RT compared to 14 treated by cisplatin-RT. 30% of pts (7 of 23 pts) in cet-RT group received a dose reduction versus 28% (4 of 14 pts) in cisplatin-RT group. Then, compliance to cetuximab is comparable to cisplatin and dose reduction is close.This finding disclaim a general assumption that cetuximab is better tolerated than cisplatin concurrently to radiotherapy in elderly pts. When we recalculated the dose reduction including also over 65 years old pts, we endrolled 64 pts, dose reduction in cet-RT pts remains about 28% (10 of 35pts) versus only 17% (5 of 29) in cisplatin-RT group. A clear increasing in dose reduction of cisplatin appears once pts passed 70 years old. Finally, we redistributed the 35 cetuximab-RT pts according to period of treatment, the first group included pts treated between 2007 and 2011, dose reduction was 35% (7 of 20patients),the second group included pts treated between 2012 and 2016, dose reduction was only 20% (3 of 15). This supports that good handling of cetuximab's toxicities improves the treatment's compliance. Conclusions: Dose reduction in elderly pts is equal in cetuximab and cisplatin. Dose reduction to cisplatin clearly increases among over 70years old pts. Good handling of cetuximab improves the compliance to treatment

Effect of magnetosomes on cell proliferation, apoptosis induction and expression of Bcl-2 in the human lung cancer cell line A549

AbstractMagnetosomes are nanoparticles coated with organic membrane produced by magnetotactic bacteria. They appear to be a suitable carrier for the targeted drug transport, which represents a new method of cancer treatment. Advantages of targeted drugs transport are the minimizing of hurt to the organism, specific focusing on certain types of tissues, increased effect of the drug, reduced drug dose and hence side effects. The main goal of the present study was to verify the effect of bacterial magnetic nanoparticles produced by

Photodynamic Synergistic Effect of Pheophorbide a and Doxorubicin in Combined Treatment against Tumoral Cells

A combination of therapies to treat cancer malignancies is at the forefront of research with the aim to reduce drug doses (ultimately side effects) and diminish the possibility of resistance emergence given the multitarget strategy. With this goal in mind, in the present study, we report the combination between the chemotherapeutic drug doxorubicin (DOXO) and the photosensitizing agent pheophorbide a (PhA) to inactivate HeLa cells. Photophysical studies revealed that DOXO can quench the excited states of PhA, detracting from its photosensitizing ability. DOXO can itself photosensitize the production of singlet oxygen; however, this is largely suppressed when bound to DNA. Photodynamic treatments of cells incubated with DOXO and PhA led to different outcomes depending on the concentrations and administration protocols, ranging from antagonistic to synergic for the same concentrations. Taken together, the results indicate that an appropriate combination of DOXO with PhA and red light may produce improved cytotoxicity with a smaller dose of the chemotherapeutic drug, as a result of the different subcellular localization, targets and mode of action of the two agents.

Solid lipid nanoparticles delivering anti-inflammatory drugs to treat inflammatory bowel disease: Effects in an in vivo model.

AIMTo improve anti-inflammatory activity while reducing drug doses, we developed a nanoformulation carrying dexamethasone and butyrate.METHODSDexamethasone cholesteryl butyrate-solid lipid nanoparticles (DxCb-SLN) were obtained with the warm microemulsion method. The anti-inflammatory activity of this novel nanoformulation has been investigated in vitro (cell adhesion to human vascular endothelial cells and pro-inflammatory cytokine release by lipopolysaccharide-induced polymorphonuclear cells) and in vivo (disease activity index and cytokine plasma concentrations in a dextran sulfate sodium-induced mouse colitis) models. Each drug was also administered separately to compare its effects with those induced by their co-administration in SLN at the same concentrations.RESULTSDxCb-SLN at the lowest concentration tested (Dx 2.5 nmol/L and Cb 0.1 μmol/L) were able to exert a more than additive effect compared to the sum of the individual effects of each drug, inducing a significant in vitro inhibition of cell adhesion and a significant decrease of pro-inflammatory cytokine (IL-1β and TNF-α) in both in vitro and in vivo models. Notably, only the DxCb nanoformulation administration was able to achieve a significant cytokine decrease compared to the cytokine plasma concentration of the untreated mice with dextran sulfate sodium-induced colitis. Specifically, DxCb-SLN induced a IL-1β plasma concentration of 61.77% ± 3.19%, whereas Dx or Cb used separately induced a concentration of 90.0% ± 2.8% and 91.40% ± 7.5%, respectively; DxCb-SLN induced a TNF-α plasma concentration of 30.8% ± 8.9%, whereas Dx or Cb used separately induced ones of 99.5% ± 4.9% and 71.1% ± 10.9%, respectively.CONCLUSIONOur results indicate that the co-administration of dexamethasone and butyrate by nanoparticles may be beneficial for inflammatory bowel disease treatment.

Role of antivirals in treatment of vertigo due to vestibulopathies

Objective: The objective of this study is to study the role of antiviral medication on treatment of recurrent vertigo due to various vestibulopathies. Materials and Methods: Sixty-six adult patients of vestibular neuronitis (VN), Meniere's disease (MD), and benign paroxysmal positional vertigo were enrolled in this study, patients in each disorder where distributed randomly in two groups, Group A (antiviral) and Group B (nonantiviral). All Patients were assessed on the basis of reduction in dose of vestibular sedative drugs needed for control of vertigo on 1st, 3rd, and 5th day of treatment. Results: Statistically significant reduction in dose of labyrinthine sedatives was found to control vertigo in Group A patients as compared to Group B patients in both VN and MD. This reduction in dose of labyrinthine sedatives was seen on day 3 as well as on day 5 of treatment. Conclusion: This study shows that use of antiviral drugs significantly reduces the dose of vestibular sedatives needed for control of vertigo in MD and VN and hence should be used on a regular basis to treat these ailments.

Latest advances in the efficacy, tolerability, and monotherapy of integrase inhibitors.

More than 30 drugs for antiretroviral therapy (ART), including integrase inhibitors (INIs), have been approved by the U.S. Food and Drug Administration (FDA) as of 2017. Integrase is the third essential enzyme in the cycle of human immunodeficiency virus (HIV) replication. INIs can effectively inhibit the replication of HIV and HIV is less prone to develop resistance to INIs clinically. Previous studies based on 7 phase III clinic trials indicate that INIs have satisfactory efficacy and tolerability in patients infected with HIV. The latest advances in INIs indicate that: i) dolutegravir (DTG)-based regimens are more efficacious, tolerable, and safer forms of first-, second-, and third-Line ART; ii) current studies have indicated that DTG monotherapy fails both virologically and clinically; and iii) whether the most cost-effective treatment for DTG is to replace efavirenz (EFV) as a first-line ART, to replace protease inhibitors (PIs) in second-line ART, or to replace both as a monotherapy is unclear. Given these circumstances, further study of INIs in terms of drug interactions, dose reduction, drug convenience, and drug costs is warranted.

Ameliorative Effect of Curcumin-Encapsulated Hyaluronic Acid-PLA Nanoparticles on Thioacetamide-Induced Murine Hepatic Fibrosis.

In this study, we developed curcumin-encapsulated hyaluronic acid–polylactide nanoparticles (CEHPNPs) to be used for liver fibrosis amelioration. CD44, the hyaluronic acid (HA) receptor, is upregulated on the surface of cancer cells and on activated hepatic stellate cells (aHSCs) rather than normal cells. CEHPNPs could bind to CD44 and be internalized effectively through endocytosis to release curcumin, a poor water-soluble liver protective agent. Thus, CEHPNPs were potentially not only improving drug efficiency, but also targeting aHSCs. HA and polylactide (PLA) were crosslinked by adipic acid dihydrazide (ADH). The synthesis of HA–PLA was monitored by Fourier-transform infrared (FTIR) and Nuclear Magnetic Resonance (NMR). The average particle size was approximately 60–70 nm as determined by dynamic light scattering (DLS) and scanning electron microscope (SEM). Zeta potential was around −30 mV, which suggested a good stability of the particles. This drug delivery system induced significant aHSC cell death without affecting quiescent HSCs, hepatic epithelial, and parenchymal cells. This system reduced drug dosage without sacrificing therapeutic efficacy. The cytotoxicity IC50 (inhibitory concentration at 50%) value of CEHPNPs was approximately 1/30 to that of the free drug treated group in vitro. Additionally, the therapeutic effects of CEHPNPs were as effective as the group treated with the same curcumin dose intensity in vivo. CEHPNPs significantly reduced serum aspartate transaminase/alanine transaminase (ALT/AST) significantly, and attenuated tissue collagen production and cell proliferation as revealed by liver biopsy. Conclusively, the advantages of superior biosafety and satisfactory therapeutic effect mean that CEHPNPs hold great potential for treating hepatic fibrosis.

PEGylated Cationic Vectors Containing a Protease-Sensitive Peptide as a miRNA Delivery System for Treating Breast Cancer.

Several targeted drug delivery systems have recently been developed to increase the bioavailability of a drug at its site of action, allowing simultaneous reduction of the total necessary drug dose as well as side effects. Here, we designed a cationic gene vector containing matrix metalloproteinase-2 (MMP2)-cleavable substrate peptides that specifically target tumor sites where MMP2 levels are high. The targeted delivery system is fabricated by linking enzyme-cleavable polyethylene glycol (PEG) derivatives to cationic β-cyclodextrin-polyethylenimine conjugates, which reduce the toxicity of polyethylenimine and condense the therapeutic cargo. In the present study, tumor suppressor microRNA miR-34a, which suppresses onset and progression of many types of cancers, was investigated for its therapeutic potential for treating breast cancer. The PEG coating markedly reduces nonspecific interaction between cationic particles and serum proteins, permitting accumulation at the target site; subsequent peptide cleavage by MMP2 facilitates miR-34a delivery into tumor cells. The nanopreparation shows excellent stability, and its internalization, tumor targeting, and antitumor efficacy in vitro and in vivo are better than those of a nanopreparation containing MMP2-uncleavable peptide.

Combined Use of the Rationalization of Home Medication by an Adjusted STOPP in Older Patients (RASP) List and a Pharmacist-Led Medication Review in Very Old Inpatients: Impact on Quality of Prescribing and Clinical Outcome.

Polypharmacy and potentially inappropriate drugs have been associated with negative outcomes in older adults which might be reduced by pharmacist interventions. Our objective was to evaluate the effect of a pharmacist intervention, consisting of the application of the Rationalization of home medication by an Adjusted STOPP in older Patients (RASP) list and a pharmacist-led medication review on polypharmacy, the quality of prescribing, and clinical outcome in geriatric inpatients. A monocentric, prospective controlled trial was undertaken at the geriatric wards of a large university hospital. Pharmacists applied the RASP list to the drugs reconciled on admission and additionally performed an expert-based medication review, upon which recommendations were provided to the treating physicians. The primary outcome was the composite endpoint of drug discontinuation and dose reduction of drugs taken on admission. Secondary outcomes included RASP-identified potentially inappropriate medications (PIMs), the number of Emergency Department (ED) visits and quality of life (QOL) registered up to 3months after discharge. On average, patients (n=172) took 10 drugs on admission and were 84.5years (standard deviation 4.8) of age. More drugs were discontinued or reduced in dose in the intervention group {control vs.intervention:median (interquartile range [IQR]) 3 (2-5) vs. 5 (3-7); p<0.001}. More PIMs were discontinued in the intervention group, leading to less PIM at discharge [control vs.intervention:median (IQR) 2 (1-3) vs. 0.5 (0-1); p<0.001]. No signal of harm was seen, and a significant improvement of QOL and less ED visits without hospitalization were observed. The combined intervention safely reduced drug use in very old inpatients and outperformed usual geriatric care. An increased QOL was seen, as well as a trend towards less ED visits. ClinicalTrials.gov Identifier: NCT01513265.

Thrombosis and anticoagulation in the setting of renal or liver disease.

Thrombosis and bleeding are among the most common causes of morbidity and mortality in patients with renal disease or liver disease. The pathophysiology underlying the increased risk for venous thromboembolism and bleeding in these 2 populations is distinct, as are considerations for anticoagulation. Anticoagulation in patients with kidney or liver disease increases the risk of bleeding; this risk is correlated with the degree of impairment of anticoagulant elimination by the kidneys and/or liver. Despite being in the same pharmacologic category, anticoagulant agents may have varied degrees of renal and liver metabolism. Therefore, specific anticoagulants may require dose reductions or be contraindicated in renal impairment and liver disease, whereas other drugs in the same class may not be subject to such restrictions. To minimize the risk of bleeding, while ensuring an adequate therapeutic effect, both appropriate anticoagulant drug choices and dose reductions are necessary. Renal and hepatic function may fluctuate, further complicating anticoagulation in these high-risk patient groups.

27P Pectin-Chitosan conjugates novel biomaterial as platform for colon cancer drug delivery

Background In comparison to injectable, oral delivery of chemotherapeutic agents, especially in the form of a colon specific delivery system is expected to increase drug bioavailability at target site, reduce drug dose and systemic adverse effects. Pectin (PEC) and Chitosan (CS) are suitable and well documented independently drug delivery polymers for use as colon specific drug delivery as it is selectively digested by colonic microflora to release drug with minimal degradation in upper gastrointestinal tract. Pectin chitosan bioconjugate has not been synthesized and well studied for their suitability in colon cancer drug delivery applications; hence we have attempted to synthesize PEC-CS conjugate system. Methods Pectin-chitosan conjugate system was developed by conjugating the free carboxyl group of moiety of pectin and primary amine group of CS. Synthesized material was characterized by FTIR, XRD, DSC, TGA and SEM. Cancer cell toxicity study of the synthesized material were done in HT29 colon adeno- carcinoma cell lines using MTT assay. Results Pectin reacts with -NHS to form an ester in presence of DCC in anhydrous conditions along with the side product dicyclohexylurea, and finally CS reacts with this mixture replacing NHS to form the conjugate. The peaks in the region 1709 cm-1 and 1641 cm-1 corresponds to weak carbonyl stretch due to H-bonding and the amide-I band of the formed conjugate. Also seen in the FTIR spectrais the peak belongingt o amide-II band of secondary amides at 1554 cm-1 and C-C ring stretch at 1509 cm-2. The conjugate showed significantly low weight loss till 300 C (23.6%) as comparedto PEC.TheaboveresultopinedthatPEC-CSexhibitedhighthermalstabilityascompared to its native precursor. The plain PEC showed its Tgat69.55 C, while in PEC-CS itwas observed at55.13 C. This result confirmsthat movementof molecule in PEC-CS is unhindered as compared to in PEC. The conjugation was confirmed by FTIR, and XRD. TheDSCandTGAanalysisexhibitedformationofamorethermostablematerialas compared to its native precursors. The conjugated material did not exhibit any cytotoxicity in HT29 cells. Conclusions The results showed a potential to be used this novel conjugate material for colon cancer drug delivery application. Legal entity responsible for the study Akhilesh Vikram Singh Funding UGC-MHRD, New Delhi, India Disclosure A.V.Singh: The presented work is purely academic research and funded by Government of India (UGC-MHRD,NewDelhi).

Low dose angiostatic treatment counteracts radiotherapy-induced tumor perfusion and enhances the anti-tumor effect.

The extent of tumor oxygenation is an important factor contributing to the efficacy of radiation therapy (RTx). Interestingly, several preclinical studies have shown benefit of combining RTx with drugs that inhibit tumor blood vessel growth, i.e. angiostatic therapy. Recent findings show that proper scheduling of both treatment modalities allows dose reduction of angiostatic drugs without affecting therapeutic efficacy. We found that whilst low dose sunitinib (20 mg/kg/day) did not affect the growth of xenograft HT29 colon carcinoma tumors in nude mice, the combination with either single dose RTx (1x 5Gy) or fractionated RTx (5x 2Gy/week, up to 3 weeks) substantially hampered tumor growth compared to either RTx treatment alone. To better understand the interaction between RTx and low dose angiostatic therapy, we explored the effects of RTx on tumor angiogenesis and tissue perfusion. DCE-MRI analyses revealed that fractionated RTx resulted in enhanced perfusion after two weeks of treatment. This mainly occurred in the center of the tumor and was accompanied by increased tissue viability and decreased hypoxia. These effects were accompanied by increased expression of the pro-angiogenic growth factors VEGF and PlGF. DCE-MRI and contrast enhanced ultrasonography showed that the increase in perfusion and tissue viability was counteracted by low-dose sunitinib. Overall, these data give insight in the dynamics of tumor perfusion during conventional 2 Gy fractionated RTx and provide a rationale to combine low dose angiostatic drugs with RTx both in the palliative as well as in the curative setting.

Association of ATP-binding cassette sub-family B member 1 gene C3435T polymorphism with neutropenia in breast cancer patients treated with chemotherapy

Background: Neutropenia is the most common adverse event of breast cancer chemotherapy which can be life threatening due to opportunistic infection, neutropenic episodes may lead to delay or reduction of drug doses which may compromise treatment outcomes. In this study, we investigated the association of ATP-binding cassette sub-family B member 1 (ABCB1) gene C3435T polymorphism with the grading of neutropenia in breast cancer patients who treated with doxorubicin-taxan.Methods: 72 Indonesian female breast cancer patients from Haji Adam Malik Hospital who had been diagnosed and treated with doxorubicin-taxane regimen were selected for this cohort study. DNA was extracted from peripheral leucocytes and ABCB1 C3435T polymorphism was analyzed with PCR-RFLP. Patient data were collected from patient’s medical record for 3 cycles of chemotherapy. Association between ABCB1 C3435T polymorphism with neutropenia was assessed using Kruskal-Wallis test. Decline of absolute neutrophil count was assessed using Wilcoxon test. Genotype deviation and allele frequencies were also determined by Hardy-Weinberg Equilibrium.Results: The frequencies of ABCB1 C3435T genotype for wildtype (CC), heterozygous (CT) and homozygous mutant (TT) was 22 (30.6%), 38 (52.8%) and 12 (16.7%) respectively. No association were found between ABCB1 C3435T polymorphism and the grading of neutropenia (p&gt;0.05). There was a difference on the average of absolute neutrophil count after the first chemotherapy and after the third chemotherapy (p&lt;0.05). There was no significant deviation of allele and genotype frequency from Hardy-Weinberg Equilibrium.Conclusion: ABCB1 C3435T polymorphism had no association with the grading of neutropenia in breast cancer patients treated with doxorubicin-taxane regimen, however there was a trend of absolute neutrophil count declining during the 3 cycles of chemotherapy.